Disease control of acromegaly does not prevent excess mortality in the long term: results of a nationwide survey in Italy.

OBJECTIVE: This study aimed to assess the long-term outcome of patients with acromegaly. DESIGN: This is a multicenter, retrospective, observational study which extends the mean observation period of a previously reported cohort of Italian patients with acromegaly to 15 years of follow-up. METHODS: Only patients from the centers that provided information on the life status of at least 95% of their original cohorts were included. Life status information was collected either from clinical records or from the municipal registry offices. Standardized mortality ratios (SMRs) were computed comparing data with those of the general Italian population. RESULTS: A total of 811 patients were included. There were 153 deaths, with 90 expected and an SMR of 1.7 (95% CI 1.4-2.0, p < 0.001). Death occurred after a median of 15 (women) or 16 (men) years from the diagnosis, without gender differences. Mortality remained elevated in the patients with control of disease (SMR 1.3, 95% CI 1.1-1.6). In the multivariable analysis, only older age and high IGF1 concentrations at last available follow-up visit were predictors of mortality. The oncological causes of death outweighed the cardiovascular ones, bordering on statistical significance with respect to the general population. CONCLUSIONS: Mortality remains significantly high in patients with acromegaly, irrespectively of disease status, as long as the follow-up is sufficiently long with a low rate of patients lost to follow-up. Therapy strategy including radiotherapy does not have an impact on mortality. Oncological causes of death currently outweigh the cardiovascular causes.

Paradoxical GH increase after oral glucose load in subjects with and without acromegaly.

OBJECTIVE: A paradoxical GH rise after the glucose load (GH-Par) is described in about one-third of acromegalic patients. Here, we evaluated the GH profile in subjects with and without acromegaly aiming to refine the definition of GH-Par. DESIGN: Observational case-control study. METHODS: Our cohort consisted of 60 acromegalic patients, and two groups of subjects presenting suppressed GH (< 0.4 µg/L) and high (non-acro↑IGF-1, n = 116) or normal IGF-1 levels (non-acro, n = 55). The distribution of GH peaks ≥ 120% from baseline, insulin, and glucose levels were evaluated over a 180-min time interval after glucose intake. RESULTS: A similar proportion of subjects in all three groups shows a GH ratio of ≥ 120% starting from 120 min. Re-considering the definition of paradoxical increase of GH within 90 min, we observed that the prevalence of GH peaks ≥ 120% was higher in acromegaly than in non-acro↑IGF-1 and non-acro (respectively 42%, 16%, and 7%, both p < 0.001). In patients without GH-Par, a late GH rebound was observed in the second part of the curve. Higher glucose peak (p = 0.038), slower decline after load, 20% higher glucose exposure (p = 0.015), and a higher prevalence of diabetes (p = 0.003) characterized acromegalic patients with GH-Par (with respect to those without). CONCLUSIONS: GH-Par response may be defined as a 20% increase in the first 90 min after glucose challenge. GH-Par, common in acromegaly and associated with an increased prevalence of glucose metabolism abnormalities, is found also in a subset of non-acromegalic subjects with high IGF-1 levels, suggesting its possible involvement in the early phase of the disease.

Corticotropin-releasing hormone test predicts the outcome of unilateral adrenalectomy in primary bilateral macronodular adrenal hyperplasia.

PURPOSE: Primary bilateral adrenal hyperplasia (PBMAH) is associated with hypercortisolism and a heterogeneous clinical expression in terms of cortisol secretion and related comorbidities. Historically, treatment of choice was bilateral adrenalectomy (B-Adx); however, recent data suggest that unilateral adrenalectomy (U-Adx) may be an effective alternative. For the latter, factors predicting the postsurgical outcome (e.g., biochemical control) have not been identified yet. METHODS: PBMAH patients undergoing U-Adx for overt Cushing's syndrome (CS) in two tertiary care centers were retrospectively analysed. Remission was defined as a normalization of urinary free cortisol (UFC) without the need for medical treatment. The potential of hCRH test as a predictor of U-Adx outcome was evaluated in a subgroup. RESULTS: 23 patients were evaluated (69% females, mean age 55 years). Remission rate after U-Adx was 74% at last follow up (median 115 months from UAdx). Before U-Adx, a positive ACTH response to hCRH (Δ%ACTH increase > 50% from baseline) was associated with higher remission rates. CONCLUSIONS: Three of four patients with PBMAH are surgically cured with U-Adx. Pre-operative hCRH testing can be useful to predict long-term remission rates.

