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

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

LAPAROSCOPIC ADRENAL-SPARING SURGERY CASE SERIES: PARTIAL ADRENALECTOMY AND CYST RESECTION.

The aim is to present our case series documenting indications, laparoscopic technique, surgical and endocrinologic outcomes of laparoscopic partial adrenalectomy. In the period from April 2011 until October 2021, we performed 39 procedures. The patients were divided into three groups: unilateral adrenal gland tumor with a normal contralateral gland (group 1), tumor of the solitary adrenal gland (group 2), and adrenal cysts (group 3). There were 20 patients in group 1, 6 patients in group 2, and 13 patients in group 3. The most common histology in group 1 was adenoma (40%), all tumors in group 2 were renal cell carcinoma metastases, and all cysts in group 3 were benign. There were no major complications (Clavien Dindo grade ≥2) in the whole cohort. All patients in groups 1 and 3 had favorable endocrinologic outcomes, and 50% of group 2 patients required lifelong hydrocortisone replacement therapy. The procedure is safe and feasible with favorable outcomes in the hands of a high volume adrenal surgeon.

Subtyping primary aldosteronism by inconclusive adrenal vein sampling: A derivation and validation study in a tertiary centre.

OBJECTIVE: Indices based on aldosterone/cortisol (A/C) concentration in the successfully cannulated adrenal vein (AV) and in the inferior vena cava (IVC) (AV/IVC) appear to be possible markers to verify the subtype of primary aldosteronism (PA) in the case of inconclusive results of adrenal vein sampling (AVS). The variability of results in previous studies encouraged us to calculate AV/IVC and adrenal A/C cutoff values that could predict the aetiology of PA. METHODS: This retrospective study included 96 patients who underwent AVS due to PA between 2015 and 2020. The derivation cohort ultimately consisted of 60 patients with bilaterally successful AVS and a clear diagnosis of unilateral or bilateral disease. Receiver operating characteristic analysis was used to find the optimal A/C and AV/IVC cutoff values predicting the subtype of PA. The validation cohort consisted of 11 patients with either unsuccessful cannulation or a borderline lateralization index (LI), those patients underwent adrenalectomy because their indices were suggestive of unilateral disease based on the derivation cohort data. RESULTS: The cutoff values of A/C ≤ 0.63 or AV/IVC ≤ 0.37 identified unaffected glands with a sensitivity of 91.2% and 97.1%, respectively, and a specificity of 90.7% and 88.4%, respectively. Unilateral ipsilateral gland involvement was characterized by A/C ≥ 3.5 or AV/IVC ≥ 3.4 with a corresponding specificity of 100%. All patients in the validation cohort achieved biochemical remission postoperatively. CONCLUSIONS: A/C and AV/IVC cutoff values could be a useful tool to determine the subtype of PA in patients with unilateral successful AVS as well as in patients with a borderline LI.

Neutrophil-Lymphocyte Ratio as a Prognostic Marker in Adrenocortical Carcinoma.

PURPOSE: The purpose of the present study was to analyze the impact of the neutrophil-lymphocyte ratio (NLR) on the long-term outcomes of patients with adrenocortical carcinoma (ACC). METHODS: This retrospective, single-institution study included 48 patients with the diagnosis of ACC. The primary outcomes of the study were differences in overall survival (OS) and disease-specific survival (DSS) with respect to the NLR level. RESULTS: Patients with ENSAT stage IV had higher levels of NLR compared to those with ENSAT stage I-III (5.7 (1.6-12.5) vs 3.3 (1.3-11); p = .01). A higher NLR was also observed among patients with cortisol-secreting tumors (4.6 (1.7-12.5) vs 2.8 (1.3-10.3); p = .003) and those with Ki-67 index >10% (4.3 (1.3-12.5) vs 2.6 (1.6-11.0); p = .005). With respect to survival, the univariate analysis revealed worse ACC-related survival (p = .02) and OS (p = .004) in patients with NLR >3.9 than in those with NLR ≤3.9. In addition, patients with NLR >3.9 had a higher Weiss score (p = .046), a higher Ki-67 index (p = .006) and a higher disease stage (p = .01) compared to patients with NLR ≤3.9. No differences between the groups were observed regarding excess glucocorticoid secretion. CONCLUSION: The study demonstrated that a higher NLR level in ACC patients was associated with unfavorable outcomes in terms of DSS and OS. These results indicate that NLR might be used as an additional marker in ACC risk stratification and identification of patients with the most adverse prognosis.

