The Choosing Wisely Initiative (CWI) was founded in 2012 and aims to reduce unnecessary healthcare to promote the common good. The Austrian Society for Endocrinology and Metabolism (& Ouml;GES) and the Institute of General Practice and Evidence-Based Health Services Research at the Medical University of Graz released five Choosing Wisely recommendations in the field of endocrinology. The recommendations presented and discussed in this article are the following: 1. "Thyroid nodules patients should not be treated with L-thyroxine except in selected cases." 2. "Avoid excess bone mineral density testing: intervals less than two years are rarely necessary." 3. "Don't prescribe testosterone therapy to older men except in confirmed cases of hypogonadism." 4. "Don't routinely test for anti-thyroid peroxidase antibodies (TPO-Ab)."5. "Do not routinely request/perform thyroid ultrasound in subjects without signs and/or symptoms of thyroid disease and not belonging to risk groups for thyroid cancer and limit the indication and execution of fine-needle aspirations on low-risk nodules." Resources unnecessarily consumed in one area of the healthcare system are lacking in others, which is why it is an important ethical responsibility, for the common good, to minimize unnecessary overdiagnosis and overtreatment.

OBJECTIVE:The aim of the study was to investigate bone comorbidities and their management in patients included in the European Register on Cushing's syndrome (ERCUSYN). DESIGN:A retrospective multicentric cohort study and on-line survey. METHODS:We analyzed the prevalence of osteoporosis (OP) and fractures among 1682 patients with Cushing's syndrome (CS), at initial evaluation and during follow-up. All the ERCUSYN partners received a survey addressing bone disease management in CS. RESULTS:Seven hundred and sixty-six patients (45%) had DXA examination at baseline, of whom 157 (21%) presented OP at spine and 103 (13%) at hip. Risk factors for OP were older age (P=0.038) and lower BMI (P=0.022). An X-ray was performed in 492 (29%) patients and fracture was detected in 87 (18%). Risk factors for fractures at baseline were male sex (P<0.001), muscle weakness (P=0.026) and bone mineral density (BMD) at hip indicating OP (P=0.026). During follow-up, spine BMD deterioration was more common in older patients (P=0.005) and in those with diabetes mellitus (P=0.024), while worsening of hip BMD was more frequent in patients with hypopituitarism (P=0.021), diabetes mellitus (P=0.034), on levothyroxine substitution (P=0.008) and those less often treated with anti-osteoporotic agents (P=0.022). The survey evidenced significant heterogeneity in terms of timing of bone evaluation and treatment initiation. CONCLUSIONS:A significant number of patients with CS experienced OP and fractures. Clinical factors may help to select patients at the highest risk. There are currently no standards of care for the management of bone complications in CS across Europe.

BACKGROUND:Limited availability of corticotropin-releasing hormone (CRH) currently complicates the differentiation of adrenocorticotropin (ACTH)-dependent Cushing's syndrome (CS). The diagnostic value of common screening tests in distinguishing Cushing's disease (CD) from ectopic CS (ECS) remains unclear. OBJECTIVE:To assess the diagnostic performance of screening tests, alone and in combination, in differentiating CD from ECS. METHODS:Retrospective multicenter study enrolling patients with confirmed ACTH-dependent CS and available screening tests at diagnosis. Data are expressed as multiples of upper limit of normal (×ULN). Optimal cut-offs were determined using Youden's Index. Combination with composite score models and machine learning algorithm were performed. RESULTS:A total of 566 patients were included (509 [90%] with CD). The optimal morning ACTH cut-off was 1.8×ULN (sensitivity 74%, specificity 77%, AUC=0.776 [CI-95% .688-.853]). 24h-urinary free cortisol (24h-UFC) showed the best performance (cut-off 5.9×ULN, sensitivity 72%, specificity 83%, AUC=0.854 [.816-.923]), followed by the 1 mg dexamethasone suppression test (12.8×ULN, sensitivity 70%, specificity 86%, AUC=.828 [.740-.906]). Using a composite score, a cut-off of 1.5 yielded 78% sensitivity and 92% specificity (AUC=0.865 [.798-.933]). Combining this score with findings derived from pituitary magnetic resonance imaging (MRI), sensitivity and specificity were 88% and 85% (AUC=0.931 [.887-.974]). Machine learning algorithm (balanced random forest) including screening tests-results yielded a sensitivity of 71% and specificity of 84% (AUC=0.853 [.741-.966]), while including the MRI-findings variant achieved a sensitivity and specificity of 76% and 91% (AUC=0.902 [.805-.999]). CONCLUSION:Combining screening tests in composite scoring and machine learning differentiates subtypes of ACTH-dependent CS and offers a potential diagnostic alternative to the CRH stimulation test.