Second-line tests in the differential diagnosis of neoplastic and non-neoplastic hypercortisolism: a systematic review and meta-analysis.

PURPOSE: The clinical and hormonal overlap between neoplastic (CS) and non-neoplastic (NNH/pCS) hypercortisolism is a challenge. Various dynamic tests have been proposed to allow an early discrimination between these conditions, but to date there is no agreement on which of them should be used. AIM: To provide an overview of the available tests and to obtain a quantitative synthesis of their diagnostic performance in discriminating NNH/pCS from CS. METHODS: The included articles, published between 1990 and 2022, applied one or more second line tests to differentiate NNH/pCS from CS patients. For the NNH/pCS group, we admitted the inclusion of patients presenting clinical features and/or biochemical findings suggestive of hypercortisolism despite apparent lack of a pCS-related condition. RESULTS: The electronic search identified 339 articles. After references analysis and study selection, we identified 9 studies on combined dexamethasone-corticotropin releasing hormone (Dex-CRH) test, 4 on Desmopressin test and 3 on CRH test; no study on Dex-Desmopressin met the inclusion criteria. Dex-CRH test provided the highest sensitivity (97%, 95 CI% [88%; 99%]). CRH tests showed excellent specificity (99%, 95% CI [0%; 100%]), with low sensitivity. Although metaregression analysis based on diagnostic odds ratio failed to provide a gold standard, CRH test (64.77, 95% CI [0.15; 27,174.73]) seemed to lack in performance compared to the others (Dex-CRH 138.83, 95% CI [49.38; 390.32] and Desmopressin 110.44, 95% CI [32.13; 379.63]). DISCUSSION: Both Dex-CRH and Desmopressin tests can be valid tools in helping discrimination between NNH/pCS and CS. Further studies are needed on this topic, possibly focusing on mild Cushing's Disease and well-characterized NNH/pCS patients. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022359774 , identifier CRD42022359774.

Renin and electrolytes indicate the mineralocorticoid activity of fludrocortisone: a 6 year study in primary adrenal insufficiency.

CONTEXT: Fludrocortisone (FC) is the mineralocorticoid (MC) replacement treatment for patients with primary adrenal insufficiency (PAI). OBJECTIVE: To explore the dose of FC treatment and its relationship with glucocorticoid therapy, sodium, potassium, renin and clinical parameters. SETTING: Monocentric cohort. PATIENTS: Data of 193 patients with PAI (130 autoimmune) were collected during baseline (T0), intermediate (T1) and last follow-up visit (T2, respectively, after a mean of 38 and 72 months). MAIN OUTCOME MEASURE: Utility of endocrine and clinical parameters to titrate FC dose. RESULTS: FC dose (50-75 µg/daily) was stable in the follow-up in half patients. The MC activity of FC was dose-dependent: we observed a reduced but significant positive linear correlation between FC dose and sodium (r = 0.132) and negative linear correlation between FC and potassium (r = - 0.162) or renin (r = - 0.131, all p < 0.01). An overall reduction in the FC dose was observed at T2 in the group with longer follow-up (> 60 months, p < 0.05). Higher doses of FC were observed in patients with low-normal renin, especially in autoimmune PAI (86 vs 65 µg/daily, p < 0.05). On the contrary, reduced sodium and increased potassium levels were observed in patients with high renin at T2. The number of cardiovascular events (15 in the whole cohort) was similar in patients sorted by renin levels or FC dose. CONCLUSIONS: Renin and electrolytes can indicate the MC activity of FC treatment: they should be routinely evaluated and used to titrate its dose that can be reduced in the long-term follow-up.

Indication to dynamic and invasive testing in Cushing's disease according to different neuroradiological findings.