Gamma-knife radiosurgery in acromegaly: the results from the Croatian acromegaly registry.

PURPOSE: The aim of our study was to evaluate the efficacy and safety of Leksell gamma-knife radiosurgery in the treatment of residual growth hormone-secreting pituitary adenomas after the surgery. MATERIALS AND METHODS: We conducted a retrospective analysis of 23 acromegaly patients treated with gamma-knife radiosurgery between 1996 and 2019. The therapeutic success of radiosurgery was defined as IGF-1 normalization without suppressive medication (complete response) or as IGF-1 normalization with medication (partial response). RESULTS: The median follow-up was 57 (10-198) months. Complete response was achieved in 11 patients (47.8%) with actuarial remission rates of 17.4%, 26.1%, 39.1% and 47.8% at 1, 2, 4, and 7 years, respectively. The median time to complete the response was 21 (6-85) months. Partial response was achieved in another nine patients (39.1%) after a median time of 48 (6-144) months from radiosurgery. Patients who achieved complete remission had significantly lower IGF-1 levels before radiosurgery (p = 0.016) as well as smaller tumour volume (p = 0.016) and radiologically less invasive tumours (p = 0.022) in comparison to patients who did not achieve IGF-1 normalization. Tumour growth control after radiosurgery was established in all patients. During the follow-up, new hormone deficiencies were found in seven patients (30.4%) which corresponds to the incidence of one new case of hypopituitarism per 7.1 patient years. CONCLUSIONS: Gamma-knife radiosurgery offers endocrine remission and tumour growth control in a substantial proportion of patients with GH-secreting adenomas. Given the high cost of life-long medical treatment and a moderate risk of radiation-induced side effects, radiosurgery for growth hormone-secreting pituitary adenomas should be considered in all patients with residual tumours.

Open vs laparoscopic adrenalectomy for localized adrenocortical carcinoma.

OBJECTIVE: The purpose of the study was to compare the long-term outcomes of patients with localized adrenocortical carcinoma (ACC) subjected to open vs laparoscopic surgery. DESIGN: Retrospective study. PATIENTS: This retrospective study included 46 patients with the ACC ENSAT stage I-stage III of whom 23 underwent open surgery (OA group), whereas 23 were subjected to laparoscopic adrenalectomy (LA group). The main outcomes analysed in the study were differences between the OA and LA groups in recurrence-free survival (RFS) and overall survival (OS). RESULTS: Patients in OA group had larger tumours (120 [70-250] mm vs 75 [26-110] mm; P < .001), higher Ki-67 index (16 [1-65] % vs 10 [1-25] %; P = .04) and higher disease stage (P = .01) compared with the patients in the LA group. The median duration of follow-up for patients underwent OA and LA was 51 (12-174) and 53 (5-127) months, respectively. Eight patients (5 OA and 3 LA) experienced recurrent disease, whereas six patients (3 OA and 3 LA) died during follow-up. No differences in RFS and OS were found between patients who underwent open or laparoscopic surgery. CONCLUSION: The study demonstrated that in patients with localized ACC and without invasion of extra-adrenal tissues, LA is a plausible treatment option in terms of RFS and OS. However, our results are limited to referral centres with large experience in the management of patients with ACC and may not necessarily apply to nonspecialized centres.

Hypopituitarism after gamma knife radiosurgery for pituitary adenoma.