BackgroundMild autonomous cortisol secretion (MACS) is associated with an increased cardiovascular mortality, but even patients with non-functioning adrenal adenoma (NFA) might be at risk for cardio-metabolic comorbidities compared to a control group with absence of an adrenal tumor (CON).Material and methodsSeventyfour individuals were included in cross-sectional analysis [MACS: n=25(84% females), age: 63(55-67)years, BMI:27.00(24.20-30.50)kg/m2; NFA: n=25(84%females), age: 61(54-68)years, BMI:28.50(27.50-32.20)kg/m2 and CON: n=24 (75%females), age: 58 (51-64)years, BMI: 27.39(22.03-30.17) kg/m2]. Visceral and ectopic fat stores, as well as heart function were assessed by magnetic resonance imaging and spectroscopy. Blood pressure was measured by standardized protocols. Blood was drawn in the fasting state and during an oral glucose tolerance test to assess glucose and lipid metabolism.ResultsThe prevalence of hypertension (MACS:84% vs NFA:76% vs CON: 43.5%), dyslipidemia (MACS:96% vs NFA:80% vs CON:62.5%) and prediabetes (MACS:56% vs. NFA:72% vs CON:29.2%) was significantly different between the groups. Markers of glucose metabolism were worse in MACS and best in CON (HbA1c: 5.70 (5.40-5.90)% vs 5.50 (5.40-5.80)% vs 5.40 (5.27-5.60)%, p=0.043); HOMA_IR:2.91(2.19-4.15) vs 2.55 (1.57- 4.97) vs 1.73 (1.00-2.61), p=0.007). epicardial adipose tissue area was highest in MACS patients, followed by NFA, with lowest values in CON (MACS:1159.68 (930.38-1454.11) mm2vs NFA: 873.23 (638.03-1195.33) mm2vs CON:672.37 (549.44-890.30) mm2, p<0.001). No relevant between-group-differences in cardiac morphology, intramyocardial fat or intrahepatic fat were observed.ConclusionsIn this exploratory study, MACS was associated with epicardial adiposity and an adverse cardio-metabolic risk profile.

BACKGROUND:The renin-angiotensin system (RAS) constitutes an important cornerstone in blood pressure (BP) regulation. Previous evidence on the relationship between growth hormone (GH), insulin-like growth factor I (IGF-I), and the RAS is conflicting, depending on study conditions and exposure duration. This exploratory study therefore investigated the effects of short- and long-term GH excess on RAS activity. METHODS:RAS activity was assessed in 10 healthy, male volunteers (26 ± 5years, BMI 23 ± 3.4 kg/m2) before and after 1 week of daily, subcutaneous GH treatment (2 mg) serving as model of short-term GH excess. Regarding long-term GH excess, RAS activity in 19 patients with active acromegaly (54 [48-59] years, 52.6% females, IGF-I/ULN 2.8 [2.3-3.3]) was compared to a cohort of 25 controls (39 [32-47] years, 76% females). In 12 patients, measurements were re-conducted after successful treatment of acromegaly. RESULTS:One week of GH treatment increased IGF-I concentrations to 1.6 ± 0.5 ULN and overall RAS activity, including angiotensin II levels (117.5 ± 50.3 pMol/L vs. 205.9 ± 135.7 pMol/L, P = .03) and the surrogate of renin activity (PRA-S: 149.8 ± 63.3 pMol/L vs. 269.1 ± 177.4 pMol/L, P = .03) alongside increased concentrations of insulin and C-peptide in healthy males. In contrast, patients with acromegaly showed lower concentrations of angiotensin II (47.2 [33-145] pMol/L vs. 155.3 [64-326] pMol/L, P = .017), aldosterone (118 [71-193] pMol/L vs. 227.8 [165-305] pMol/L, P = .009), and PRA-S(84.2 [51-200] pMol/L vs. 230 [85-403] pMol/L, P = .032) despite higher mean arterial BP(105 [99-115] mmHg vs. 91 [85-97] mmHg, P < .001) compared to controls. CONCLUSION:Short-term GH excess stimulates RAS activity which may be related to the increase in insulin and C-peptide. In contrast, RAS activity is down-regulated in long-term GH excess despite high BP.

