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Background Many patients with Cushing’s disease (CD) require long-term medical therapy to control their hypercortisolism. In the core phase of a Phase II study (LINC 2; NCT01331239), osilodrostat normalized mean urinary free cortisol (mUFC) in 78.9% of patients with CD. Here, we report long-term efficacy and safety data for osilodrostat following completion of an optional extension to LINC 2. Methods Adult patients with CD were enrolled in a 22-week prospective Phase II study. Patients with mUFC ≤ upper limit of normal (ULN) or receiving clinical benefit at week 22 could enter the optional extension. The proportion of complete (mUFC ≤ ULN) or partial (mUFC > ULN but ≥ 50% decrease from baseline) mUFC responders was assessed over time. Results Sixteen of 19 enrolled patients entered the extension. Median (range) osilodrostat exposure from baseline to study end was 5.4 years (0.04–6.7); median (range) average dose was 10.6 mg/day (1.1–47.9). Overall response rate (complete and partial mUFC responders) was consistently ≥ 50%. Sustained control of most cardiovascular-related parameters was observed during the extension. The long-term safety profile was consistent with that reported during the core phase. Testosterone levels (females) decreased towards baseline levels during long-term follow-up, with no new or worsening cases of hirsutism during the extension. Conclusions In the longest prospective study of a steroidogenesis inhibitor to date, osilodrostat provided sustained reductions in mUFC for up to 6.7 years of treatment, with no new safety signals emerging during the extension. These findings support osilodrostat as an effective long-term treatment for patients with CD.

Acromegaly is a rare pathology characterized by chronic hypersecretion of Growth Hormone (GH) and Insulin-like Growth Factor-1 (IGF-1) that causes somatic, metabolic, and systemic changes. The somatotropic axis acts physiologically favoring gonadal function, but when GH is produced in excess it has deleterious effects on many aspects of male sexuality. It is widely demonstrated, in fact, that acromegaly induces hypogonadism through different mechanisms, both through direct mass effect on gonadotropic cells and through increased plasma levels of prolactin. Moreover, hypogonadism is also one of the factors linking acromegaly to erectile dysfunction (ED), but also metabolic complications of acromegaly and, probably, GH itself contribute to the genesis of this disorder. There are few data in the literature on the impact of the disease on fertility and testicular volume. Finally, knowledge of the role of GH hypersecretion on the occurrence of prostatic diseases such as benign prostatic hypertrophy and prostatic cancer appears to be of fundamental clinical importance in the long-term management of these patients.

Objective Dysnatremia is common in hospitalized patients, often worsening the prognosis in pneumopathies and critical illnesses. Information on coronavirus disease-19 (COVID-19)-related hyponatremia is partially conflicting, whereas data on hypernatremia in this context are scarce. We assessed, in a cohort of COVID-19 inpatients: the prevalence of sodium alterations at admission and throughout their hospitalization; their association with inflammation/organ damage indexes; their short-term prognostic impact. Study design and methods 117 patients (81 males, 64 ± 13 years) hospitalized for COVID-19 between 1 March and 30 April 2020 were retrospectively followed-up for their first 21 days of stay by collecting all serum sodium measurements, basal CRP and serum lactate levels, maximum IL-6 and information on care setting, required ventilation, length of hospitalization, in-hospital death. Results At admission, 26.5% patients had hyponatremia, and 6.8% had hypernatremia. During their hospitalization, 13.7% patients experienced both disorders ('mixed dysnatremia'). Lower sodium levels at admission were correlated with higher C reactive protein (CRP) (P = 0.039) and serum lactate levels (P = 0.019), but not interleukin-6 (IL-6). Hypernatremia and a wider sodium variability were associated with maximum required ventilation, need for ICU assistance and duration of the hospitalization. Mean estimated time to Intensive Care Unit (ICU) admission was 20 days shorter in patients exposed to sodium alterations at any time of their hospital course (log-rank test P = 0.032). Conclusions Sodium alterations frequently affect hospitalized COVID-19 patients. Hyponatremia could indicate pulmonary involvement, whereas hypernatremia is associated to prolonged hospitalization and the need for intensive care/mechanical ventilation, particularly when resulting from prior hyponatremia. Optimizing in-hospital sodium balance is crucial to improve patients’ prognosis.