PURPOSE: The aim of the study was to investigate the incidence of and risk factors for hypopituitarism after gamma knife radiosurgery (GKRS) for pituitary adenoma. MATERIALS AND METHODS: We conducted a retrospective analysis of the pituitary function of 90 patients who underwent GKRS for pituitary adenoma at the University Hospital Centre Zagreb between 2003 and 2014. Twenty seven of them met the inclusion criteria and the others were excluded from the study due to pituitary insufficiency which was present before GKRS. Eighteen patients had non-functioning and 9 patients had secretory adenomas. Median patients' age was 56 years (24-82). GKRS was performed using the Leksell gamma knife Model C. The median prescription radiation dose was 20 Gy (15-25) and the median tumor volume size was 3.4 cm3 (0.06-16.81). New onset hypopituitarism was defined as a new deficit of one of the three hormonal axes (corticotroph, thyreotroph, or gonadotroph) ≥3 months following GKRS. SPSS was used for statistical analysis, with the significance level at P<0.05. RESULTS: During the median follow-up period of 72 months (range 6-144), 30% of patients developed new hypopituitarism after GKRS. This corresponds to incidence of one new case of hypopituitarism per 15 patient-years. Age, gender, tumor function, tumor volume, suprasellar extension, prescription dose of radiation, as well as dose-volume to the pituitary gland, stalk and hypothalamus were not predictive factors for the development of hypopituitarism. CONCLUSIONS: In our cohort of patients with pituitary tumors who underwent GKRS, 30% developed new hypopituitarism during the follow-up period.

Advanced Age, High ß-CTX Levels, and Impaired Renal Function are Independent Risk Factors for All-Cause One-Year Mortality in Hip Fracture Patients.

Risk factors for increased mortality in hip fracture patients include older age, male sex, fracture type, bone mineral density, and pre-existing co-morbidities. The role of biochemical and other anthropometric parameters on hip fracture mortality remains unclear. The aim of this study was to identify the risk factors for one-year mortality in patients with hip fractures. A total of 236 consecutive patients (59 males) with hip fractures were followed over a one-year period. Patient age, gender, type of fracture, type of treatment, time from admission to surgery, type of anesthesia, body mass index, and electrocardiograms were recorded. Complete blood counts, serum electrolytes, urea, creatinine, d-dimers, calcium, phosphate, osteocalcin, and beta-isomerised C-terminal telopeptide of collagen type I (ß-CTX) were measured at admission and estimated glomerular filtration rate (eGFR) was calculated. Multivariate Cox regression models were used to analyze the association of these parameters with survival. One-year mortality rate was 28.4%. Age was independently associated with mortality (HR 1.117, 95% CI 1.062-1.174, P < 0.001). In a multivariable model, mortality was increased in patients with higher ß-CTX (HR 4.63 95% CI 1.87-11.45, P = 0.001) and lower eGFR (HR 0.972, 95% CI 0.956-0.987, P < 0.001). Patients younger than 84 years, with eGFR < 55.4 ml/min had ten times higher mortality rates (3.2 vs. 24.5%, HR 9.73, 95% CI 2.06-45.93) as well as those with ß-CTX > 0.276 g/L (3.5 vs. 25.7%, HR 9.5, 95% CI 2.11-42.76). Advanced age, high ß-CTX levels, and impaired renal function are independent risk factors of mortality in patients with hip fractures.

Diagnostic Performance of 99mTc-Sestamibi SPECT/CT and 18F-Choline PET/CT in Locating Hyperfunctioning Parathyroid Glands in Patients with Primary Hyperparathyroidism.

OBJECTIVE: This study aimed to assess the diagnostic performance of 99mTc-sestamibi SPECT/CT and 18F-choline PET/CT in detecting hyperfunctioning parathyroid glands in patients undergoing surgery for primary hyperparathyroidism (PHPT). METHODS: A retrospective analysis was conducted on patients who underwent PHPT-related surgery between April 2019 and May 2022. The study focused on patients undergoing either 99mTc-sestamibi SPECT/CT (81 patients) or 18F-choline PET/CT (33 patients) scans before surgery to pinpoint hyperfunctioning parathyroid gland(s). In the majority of patients, 18F-choline PET/CT was performed after negative or inconclusive findings on 99mTc-sestamibi SPECT/CT. Pathohistological reports were utilized as the reference standard for evaluating the accuracy of the imaging findings. RESULTS: The study encompassed 83 patients (70 females, 84.3%) with an average age of 57.2 years (24-80 years). The pathohistological analysis identified a total of 98 glands. In a per-lesion analysis, the detection rate of 99mTc-sestamibi SPECT/CT was 57% (95% CI 45.3-68.1), while the detection rate of 18F-choline PET/CT was 90.3% (95% CI 74.3-98.0). CONCLUSION: The results of our study showed the significant usefulness of 18F-choline PET/CT in patients with negative or inconclusive results of 99mTc-sestamibi SPECT/CT in accurately locating hyperfunctioning parathyroid glands in PHPT patients.