CONTEXT AND OBJECTIVE:Mild autonomous cortisol secretion (MACS) is associated with increased mortality, mainly because of cardiovascular disease. Here we investigated the effects of cortisol-lowering medical treatment on blood pressure regulation, cardiac fat depots, heart function and morphology, and other cardiovascular risk factors. DESIGN, SETTING AND INTERVENTION:In this secondary analysis of our prospective, open-label, single-center study at the Medical University of Vienna, we investigated 15 patients with MACS (12 females; age 59 [53-64] years) before and after 12 weeks of treatment with evening doses of metyrapone (500 mg at 6 p.m. and 250 mg at 10 p.m.). OUTCOME MEASURES AND METHODS:Cardiac fat stores, morphology and myocardial function were evaluated using cardiac magnetic resonance imaging and spectroscopy. Orthostatic blood pressure regulation was measured by standardized protocols. Lipidomics, renin-angiotensin-aldosterone-system activity and branched-chain amino acid (BCAA) concentrations were assessed. RESULTS:Mean supine systolic (137[121-139] vs 122[115-129] mmHg; p=0.041) and diastolic (89[80-93] vs 75[71-86] mmHg; p=0.045) blood pressure decreased after treatment in patients without changes in concomitant antihypertensive medication. Epicardial fat was lower at follow up compared to baseline (1032.70[894.23-1482.90] vs 929.37[736.12-1317.15]mm2; p=0.022). No changes in paracardial- and intramyocardial fat, as well as in cardiac function and morphology were observed. The aldosterone-to-angiotensin II ratio was lower at follow up (1.56[0.87-2.82] vs 1.21[0.98-1.92]; p=0.042) and alterations in lipid profiles, but not in BCAA levels were identified. CONCLUSIONS:Treatment with evening doses of metyrapone improved blood pressure and reduced epicardial adipose tissue.

Background:Mild autonomous cortisol secretion (MACS) is associated with an increased morbidity and mortality. Treatment options range from adrenalectomy to conservative management of comorbidities, but evidence on the effects of medical treatment is scarce. We therefore aimed to investigate the metabolic effects of evening metyrapone treatment in patients with MACS. Methods:We did a prospective, open-label, proof-of-concept trial (EudraCT: 2022-000161-40). Patients with uni-or bilateral adrenal incidentaloma and MACS defined by cortisol >1·8 μg/dL after 1 mg-dexamethasone-suppression-testing without clinical signs of Cushing's syndrome were included. Participants were investigated at baseline and after 12 weeks of treatment with metyrapone (500 mg at 6 p.m. and 250 mg at 10 p.m.). Intrahepatic lipid content (IHL) and abdominal visceral/subcutaneous fat mass were measured by magnetic resonance spectroscopy and imaging. Resting blood pressure measurements and blood sampling before and during an oral glucose tolerance test were conducted. IHL was the primary outcome parameter. Wilcoxon-signed-rank-tests were used for statistical analysis. Findings:Between May 2023 and September 2024, 19 patients were enrolled. Fifteen patients were included in the final analysis (12 female, median age 59 years [IQR 53-64]; median BMI 28 kg/m2 [25-32]; median cortisol after 1 mg-dexamethasone-suppression-testing 2·9 μg/dL [2·4-4·6]). Metyrapone treatment significantly lowered median IHL at follow up compared with baseline (3·85% of water signal [IQR 1·52-6·58] vs 1·92% [1·12-5·91]; p = 0·010). Median fasting insulin (12·6 μlU/mL [IQR 10·5-19·5] vs 9·3 μlU/mL [7·2-14·4]; p = 0·041), median c-peptide concentrations (3·0 ng/mL [2·5-4·4] vs 2·8 ng/mL [2·2-3·4], p = 0·024) and inflammatory parameters (median leukocyte count 8·1 G/L [6·4-8·9] vs 7·4 G/L [6·0-8·8]; p = 0·018; median neutrophil-to-lymphocyte-ratio 2·39 [1·74-2·75] vs 2·04 [1·47-2·55]; p = 0·00020) improved. Median systolic (128 mmHg [IQR 122-139] vs 122 mmHg [119-126]; p = 0·075) and diastolic (83 mmHg [80-95] vs 78 mmHg [75-91]; p = 0·10) blood pressure was non-significantly lower at follow up. No patient reported adverse symptoms of adrenal insufficiency during the study period. Interpretation:Treatment of MACS with evening doses of metyrapone lowers hepatic lipid content and improves the metabolic risk profile and might offer a novel therapeutic approach. Funding:Esteve (formerly HRA pharma) to the Medical University of Vienna (PI:PW).