PURPOSE: Dynamic testing represents the mainstay in the differential diagnosis of ACTH-dependent Cushing's syndrome. However, in case of undetectable or detectable lesion < 6 mm on MRI, bilateral inferior petrosal sinus sampling (BIPSS) is suggested by current guidelines. Aim of this study was to analyze the performance of CRH, desmopressin and high-dose dexamethasone suppression test (HDDST) in the differential diagnosis of ACTH-dependent Cushing's syndrome as well as the impact of invasive and noninvasive tests on surgical outcome in patients affected by Cushing's disease (CD). METHODS: Retrospective analysis on 148 patients with CD and 26 patients with ectopic ACTH syndrome. RESULTS: Among CD patients, negative MRI/lesion < 6 mm was detected in 97 patients (Group A); 29 had a 6-10 mm lesion (Group B) and 22 a macroadenoma (Group C). A positive response to CRH test, HDSST and desmopressin test was recorded in 89.4%, 91·4% and 70.1% of cases, respectively. Concordant positive response to both CRH/HDDST and CRH/desmopressin tests showed a positive predictive value of 100% for the diagnosis of CD. Among Group A patients with concordant CRH test and HDDST, no difference in surgical outcome was found between patients who performed BIPSS and those who did not (66.6% vs 70.4%, p = 0.78). CONCLUSIONS: CRH, desmopressin test and HDDST have high accuracy in the differential diagnosis of ACTH-dependent CS. In patients with microadenoma < 6 mm or non-visible lesion, a concordant positive response to noninvasive tests seems sufficient to diagnose CD, irrespective of MRI finding. In these patients, BIPSS should be reserved to discordant tests.

Frequently asked questions and answers (if any) in patients with adrenal incidentaloma.

PURPOSE: Adrenal incidentalomas (AIs) are incidentally discovered adrenal masses, during an imaging study undertaken for other reasons than the suspicion of adrenal disease. Their management is not a minor concern for patients and health-care related costs, since their increasing prevalence in the aging population. The exclusion of malignancy is the first question to attempt, then a careful evaluation of adrenal hormones is suggested. Surgery should be considered in case of overt secretion (primary aldosteronism, adrenal Cushing's Syndrome or pheochromocytoma), however the management of subclinical secretion is still a matter of debate. METHODS: The aim of the present narrative review is to offer a practical guidance regarding the management of AI, by providing evidence-based answers to frequently asked questions. CONCLUSION: The clinical experience is of utmost importance: a personalized diagnostic-therapeutic approach, based upon multidisciplinary discussion, is suggested.

Radiomics: a new tool to differentiate adrenocortical adenoma from carcinoma.

BACKGROUND: The main challenge in the management of indeterminate incidentally discovered adrenal tumours is to differentiate benign from malignant lesions. In the absence of clear signs of invasion or metastases, imaging techniques do not always precisely define the nature of the mass. The present pilot study aimed to determine whether radiomics may predict malignancy in adrenocortical tumours. METHODS: CT images in unenhanced, arterial, and venous phases from 19 patients who had undergone resection of adrenocortical tumours and a cohort who had undergone surveillance for at least 5 years for incidentalomas were reviewed. A volume of interest was drawn for each lesion using dedicated software, and, for each phase, first-order (histogram) and second-order (grey-level colour matrix and run-length matrix) radiological features were extracted. Data were revised by an unsupervised machine learning approach using the K-means clustering technique. RESULTS: Of operated patients, nine had non-functional adenoma and 10 carcinoma. There were 11 patients in the surveillance group. Two first-order features in unenhanced CT and one in arterial CT, and 14 second-order parameters in unenhanced and venous CT and 10 second-order features in arterial CT, were able to differentiate adrenocortical carcinoma from adenoma (P < 0.050). After excluding two malignant outliers, the unsupervised machine learning approach correctly predicted malignancy in seven of eight adrenocortical carcinomas in all phases. CONCLUSION: Radiomics with CT texture analysis was able to discriminate malignant from benign adrenocortical tumours, even by an unsupervised machine learning approach, in nearly all patients.

What we have to know about corticosteroids use during Sars-Cov-2 infection.