The Value of Local Therapies in Advanced Adrenocortical Carcinoma.

International guidelines recommend local therapies (LTs) such as local thermal ablation (LTA; radiofrequency, microwave, cryoablation), transarterial (chemo)embolisation (TA(C)E), and transarterial radioembolisation (TARE) as therapeutic options for advanced adrenocortical carcinoma (ACC). However, the evidence for these recommendations is scarce. We retrospectively analysed patients receiving LTs for advanced ACC. Time to progression of the treated lesion (tTTP) was the primary endpoint. The secondary endpoints were best objective response, overall progression-free survival, overall survival, adverse events, and the establishment of predictive factors by multivariate Cox analyses. A total of 132 tumoural lesions in 66 patients were treated with LTA (n = 84), TA(C)E (n = 40), and TARE (n = 8). Complete response was achieved in 27 lesions (20.5%; all of them achieved by LTA), partial response in 27 (20.5%), and stable disease in 38 (28.8%). For the LTA group, the median tTTP was not reached, whereas it was reached 8.3 months after TA(C)E and 8.2 months after TARE (p < 0.001). The median time interval from primary diagnosis to LT was >47 months. Fewer than four prior therapies and mitotane plasma levels of >14 mg/L positively influenced the tTTP. In summary, this is one of the largest studies on LTs in advanced ACC, and it demonstrates a very high local disease control rate. Thus, it clearly supports the guideline recommendations for LTs in these patients.

Are comorbidities of patients with adrenal incidentaloma tied to sex?

Background: A recent cross-sectional study showed that both comorbidities and mortality in patients with adrenal incidentaloma (AI) are tied to sex. However, few longitudinal studies evaluated the development of arterial hypertension, hyperglycemia, dyslipidemia and bone impairment in patients with AI. The aim of this study is to analyze the impact of sex in the development of these comorbidities during long-term follow-up. Methods: We retrospectively evaluated 189 patients (120 females, 69 males) with AI, from four referral centers in Italy and Croatia. Clinical characteristics, comorbidities and cortisol after 1-mg dexamethasone suppression test (1-mg DST) were assessed at baseline and at last follow-up visit (LFUV). Median follow-up was 52 (Interquartile Range 25-86) months. Results: The rates of arterial hypertension and hyperglycemia increased over time both in females (65.8% at baseline versus 77.8% at LFUV, p=0.002; 23.7% at baseline versus 39.6% at LFUV, p<0.001; respectively) and males (58.0% at baseline versus 69.1% at LFUV, p=0.035; 33.8% at baseline versus 54.0% at LFUV, p<0.001; respectively). Patients were stratified in two groups using 1.8 µg/dl as cut-off of cortisol following 1-mg DST: non-functional adrenal tumors (NFAT) and tumors with mild autonomous cortisol secretion (MACS). In the NFAT group (99 patients, females 62.6%), at baseline, we did not observe any difference in clinical characteristics and comorbidities between males and females. At LFUV, males showed a higher frequency of hyperglycemia than females (57.6% versus 33.9%, p=0.03). In the MACS group (89 patients, females 64.0%), at baseline, the prevalence of hypertension, hyperglycemia and dyslipidemia was similar between sexes, despite females were younger (60, IQR 55-69 versus 67.5, IQR 61-73, years; p=0.01). Moreover, females presented higher rates of bone impairment (89.3% versus 54.5%, p=0.02) than males. At LFUV, a similar sex-related pattern was observed. Conclusion: Patients with AI frequently develop arterial hypertension and hyperglycemia and should be periodically checked for these comorbidities, regardless of sex. In patients with MACS, the lack of difference between sexes in the frequency of cardiometabolic comorbidities despite that females are younger, and the higher frequency of bone impairment in females, suggest a sex-specific effect of cortisol.

Assessing Lateralization Index of Adrenal Venous Sampling for Surgical Indication in Primary Aldosteronism.