SommarioL’ipercortisolismo funzionale rappresenta una condizione di attivazione cronica dell’asse ipotalamo-ipofisi-surrene che si verifica in condizioni cliniche eterogenee (depressione e altri disordini psichici, disturbi del comportamento alimentare, diabete mellito, obesità, alcolismo, sindrome dell’ovaio policistico, sindrome delle apnee ostruttive notturne, lavoro a turni). Solitamente è un ipercortisolismo di lieve entità e reversibile alla remissione della condizione sottostante. Deve essere distinto dalla Sindrome di Cushing con la quale, però, condivide manifestazioni cliniche, alterazioni biochimiche e problematiche di diagnostica differenziale. Si può ipotizzare che l’ipercortisolismo funzionale abbia comunque un’azione deleteria tessuto-specifica. In questa rassegna verranno illustrati sinteticamente meccanismi ed effetti nocivi dell’ipercortisolismo funzionale.

The Coronavirus-19 (COVID-19) pandemic, which began in December 2019 in Wuhan, China, has spread rapidly worldwide, affecting mostly frail individuals and resulting in high lethality among people with chronic conditions. The management of chronic endocrine disorders during the pandemic period proved particularly challenging, as they require close physician-patient contact for proper long-term management. In addition, acute endocrinologic conditions that presented during the COVID-19 period required timely management in an unusual clinical setting, providing an ongoing challenge for clinicians. This article summarizes the most recent guidance on the management and therapy of frequent conditions such as diabetes and osteoporosis and less common endocrine disorders (e.g., adrenal insufficiency) in this setting.

The pandemic of coronavirus disease (COVID-19), a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is causing high and rapid morbidity and mortality. Immune system response plays a crucial role in controlling and resolving the viral infection. Exogenous or endogenous glucocorticoid excess is characterized by increased susceptibility to infections, due to impairment of the innate and adaptive immune system. In addition, diabetes, hypertension, obesity and thromboembolism are conditions overrepresented in patients with hypercortisolism. Thus patients with chronic glucocorticoid (GC) excess may be at high risk of developing COVID-19 infection with a severe clinical course. Care and control of all comorbidities should be one of the primary goals in patients with hypercortisolism requiring immediate and aggressive treatment. The European Society of Endocrinology (ESE), has recently commissioned an urgent clinical guidance document on management of Cushing’s syndrome in a COVID-19 period. In this review, we aim to discuss and expand some clinical points related to GC excess that may have an impact on COVID-19 infection, in terms of both contagion risk and clinical outcome. This document is addressed to all specialists who approach patients with endogenous or exogenous GC excess and COVID-19 infection.

Context Pathogenesis of autonomous steroid secretion and adrenocortical tumorigenesis remains partially obscure. Objective To investigate the relationship between transcriptome profile and genetic background in a large series of adrenocortical tumors and identify new potential pathogenetic mechanisms. Design Cross-sectional study. Setting University Hospitals of the European Network for the Study of Adrenal Tumors (ENSAT). Patients We collected snap-frozen tissue from patients with adrenocortical tumors (n = 59) with known genetic background: 26 adenomas with Cushing syndrome (CS- cortisol-producing adenoma [CPA]), 17 adenomas with mild autonomous cortisol secretion (MACS-CPAs), 9 endocrine-inactive adenomas (EIAs), and 7 adrenocortical carcinomas (ACCs). Intervention Ribonucleic acid (RNA) sequencing. Main Outcome Measures Gene expression, long noncoding RNA (lncRNA) expression, and gene fusions. Correlation with genetic background defined by targeted Sanger sequencing, targeted panel- or whole-exome sequencing. Results Transcriptome analysis identified 2 major clusters for adenomas: Cluster 1 (n = 32) mainly consisting of MACS-CPAs with CTNNB1 or without identified driver mutations (46.9% of cases) and 8/9 EIAs; Cluster 2 (n = 18) that comprised CP-CPAs with or without identified driver mutation in 83.3% of cases (including all CS-CPAs with PRKACA mutation). Two CS-CPAs, 1 with CTNNB1 and 1 with GNAS mutation, clustered separately and relatively close to ACC. lncRNA analysis well differentiate adenomas from ACCs. Novel gene fusions were found, including AKAP13-PDE8A in one CS-CPA sample with no driver mutation. Conclusions MACS-CPAs and EIAs showed a similar transcriptome profile, independently of the genetic background, whereas most CS-CPAs clustered together. Still unrevealed molecular alterations in the cAMP/PKA or Wnt/beta catenin pathways might be involved in the pathogenesis of adrenocortical tumors.