PURPOSE: Glucocorticoids (GCs), alone or associated to other drugs, were widely used in the management of patients affected by severe acute respiratory syndrome caused by SARS-CoV-2 infection, during the recent COVID-19 outbreak. This review summarizes the available data on HPA axis impairment in GC-treated SARS-CoV-2 patients, focusing on the risk of adrenal insufficiency and on potential drug interactions during concomitant treatments. METHODS: Literature on the impact of GCs therapy on HPA axis and on the consequences of coadministration of GCs and other drugs in SARS-CoV-2 patients has been reviewed. RESULTS: GC treatment can cause symptoms of hypercortisolism, especially in patients with individual hypersensibility, or hypoadrenalism after drug withdrawal, due to hypothalamic-pituitary-adrenal (HPA) axis suppression, with consequences in terms of increased morbidity and mortality risk. On the other hand, in SARS-CoV-2-infected patient's cortisol secretion could be insufficient also due to critical illness-related corticosteroid insufficiency (CIRCI). In addition, in this clinical context, the co-administration of antiretroviral drugs and corticosteroids may trigger drug-drug interaction and enhance the exposure to the latter ones, metabolized through the CYP450 CYP3A pathway, severely impacting on HPA axis. CONCLUSION: Physicians involved in the management of patients affected by COVID-19 should be aware of the need of an appropriate GC dose tapering, and of potential interaction of GCs with antiviral therapy and drugs used to treat associated co-morbidities.

Tele-medicine versus face-to-face consultation in Endocrine Outpatients Clinic during COVID-19 outbreak: a single-center experience during the lockdown period.

CONTEXT: The COVID-19 outbreak in Italy is the major concern of Public Health in 2020: measures of containment were progressively expanded, limiting Outpatients' visit. OBJECTIVE: We have developed and applied an emergency plan, tailored for Outpatients with endocrine diseases. DESIGN: Cross-sectional study from March to May 2020. SETTING: Referral University-Hospital center. PATIENTS: 1262 patients in 8 weeks. INTERVENTIONS: The emergency plan is based upon the endocrine triage, the stay-safe procedures and the tele-Endo. During endocrine triage every patient was contacted by phone to assess health status and define if the visit will be performed face-to-face (F2F) or by tele-Medicine (tele-Endo). In case of F2F, targeted stay-safe procedures have been adopted. Tele-Endo, performed by phone and email, is dedicated to COVID-19-infected patients, to elderly or frail people, or to those with a stable disease. MAIN OUTCOME MEASURE: To assess efficacy of the emergency plan to continue the follow-up of Outpatients. RESULTS: The number of visits cancelled after endocrine triage (9%) is lower than that cancelled independently by the patients (37%, p < 0.001); the latter reduced from 47 to 19% during the weeks of lockdown (p = 0.032). 86% of patients contacted by endocrine-triage received a clinical response (F2F and tele-Endo visits). F2F visit was offered especially to young patients; tele-Endo was applied to 63% of geriatric patients (p < 0.001), visits' outcome was similar between young and aged patients. CONCLUSIONS: The emergency plan respects the WHO recommendations to limit viral spread and is useful to continue follow-up for outpatients with endocrine diseases.

Dexamethasone measurement during low-dose suppression test for suspected hypercortisolism: threshold development with and validation.