BACKGROUND: Clinical practice guidelines recommend the Lateralization Index (LI) as the standard for determining surgical eligibility in primary aldosteronism (PA). Our goal was to identify the optimal LI cut-offs in adrenal venous sampling (AVS) for diagnosing PA that is amenable to surgical cure. METHODS: We conducted a retrospective international cohort study across 16 institutions in 11 countries, including 1,550 patients with PA who underwent AVS, with and/or without ACTH stimulation. The establishment of optimal cut-offs was informed by a survey of 82 PA patients in Japan, aimed at determining the LI cut-off aligned with patient expectations for a surgical cure rate. RESULTS: The survey revealed that a median cure rate expectation of 80% would motivate PA patients towards undergoing adrenalectomy. The optimal LI cut-offs achieving an adjusted positive predictive value (PPV) of 80% were identified as 3.8 for unstimulated AVS and 3.4 for ACTH-stimulated AVS. Furthermore, a contralateral ratio of less than 0.4 and the detection of an adrenal nodule on CT imaging were identified as independent predictors of surgically curable PA. Incorporating these factors with the optimal LI cut-offs, the adjusted PPV increased to 96.6% for unstimulated AVS and 89.6% for ACTH-stimulated AVS. No clear differences in predictive ability between unstimulated and ACTH-stimulated LI were found. CONCLUSIONS AND RELEVANCE: The present study clarified the optimal LI cut-offs for without and with ACTH stimulation. The presence of contralateral suppression and adrenal nodule on CT imaging seems to provide additional available information besides LI for surgical indication.

Hypercoagulable state in Cushing's syndrome is reversible following remission.

OBJECTIVE: Hypercoagulability is a commonly described complication in patients with Cushing's syndrome (CS). The aim of this study was to assess the long-term effects of surgical remission from CS on serum levels of coagulation and fibrinolytic markers. DESIGN AND METHODS: Eighteen patients with active CS (16 women, 2 men; age: 38.6 ± 13.7 years) were enrolled in the study. We measured serum levels of coagulation and fibrinolytic markers during active CS and 6 months after remission. The control group comprised 18 age- and sex-matched healthy individuals. RESULTS: Six months after remission from CS, patients had lower levels of factors II (P < 0.001), V (P = 0.02), XI (P = 0.04) and XII (P < 0.001), protein C (P < 0.001), protein S (P = 0.002), antithrombin (P = 0.03), antithrombin Ag (P = 0.008), plasminogen (P = 0.03) and C1 inhibitor (P = 0.001), and aPTT was longer than at enrollment (P = 0.001). Levels of PAI-1 and factors VII, VIII and IX tended to normalize, but there were no significant differences in these parameters before and after surgery, nor were differences found in haemostatic and fibrinolytic markers between the patients in remission and control individuals, except for factor XII (P = 0.02) and protein C (P = 0.004), which were lower among patients in remission. CONCLUSION: Six months after remission from CS, patients' risk of thromboembolism is comparable to that of healthy individuals.

Medical treatment of acromegaly-experience from the Croatian acromegaly registry.

PURPOSE: The aim of this study was to review therapeutic outcomes of the medical treatment of patients with acromegaly based on real-world data from the Croatian Acromegaly Registry. METHODS: In this retrospective study we investigated 163 patients (101 female, 62 male, age at diagnosis 47.2 ± 13.4 years) treated between 1990 and 2020, of which 53 were treated medically (32.5%). The duration of follow-up was 115.8 ± 304.4 months. The remission rate after the pituitary surgery was achieved in 66.5% (n = 105/158; 5 patients refused surgery). Patients who did not achieve disease remission or had a relapse during follow-up (n = 2), underwent reoperation (n = 18/60, 30%) and/or radiotherapy (n = 33/60, 55%) and/or medical treatment (n = 53/60, 88.3%). One patient refused further treatment after the failure of the first pituitary surgery. RESULTS: Out of 53 patients treated with medical therapy, monotherapy was used in 34 (64.2%) and combination therapy in 19 (35.8%) patients. Remission (IGF-I < 1.2 upper limit of normal, ULN) was achieved in 51 patients (96.2%). Out of 53 patients, 21 (39.6%) were treated with first-generation somatostatin receptor ligand (SRL-1) monotherapy, 10 (18.9%) with dopamine agonist (DA) monotherapy, one (1.9%) with pegvisomant monotherapy, 13 (24.4%) with a combination of SRL-1 and DA, three (5.7%) with a combination of SRL-1, DA and pegvisomant, two (3.8%) with a combination of second-generation somatostatin receptor ligand (SRL-2), DA and pegvisomant and in one (1.9%) temozolomide was added on top of SRL-1 and DA. Two patients currently have active disease, both on SRL-1 monotherapy, of whom one is non-adherent to the treatment. Radiotherapy was applied to 27 (50.9%) patients on medical therapy. CONCLUSION: Our results indicate that almost all patients with active acromegaly after pituitary surgery can achieve biochemical control with medical treatment.