This Pituitary Society Consensus article presents an evidence-based consensus on the management of pituitary incidentaloma, defined as an unexpected sellar or parasellar finding incidentally discovered on an imaging study that was not performed for a clinically suspected pituitary lesion. Recommendations are offered for when endocrinology, neurosurgery and ophthalmology consultation, dedicated pituitary imaging, pituitary hormone testing and visual assessment are warranted for macroadenomas, microadenomas, cystic lesions and empty sella, as well as when surgical resection is indicated for incidental pituitary adenomas and cystic sellar lesions. Special considerations in patients with multiple endocrine neoplasia type 1, children and adolescents, older people, and pregnant women are addressed. The Consensus workshop concluded that diagnostic and management approaches should be individualized to the specific clinical context of an incidentally discovered pituitary lesion. Consultation with a multidisciplinary pituitary tumour centre of excellence should be considered in the presence of new or deteriorating lesion-specific signs or symptoms, particularly when surgical or other adjuvant interventions are being considered and when there is uncertainty about the most appropriate subsequent management. This international Consensus Statement provides guidelines on the management of pituitary incidentalomas.

Eine latente Hypothyreose tritt häufig bei älteren Menschen auf, wobei ein moderater Anstieg des TSH im Alter (bis 7ნ mU/L) physiologisch ist. Studien zeigen, dass in diesen Fällen eine Behandlung mit Thyroxin bei Menschen über 65 Jahre meist keine Vorteile bringt, aber potenzielle Risiken hat. Da in der Praxis eine Übertherapie häufig vorkommt, wird eine altersabhängige Interpretation der TSH-Werte und Zurückhaltung bei Erstverordnung empfohlen.

CONTEXT:Growth hormone (GH) reduces intrahepatic lipids (IHL) according to investigations in healthy volunteers and patients with acromegaly, a disease characterized by long-term GH excess. OBJECTIVE:This study investigated underlying antisteatotic pathways stimulated by short-term modulation of GH action. METHODS:Ten healthy male volunteers (26 ± 5 years, body mass index [BMI] 23 ± 3.4 kg/m2) were assessed before and after 1 week of daily subcutaneous treatment with either GH or a GH-receptor antagonist in a crossover study (EK Nr.1395/2020; Eudra-CT:2020-000831-34). The assessments comprised the quantification of IHL and hepatic ATP synthesis via magnetic resonance spectroscopy, assessment of very low-density lipoprotein (VLDL) secretion by an intralipid infusion protocol, and measurement of de novo lipogenesis (DNL) using stable isotope tracer techniques. In comparison, effects of long-term GH excess on VLDL secretion were investigated in patients with active acromegaly (54 ± 5 years; BMI 29.3 ± 3.6 kg/m2; insulin-like growth factor I of 3.1 ± 1 × upper limit of normal). RESULTS:GH treatment stimulated the secretion of VLDL-triglycerides by 26.1% (590.5 ± 282.3 mg/h vs 738.8 ± 424.9 mg/h, P = .035). Contrarily, mean DNL doubled after GH-receptor blockage without statistical significance (3.06 ± 1.95 vs 7.32 ± 8.43%, P = .107). Effects on hepatic ATP synthesis were not observed. Baseline hepatic VLDL secretion was comparable between volunteers and patients with acromegaly. CONCLUSION:GH modulates hepatic lipid turnover via an increase in hepatic triglyceride export and repressed GH action tends to foster DNL, which may be of assistance for the development of future therapeutic strategies against metabolic dysfunction-associated steatotic liver disease.