BACKGROUND AND AIM: Dexamethasone Suppression Test (DST), recommended for Cushing's Syndrome (CS) diagnosis, explores the pituitary feedback to glucocorticoids. Its diagnostic accuracy could be affected by dexamethasone bioavailability, and therefore, we have developed and validated a dexamethasone threshold after 1-mg DST. MATERIALS AND METHODS: We studied 200 subjects: 125 patients were considered retrospectively and 75 were enrolled prospectively as the validation cohort. Serum dexamethasone, Late Night Salivary Cortisol (LNSC), and Urinary Free Cortisol (UFC) were measured with LC-MS/MS. Normal LNSC and UFC levels were used to exclude CS. The lower 2.5th percentile of dexamethasone distribution in non-CS patients with cortisol ≤ 50 nmol/L after 1-mg DST was used as threshold. RESULTS: 16 patients were CS and 184 non-CS (108 adrenal incidentaloma and 76 excluded CS); 4.5 nmol/L resulted the calculated threshold. Cortisol after 1-mg DST confirmed high sensitivity (100% at 50 nmol/L cut-off) and moderate-low specificity (63%, increased to 91% at 138 nmol/L) to diagnose CS in the whole cohort of patients. We could reduce the number of false-positive results (from 10 to 6 and from 7 to 4 in AI and excluded CS) considering adequate dexamethasone levels. Dexamethasone levels were not affected by hypercortisolism, age, gender, smoke, weight, and creatinine. 6% of non-CS patients did not achieve adequate dexamethasone levels (40% of tests with serum cortisol > 138 nmol/L after 1-mg DST). CONCLUSIONS: We developed and validated the routine dexamethasone measurement during 1-mg DST: it is independent from patient's clinical presentation, and it should be used to increase the specificity of serum cortisol levels.

The haemostatic system in acromegaly: a single-centre case-control study.

PURPOSE: Although the mortality from acromegaly is due in most cases to an increased cardiovascular risk, no study has globally evaluated the haemostatic balance in acromegaly to ascertain the presence of hypercoagulability. We endeavoured to assess the overall coagulation profile in patients with acromegaly using both traditional and global coagulation assays. METHODS: Consecutive outpatients with a diagnosis of acromegaly were enrolled and matched with healthy subjects. Whole blood thromboelastometry and impedance aggregometry, procoagulant, anticoagulant and fibrinolytic factors, as well as thrombin-generation assay and circulating endothelium-derived microvesicles were measured. RESULTS: Forty patients (M/F 14/26, median age 59 years) with either new diagnosis (naïve, 14 cases) or treated acromegaly (26 cases) were enrolled in this study. Median time from diagnosis was 11 years. Levels of factor VIII and fibrinogen were significantly higher in acromegalic patients vs. controls (p = 0.029 and < 0.003, respectively). Overall, thromboelastometry parameters showed a faster coagulation formation with a more stable clot. Acromegaly patients showed significantly higher endogenous thrombin potential [ETP] and thrombin peak compared to controls (p = 0.016 and p < 0.001, respectively). ETP remained significantly higher (p < 0.001) when thrombomodulin was added. Endothelial-derived microvesicles were significantly higher in acromegaly patients than controls (52 [40.5-67] MVs/µL and 30 [18-80] MVs/µL, p = 0.03). Patients with untreated (naïve) acromegaly showed significantly reduced ETP with and without thrombomodulin vs. patients with treated acromegaly (p = 0.01). CONCLUSION: Hypercoagulability in acromegaly is mainly due to higher levels of fibrinogen, factor VIII and thrombin generation, and appears to be more linked to the chronic phase of the disease.

Perioperative multidisciplinary management of endoscopic transsphenoidal surgery for sellar lesions: practical suggestions from the Padova model.

Perioperative management of patients with sellar lesion submitted to endoscopic transsphenoidal neurosurgery (TSS) lacks standardization and therefore it is committed to each center clinical practice. Although neurosurgical procedure remains the same for all sellar lesions, perioperative approach can require different measures depending on the underlying disease. With the aim of standardizing our perioperative procedures and sharing our experience with other centers involved in the management of pituitary disease, we developed a clinical care path for patients with sellar lesions candidate to endoscopic TSS. For the drafting of the following protocol, the national and international guidelines published in the last 5 years have been evaluated and integrated with our center experience accumulated in decades of clinical practice. A steering committee including medical doctors involved in management of patients with pituitary masses at the Padua Hospital reviewed current knowledge on this topic. The committee developed a first draft which was shared with a broader group of medical doctors to reach a preliminary consensus; when it was reached, the clinical care assistance pathway was confirmed, validated, and published in the local web-based health service. We want to present and share our experience with colleagues involved in the perioperative management of pituitary diseases in other centers.

The diagnostic accuracy of increased late night salivary cortisol for Cushing's syndrome: a real-life prospective study.