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

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

High prevalence of frailty in patients with adrenal adenomas and adrenocortical hormone excess: a cross-sectional multi-centre study with prospective enrolment.

OBJECTIVE: Frailty, characterized by multi-system decline, increases vulnerability to adverse health outcomes and can be measured using Frailty Index (FI). We aimed to assess the prevalence of frailty in patients with adrenal disorders (based on hormonal sub-type) and examine association between FI and performance-based measures of physical function. DESIGN: Multi-centre, cross-sectional study (March 2019-August 2022). METHODS: Adult patients with adrenal disorders (non-functioning adrenal adenomas [NFA], mild autonomous cortisol secretion [MACS], Cushing syndrome [CS], primary aldosteronism [PA]) and referent subjects without adrenal disorders completed a questionnaire encompassing 47 health variables (comorbidities, symptoms, daily living activities). FI was calculated as the average score of all variables and frailty defined as FI ≥ 0.25. Physical function was assessed with hand grip, timed up-and-go test, chair rising test, 6-minute walk test, and gait speed. RESULTS: Compared to referent subjects (n = 89), patients with adrenal disorders (n = 520) showed increased age, sex, and body mass index-adjusted prevalence of frailty (CS [odds ratio-OR 19.2, 95% confidence interval-CI 6.7-70], MACS [OR 12.5, 95% CI 4.8-42.9], PA [OR 8.4, 95% CI 2.9-30.4], NFA [OR 4.5, 95% CI 1.7-15.9]). Prevalence of frailty was similar to referent subjects when post-dexamethasone cortisol was <28 nmol/L and was higher when post-dexamethasone cortisol was 28-50 nmol/L (OR 4.6, 95% CI 1.7-16.5). FI correlated with all measures of physical function (P < .001). CONCLUSIONS: Whilst frailty prevalence was highest in patients with adrenocortical hormone excess, even patients with NFA demonstrated an increased prevalence compared to the referent population. Future longitudinal studies are needed to evaluate the impact of various management strategies on frailty.

International multicenter survey on screening and confirmatory testing in primary aldosteronism.

OBJECTIVE: Primary aldosteronism (PA) is one of the most frequent causes of secondary hypertension. Although clinical practice guidelines recommend a diagnostic process, details of the steps remain incompletely standardized. DESIGN: In the present SCOT-PA survey, we have investigated the diversity of approaches utilized for each diagnostic step in different expert centers through a survey using Google questionnaires. A total of 33 centers from 3 continents participated. RESULTS: We demonstrated a prominent diversity in the conditions of blood sampling, assay methods for aldosterone and renin, and the methods and diagnostic cutoff for screening and confirmatory tests. The most standard measures were modification of antihypertensive medication and sitting posture for blood sampling, measurement of plasma aldosterone concentration (PAC) and active renin concentration by chemiluminescence enzyme immunoassay, a combination of aldosterone-to-renin ratio with PAC as an index for screening, and saline infusion test in a seated position for confirmatory testing. The cutoff values for screening and confirmatory testing showed significant variation among centers. CONCLUSIONS: Diversity of the diagnostic steps may lead to an inconsistent diagnosis of PA among centers and limit comparison of evidence for PA between different centers. We expect the impact of this diversity to be most prominent in patients with mild PA. The survey raises 2 issues: the need for standardization of the diagnostic process and revisiting the concept of mild PA. Further standardization of the diagnostic process/criteria will improve the quality of evidence and management of patients with PA.

Adjuvant mitotane versus surveillance in low-grade, localised adrenocortical carcinoma (ADIUVO): an international, multicentre, open-label, randomised, phase 3 trial and observational study.