Subclinical hypothyroidism is frequently diagnosed in older patients. However, mild TSH elevations (up to 7 mU/L) with increasing age are physiologic. Studies demonstrate that treatment with levothyroxine in patients older than 65 years is not beneficial but may have potential risks. As overtreatment is often observed, an age-dependent interpretation of TSH levels and a conservative approach to prescription are recommended.

Disclosure: N.A. Tritos: None. M.O. Carlsson: Pfizer, Inc. G. Vila: Takeda, Lundbeck, Recordati, Ascendis, Novo Nordisk, Pharmanovia, Pfizer, Inc., HRA Pharmaceuticals, Merck. C. Jimenez: None. D. La Torre: Pfizer srl. M.P. Wajnrajch: Pfizer, Inc. B.M. Biller: Crinetics, Amolyt, Camurus, Chiesi, Crinetics, Pfizer, Inc., Recordati. L. Céspedes: Pfizer, Inc. K.K. Miller: Amgen Inc, Bristol-Myers Squibb, General Electric, Boston Scientific, Becton Dickinson. The objective of the present study was to characterize disease-specific mortality rates in patients with acromegaly on pegvisomant therapy, and identify risk factors for mortality, including on-therapy serum insulin-like growth factor I (IGF-I) levels. A retrospective cohort analysis of ACROSTUDY (global surveillance study of patients with acromegaly on pegvisomant) was conducted, and cumulative incidence functions were used to estimate disease-specific mortality rates. Regression analyses were performed to characterize pertinent risk factors. Disease-specific standardized mortality rates (SMR) were calculated, and Poisson regression models were used to characterize the association between disease-specific SMR, serum IGF-I and other risk factors. 2077 participants were followed for a median interval of 4.1 years. Mortality secondary to cardiovascular/cerebrovascular causes increased with higher on-treatment serum IGF-I levels [1.97 (1.45,2.67), P<0.0001] and older age at entry [1.09 (1.07,1.13), P<0.0001]. Mortality secondary to malignant [1.57 (1.17,2.09), P=0.0024] or respiratory [1.64 (1.23,2.19), P=0.0008] causes also increased with higher on-treatment serum IGF-I levels. On-treatment serum IGF-I exceeding the upper limit of normal were associated with higher SMR ratios for cardiovascular/cerebrovascular causes (P=0.0127). On Poisson regression, younger attained age [SMR ratio (95% CI): 0.93 (0.91,0.96), P<0.0001], younger age at diagnosis [<35 yr vs. >50 yr, 3.64 (1.33,9.93), P=0.0117], higher on-treatment serum IGF-I [1.69 (1.12,2.55), P=0.0127], and history of pituitary radiotherapy [2.25 (1.09,4.63), P=0.0280] were associated with higher SMR ratios for cardiovascular/cerebrovascular causes. Younger attained age [0.93 (0.89,0.96), P<0.0001], higher serum IGF-I at ACROSTUDY entry [>2xULN vs. <1xULN, 4.89 (1.09,21.8), P=0.0378], and history of malignancy at entry [7.05 (2.36,21.03), P=0.0005], were associated with higher SMR ratios for malignant causes. Younger age at diagnosis [35-50 yr vs. >50 yr, 4.50 (1.08,18.83), P=0.0394] and history of sleep apnea [4.98 (1.34,18.53), P=0.0168] were associated with higher SMR ratios for respiratory causes. In patients with acromegaly treated with pegvisomant, higher on-therapy serum IGF-I levels are associated with higher disease-specific mortality and higher SMR ratios for cardiovascular/cerebrovascular causes, highlighting the importance of achieving IGF-I normalization towards optimizing patient outcomes. Presentation: Saturday, July 12, 2025