INTRODUCTION AND AIM: A prompt diagnosis of Cushing's Syndrome (CS) in high-risk populations is mandatory: 1-mg dexamethasone suppression test (1-mg DST), late night salivary cortisol (LNSC), and urinary-free cortisol (UFC) are recommended, despite thresholds calculated in retrospective studies. Our aim was to study the diagnostic accuracy of LNSC measured with chemiluminescence assay in a prospective study, confirming discrepancies with mass spectrometry (MS). MATERIALS AND METHODS: We enrolled 117 controls and 164 suspected CS (CS = 47, non-CS = 117). In case of increased LNSC, high clinical suspicion of CS or adrenal incidentaloma, patients were hospitalized to exclude/confirm CS. RESULTS: LNSC levels were higher in patients with suspected CS, CS, and non-CS than controls. Considering 16 nmol/L as threshold for CS, overall LNSC revealed SE 97% and SP 84% in the whole group of subjects considered, achieving positive/negative likelihood ratio of 5.56/0.045, respectively. 35 out of 81 subjects with increased LNSC were non-CS (15 diabetic and 20 obese): considering only those patients with increased likelihood to have a CS (the non-CS patients) SP decreased to 70%, and further reduced to 60% if we discharged subjects with adrenal incidentaloma. MS analyses reduced partially the number of false-positive LNSC. CONCLUSIONS: LNSC measured in automated chemiluminescence is reliable in clinical practice: it present a high diagnostic accuracy to exclude hypercortisolism in patients with normal cortisol levels. MS could be used to reduce the number of false-positive results; nevertheless, some non-CS subjects with functional hypercortisolism could have a mild impairment of cortisol rhythm.

First-line screening tests for Cushing's syndrome in patients with adrenal incidentaloma: the role of urinary free cortisol measured by LC-MS/MS.

INTRODUCTION AND AIM: Patients with adrenal incidentaloma present a wide range of cortisol secretion, which is not always properly defined by first-line screening tests recommended to rule out Cushing's syndrome (CS), such as 1-mg dexamethasone suppression test (1-mg DST), late night salivary cortisol (LNSC), or 24-h urinary free cortisol (UFC). Therefore, we examined the diagnostic performance of each screening test in patients with adrenal incidentaloma. MATERIALS AND METHODS: In a series of 164 consecutive patients with adrenal incidentaloma, we measured serum cortisol after 1-mg DST, LNSC, and UFC (with LC-MS/MS). Medical history was investigated for cardiovascular events (CVE) in a subgroup of 93 patients with at least 2 years of follow-up. RESULTS: Serum cortisol <50 nmol/L after 1-mg DST presented the highest sensitivity (100%) to rule out CS, despite a low specificity (62%). UFC > 170 nmol/24 h achieved the highest diagnostic accuracy (sensitivity 98%, specificity 91%, and negative/positive likelihood ratios of 0.02/10.83, respectively). The prevalence of CVE was higher in patients with non-suppressed cortisol after 1-mg DST and high UFC levels (p = 0.018). Traditional cardiovascular risk factors (hypertension, diabetes mellitus, dyslipidemia, BMI > 30 kg/m2, smoke or high gender-based waist circumference) were not associated with CVE. CONCLUSIONS: The 1-mg DST at its lowest threshold presented high sensitivity in identifying CS, but its low specificity encourages us to consider UFC levels, measured with LC-MS/MS, to reduce false-positive test results. High UFC levels could also be considered as markers to stratify cardiovascular risk in patients with adrenal incidentaloma.

The GIP/GIPR axis is functionally linked to GH-secretion increase in a significant proportion of gsp- somatotropinomas.