BACKGROUND: Adjuvant treatment with mitotane is commonly used after resection of adrenocortical carcinoma; however, treatment remains controversial, particularly if risk of recurrence is not high. We aimed to assess the efficacy and safety of adjuvant mitotane compared with surveillance alone following complete tumour resection in patients with adrenocortical carcinoma considered to be at low to intermediate risk of recurrence. METHODS: ADIUVO was a multicentre, open-label, parallel, randomised, phase 3 trial done in 23 centres across seven countries. Patients aged 18 years or older with adrenocortical carcinoma and low to intermediate risk of recurrence (R0, stage I-III, and Ki67 ≤10%) were randomly assigned to adjuvant oral mitotane two or three times daily (the dose was adjusted by the local investigator with the target of reaching and maintaining plasma mitotane concentrations of 14-20 mg/L) for 2 years or surveillance alone. All consecutive patients at 14 study centres fulfilling the eligibility criteria of the ADIUVO trial who refused randomisation and agreed on data collection via the European Network for the Study of Adrenal Tumors adrenocortical carcinoma registry were included prospectively in the ADIUVO Observational study. The primary endpoint was recurrence-free survival, defined as the time from randomisation to the first radiological evidence of recurrence or death from any cause (whichever occurred first), assessed in all randomly assigned patients by intention to treat. Overall survival, defined as time from the date of randomisation to the date of death from any cause, was a secondary endpoint analysed by intention to treat in all randomly assigned patients. Safety was assessed in all patients who adhered to the assigned regimen, which was defined by taking at least one tablet of mitotane in the mitotane group and no mitotane at all in the surveillance group. The ADIUVO trial is registered with ClinicalTrials.gov, NCT00777244, and is now complete. FINDINGS: Between Oct 23, 2008, and Dec 27, 2018, 45 patients were randomly assigned to mitotane and 46 to surveillance alone. Because the study was discontinued prematurely, 5-year recurrence-free and overall survival are reported instead of recurrence-free and overall survival as defined in the protocol. 5-year recurrence-free survival was 79% (95% CI 67-94) in the mitotane group and 75% (63-90) in the surveillance group (hazard ratio 0·74 [95% CI 0·30-1·85]). Two people in the mitotane group and five people in the surveillance group died, and 5-year overall survival was not significantly different (95% [95% CI 89-100] in the mitotane group and 86% [74-100] in the surveillance group). All 42 patients who received mitotane had adverse events, and eight (19%) discontinued treatment. There were no grade 4 adverse events or treatment-related deaths. INTERPRETATION: Adjuvant mitotane might not be indicated in patients with low-grade, localised adrenocortical carcinoma considering the relatively good prognosis of these patients, and no significant improvement in recurrence-free survival and treatment-associated toxicity in the mitotane group. However, the study was discontinued prematurely due to slow recruitment and cannot rule out an efficacy of treatment. FUNDING: AIFA, ENSAT Cancer Health F2-2010-259735 programme, Deutsche Forschungsgemeinschaft, Cancer Research UK, and the French Ministry of Health.

[Croatian Society of Endocrinology guidelines for the diagnosis and treatment of acromegaly]. / Smjernice Hrvatskoga endokrinoloskog drustva za dijagnostiku i lijecenje akromegalije.

The working group of the Croatian Society of Endocrinology met in September 2011 to discuss the diagnostic and therapeutic dilemmas in patients with acromegaly. The group comprised 9 pituitary specialists including endocrinologists, neurosurgeons, and medical biochemistry specialist. After a critical analysis of published scientific papers the group has developed guidelines for the diagnosis and treatment of acromegaly.

Hypothalamic-pituitary-adrenal axis recovery after treatment of Cushing's syndrome.

After successful treatment for Cushing's syndrome (CS), secondary adrenal insufficiency develops as a result of the prior suppression of the hypothalamic-pituitary-adrenal (HPA) axis by excess cortisol in the body. Until the recovery of the HPA axis, glucocorticoid replacement therapy is required to enable normal functioning of the body and prevent adrenal crisis. Significant variation in the median time of recovery of the HPA axis is found in various cohorts of CS patients ranging from several weeks to years. Despite the use of physiological glucocorticoid replacement, after cure for CS, patients often experience symptoms of glucocorticoid withdrawal syndrome (GWS). The optimal glucocorticoid regimen to reduce GWS needs to be established and requires an individualized approach aiming to avoid overtreatment at one side and minimize the risk of undertreatment and possible adrenal crisis and GWS on the other side.