BACKGROUND:Cyclic Cushing's syndrome (cCS) features fluctuating cortisol secretion, often causing diagnostic errors or delays, and possibly poorer outcomes. We aimed to identify unpublished cCS cases to characterise clinical challenges and guide strategies for improving outcomes by characterising cycle patterns, peak frequency, and evaluating complications. METHODS:This was a retrospective observational study at 43 endocrine centres in 21 countries, including patients with confirmed Cushing's syndrome showing two or more hypercortisolaemic peaks and one or more spontaneous eucortisolaemic or hypocortisolaemic trough. Data included both clinical (eg, comorbidities and physical signs of cortisol excess) and biochemical (eg, screening and confirmatory tests) parameters, imaging, treatment, complications, and outcomes. FINDINGS:Between Dec 1, 2023 and Feb 2, 2025, 116 potentially eligible patients were identified and 110 were included. Most patients were female (84 [76%] of 110 patients), with a median age at diagnosis of 44·0 years (IQR 31·8-58·3). cCS origin was pituitary in 70 (64%), ectopic in 25 (23%), adrenal in three (3%), and occult in 12 (11%). Cyclicity was primarily determined by 24 h urinary free cortisol, with median peaks of 7·40 × ULN (range 0·44-299) and troughs of 0·31 × ULN (0·02-0·98). The median peak count was 3·0 (IQR 2·0-4·0), mostly (55 [86%] of 64 patients) occurring at irregular intervals, and was most frequent and pronounced in ectopic cCS. Symptoms worsened in 87 (81%) of 108 patients during peaks and improved in 79 (74%) of 107 patients during troughs; 31 (28%) of 110 patients had spontaneous adrenal insufficiency. Bilateral inferior petrosal sinus sampling (BIPSS) was performed during troughs in 14 patients (18% of the 78 procedures done). Imaging missed tumours in 35 (32%) of the 110 patients, and nine (8%) underwent unwarranted surgeries at the wrong anatomical site due to misclassification. After 5·8 years (IQR 2·6-10·5) median follow-up, 55 (50%) of 110 patients had complete biochemical surgical remission, seven (6%) had spontaneous remission, 22 (20%) were medically controlled, six (5%) had partial remission, 11 (10%) remained uncontrolled, nine (8%) were lost to follow-up. During the entire observation period, 3% (3/110) died. Delayed diagnosis (45 [41%] of 110 patients) and therapy (47 [43%]) were also observed. INTERPRETATION:Even in specialised centres, cCS diagnosis and management remain challenging with high rates of spontaneous adrenal insufficiency, inappropriate surgeries, and poor outcomes. Ectopic cCS showed the most frequent and severe peaks. These findings might help to guide imaging localisations or the timing of BIPSS in patients with active occult ACTH-dependent cCS. Hypercortisolism needs to be biochemically confirmed before BIPSS to enable correct tumour localisation. Patients with suspected or proven cCS should be equipped with salivary cortisol collection kits to capture dynamic changes as well as being prescribed glucocorticoids to be used as a precaution. FUNDING:None.

Die Choosing-Wisely-Initiative wurde im Jahr 2012 gegründet und verfolgt das Ziel, eine Überversorgung in der Medizin zu reduzieren, um so das Allgemeinwohl zu fördern. Die Österreichische Gesellschaft für Endokrinologie und Stoffwechsel (ÖGES) hat in Zusammenarbeit mit dem Institut für Allgemeinmedizin und evidenzbasierte Versorgungsforschung der Medizinischen Universität Graz fünf Choosing-Wisely-Empfehlungen auf dem Gebiet der Endokrinologie veröffentlicht, die in diesem Artikel vorgestellt und diskutiert werden. Diese Empfehlungen lauten wie folgt: 1. „Keine Behandlung mit L‑Thyroxin bei Knoten in der Schilddrüse, außer in ausgewählten Fällen.“ 2. „Zu häufige Knochendichtemessungen vermeiden: Intervalle von weniger als 2 Jahren sind selten notwendig.“ 3. „Keine Testosterontherapie bei älteren Männern außer in Fällen mit nachgewiesenem Hypogonadismus.“ 4. „Kein routinemäßiges Testen auf TPO-Antikörper.“ 5. „Keine routinemäßige Schilddrüsensonographie ohne Anzeichen/Symptome einer Schilddrüsenerkrankung, außer bei Risikopersonen für Schilddrüsenkrebs. Bei Knoten mit geringem Risiko die Indikation/Durchführung von Feinnadelaspirationen einschränken.“ Ressourcen, die in einem Bereich des Gesundheitssystems unnötig verbraucht werden, fehlen in anderen Bereichen, weswegen es eine wichtige ethische Verantwortung ist, zum Wohle der Allgemeinheit eine unnötige Überdiagnostik und Übertherapie zu minimieren.