OBJECTIVE: Glucose-dependent insulinotropic polypeptide receptor (GIPR) overexpression has been recently described in a proportion of gsp- somatotropinomas and suggested to be associated with the paradoxical increase of GH (GH-PI) during an oral glucose load. DESIGN AND METHODS: This study was aimed at linking the GIP/GIPR pathway to GH secretion in 25 somatotropinomas-derived primary cultures and correlating molecular with clinical features in acromegalic patients. Given the impairment of the GIP/GIPR axis in acromegaly, an additional aim was to assess the effect of GH/IGF-1 stimulation on GIP expression in the enteroendocrine cell line STC-1. RESULTS: Nearly 80% of GIPR-expressing somatotropinomas, all of them negative for gsp mutations, show increased GH secretion upon GIP stimulation, higher sensitivity to Forskolin but not to somatostatin analogs. Besides increased frequency of GH-PI, GIPR overexpression does not appear to affect acromegalic patients' clinical features. In STC-1 cells transfected with GIP promoter-driven luciferase vector, IGF-1 but not GH induced dose-dependent increase in luciferase activity. CONCLUSIONS: We demonstrate that GIPR mediates the GH-PI in a significant proportion of gsp- acromegalic patients. In these cases, the stimulatory effect of IGF-1 on GIP promoter support the hypothesis of a functional GH/IGF-1/GIP axis. Further studies based on larger cohorts and the development of a stable transgenic model with inducible GIPR overexpression targeted to pituitary somatotroph lineage will be mandatory to establish the real role of GIPR in the pathogenesis of somatotropinomas.

A multicenter experience on the prevalence of ARMC5 mutations in patients with primary bilateral macronodular adrenal hyperplasia: from genetic characterization to clinical phenotype.

ARMC5 mutations have recently been identified as a common genetic cause of primary bilateral macronodular adrenal hyperplasia (PBMAH). We aimed to assess the prevalence of ARMC5 germline mutations and correlate genotype with phenotype in a large cohort of PBMAH patients. A multicenter study was performed, collecting patients from different endocrinology units in Italy. Seventy-one PBMAH patients were screened for small mutations and large rearrangements in the ARMC5 gene: 53 were cortisol-secreting (two with a family history of adrenal hyperplasia) and 18 were non-secreting cases of PBMAH. Non-mutated and mutated patients' clinical phenotypes were compared and related to the type of mutation. A likely causative germline ARMC5 mutation was only identified in cortisol-secreting PBMAH patients (one with a family history of adrenal hyperplasia and ten apparently sporadic cases). Screening in eight first-degree relatives of three index cases revealed four carriers of an ARMC5 mutation. Evidence of a second hit at somatic level was identified in five nodules. Mutated patients had higher cortisol levels (p = 0.062), and more severe hypertension and diabetes (p < 0.05). Adrenal glands were significantly larger, with a multinodular phenotype, in the mutant group (p < 0.01). No correlation emerged between type of mutation and clinical parameters. ARMC5 mutations are frequent in cortisol-secreting PBMAH and seem to be associated with a particular pattern of the adrenal masses. Their identification may have implications for the clinical care of PBMAH cases and their relatives.

Medical Treatment for Acromegaly does not Increase the Risk of Central Adrenal Insufficiency: A Long-Term Follow-Up Study.

Central adrenal insufficiency (CAI) in acromegaly may be related to pituitary adenoma or induced by various medical treatments, transsphenoidal neurosurgery (TNS) or radiotherapy (RT), alone or combined. We assessed the role of all available treatments for acromegaly in inducing CAI. We retrospectively studied 97 patients. CAI was diagnosed if morning serum cortisol was <138 nmol/l, or if its response was inadequate in the low-dose short synacthen test. Seventy-four subjects underwent TNS (and 17 of whom also underwent RT), and 23 were on primary medical therapy: overall we diagnosed 21 cases of CAI. Duration of acromegaly, invasion of cavernous sinus, disease control, and type of medical treatment were much the same for patients with and without CAI, which was identified in 18% of patients (10/57) after one TNS, and in 53% (9/17) after RT (p=0.01); repeat surgery increased the risk of CAI (p=0.02). The risk of CAI onset during the follow-up was lower among patients treated with TNS or medical therapy than after RT (p=0.035). Medical treatment did not raise the risk of CAI, whereas a 5- and 4-fold higher risk of CAI was associated with repeat TNS and RT, respectively. Basal or stimulated cortisol levels were similar among acromegalic patients without CAI and matched controls with nonsecreting pituitary lesions. A significant proportion of patients with acromegaly developed CAI over time. While primary or secondary medical treatment did not contribute to the risk of CAI, repeat TNS and RT correlated with pituitary-adrenal axis impairment.