Objective:Characterize disease-specific mortality rates in patients with acromegaly on pegvisomant and identify pertinent risk factors, including on-therapy insulin-like growth factor I (IGF-I) levels. Design:Retrospective cohort analysis of ACROSTUDY, a global surveillance study of patients with acromegaly receiving pegvisomant. Methods:Cumulative incidence function to estimate disease-specific mortality and regression analyses to characterize risk factors. Disease-specific standardized mortality rates (SMR) were calculated; Poisson regression models characterized the association between disease-specific SMR, IGF-I, and other risk factors. Results:2077 patients were followed (median: 4.1 years). Mortality (HR,95% CI) secondary to cardiovascular/cerebrovascular causes increased with higher on-treatment IGF-I (1.97 [1.45-2.67], P<.0001) and older age at enrollment (1.10 [1.07-1.13], P<.0001). Mortality secondary to malignant (1.57 [1.17-2.09), P=.0024) or respiratory (1.64 [1.23-2.19], P=.0008) causes increased with higher on-treatment IGF-I. Younger attained age (0.93 [0.91-0.96], P<.0001), younger age (<35 vs >50 years) at diagnosis (3.64 [1.33-9.93], P=.0117), higher on-treatment IGF-I (1.69 [1.12-2.55], P=.0127), and pituitary radiotherapy (2.25 [1.09-4.63], P=.0280) were associated with higher SMR (95% CI) for cardiovascular/cerebrovascular causes. Younger attained age (0.93 [0.89-0.96], P<.0001], higher IGF-I at enrollment (>2x vs <1x upper limit of normal: 4.89 [1.09-21.8], P=.0378), and malignancy at enrollment (7.05 [2.36-21.03], P=.0005) were associated with higher SMR (95% CI) for malignant causes. Younger age (35-50 vs >50 years) at diagnosis (4.50 [1.08-18.83], P=.0394) and sleep apnea (4.98 [1.34-18.53], P=.0168) were associated with higher SMR ratios for respiratory causes. Conclusions:Younger age, higher on-therapy IGF-I and radiotherapy were associated with higher SMR for cardiovascular/cerebrovascular causes, highlighting the importance of achieving IGF-I normalization.

OBJECTIVE:Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is an autosomal recessive disease mostly caused by compound heterozygous pathogenic CYP21A2 variants. CYP21A2 promoter analysis is frequently not included in routine diagnostics, but could explain discrepancies in the usually good genotype-phenotype correlation. Here we investigate frequency and type of CYP21A2 promoter variants and their influence on 21-OHD phenotype. DESIGN:Observational cohort study in a tertiary referral center and accredited genetic laboratory. METHODS:CYP21A2 genotyping including promoter analysis was performed and clinical/biochemical parameters were retrospectively collected in 1279 individuals undergoing routine diagnostic CYP21A2 genotyping. RESULTS:We detected promoter variants in 89 individuals (7.0%). Of 207 patients with 21-OHD, 12.1% had promoter variants. A large conversion including the promoter (c.-126C>T, c.-113G>A, c.-110T>C, c.-103A>G) and p.(Pro31Leu) in exon 1 was found in 21 patients and led to a mostly simply virilizing phenotype when occurring in trans with another classic allele. Promoter variants were observed in CAH patients with only 1 known pathogenic variant (n = 4) and in clinically unaffected individuals with no other CYP21A2 variant (n = 6); conventional sequencing without the promoter region would not have suggested CAH or 21-OHD carrier status in these individuals (n = 10). CONCLUSIONS:Non-benign promoter variants occur frequently in individuals with 21-OHD and clinically unaffected carriers. Promoter variants can aggravate clinical presentation in 21-OHD and can explain cases with discrepant genotype and phenotype. Inclusion of CYP21A2 promoter analysis in diagnostic procedures can improve accuracy of diagnosis, management and genetic counseling in patients with 21-OHD and their families.

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