Pasireotide (PAS) is an effective treatment for Cushing's disease (CD) but its use is burdened by an associated high incidence of diabetes mellitus (DM). The aim of this study was to examine the effect of a single subcutaneous injection of PAS on glucose metabolism in CD, and to identify predictors of DM onset.Fifteen patients with CD (13 females, 2 males; median age 43 years [IQR 34-50]) were submitted to an acute PAS test (600 µg s.c.), measuring glucose, insulin, C-peptide, GIP, glucagon, GLP-1, ACTH, and cortisol at the baseline and every 30 min for 2 h. Then they were treated twice daily with PAS 600 µg, and followed up with clinical and hormone assessments for a median of 6 months [2-13].PAS prompted a significant decrease in all hormonal parameters considered except for glycemia, which increased (as expected), reaching the highest value at 120' (p 0.0001). Overall, 9/15 patients developed DM within 2 months of starting PAS therapy. There were no differences in age, weight, visceral adiposity, HOMA index, fasting glucose or severity of CD between patients who developed DM and those who did not. Baseline fasting glucagon levels were higher in the DM patients (17.95 [12.45-20.54] vs. 10.53 [8.11-12.33] pmol/L, p = 0.0256), and so were GIP and HbA1c levels (37 [5.5-39.5] vs. 29 [27-31.8] mmol/mol, p = 0.0008). Glucose at 120' was also significantly higher in the DM patients (9.5 [8.65-11.95] vs. 6.85 [4.48-9] mmol/L, p = 0.012).PAS was rapidly able to suppress insulin and incretin secretion, with a subsequent rise in glucose levels into the diabetic range. It also induced a significant inhibition of glucagon production. The patients at higher risk of DM during PAS therapy were those with higher glucagon levels, HbA1c 34.5 mmol/mol, and a glucose peak after PAS administration 9 mmol/L. CD patients with these features given PAS therapy should therefore be monitored more carefully.

Endogenous Cushing's syndrome (CS) is a rare, multi-systemic condition resulting from chronic glucocorticoid excess sustained by a pituitary adenoma (Cushing's disease, CD), an adrenal adenoma or, less frequently, a neuroendocrine tumor. The optimal first-line option is surgery, but when it is contraindicated/refused, or in case of severe, life-threatening disease, medical treatment is a first-line choice. Osilodrostat (LCI699, Isturisa®) is a new, orally active adrenal steroidogenesis inhibitor currently approved by the FDA and EMA for the treatment of endogenous CS.We illustrate the pharmacologic profile of osilodrostat and summarize the efficacy and safety of osilodrostat from the first phase I studies to the most recent evidence.Osilodrostat acts as a potent, reversible inhibitor of 11β-hydroxylase (CYP11B1) and 18-hydroxylase (or aldosterone synthase, CYP11B2), counteracting both gluco- and mineralocorticoid production. According to the results of the LINC1, LINC2, and LINC3 studies and the preliminary findings of LINC4, osilodrostat offers an excellent efficacy in controlling hypercortisolism with a good tolerability. The non-negligible risk of adrenal insufficiency/steroid withdrawal symptoms, hypokalemia, and hyperandrogenism disorders, and the possibility, albeit rare, of pituitary tumor enlargement, require further confirmation and careful monitoring.

To investigate the presence of pachychoroid spectrum disease (PSD) in patients with Cushing disease (CD) and to evaluate subfoveal choroidal thickness (SFCT) and choriocapillary flow using spectral domain OCT (SD-OCT) with the enhanced depth imaging (EDI) and optical coherence tomography angiography (OCT-A).Thirty-two patients with CD and 32 age- and sex-matched healthy volunteers were enrolled in this observational study. All participants had a complete ophthalmic examination including SD-OCT with EDI and OCT-A, and were subjected to the Perceived Stress Scale test (PSS). All patients with CD had hormone test including 24-h urinary-free cortisol (UFC) and plasma adrenocorticotropic hormone (ACTH). We compared SFCT and choriocapillary vessel density (CVD) between the two groups and evaluated the presence of PSD. We investigated the association of hormone level, SFTC, CVD with the presence of CD; the association between the hormone level, SFTC, CVD, the CD disease activity, and duration with the presence of PSD in CD patients; and the association between SFTC and CVD with the hormone level, the CD disease activity, and duration in CD patients.Higher values of SFCT and CVD were associated with CD (β: 0.028, 95% CI: 0.014; 0.041; β: 0.912, 95%CI: 0.205; 1.62, respectively). Twelve patients with CD (37.5%) reported a PSD in at least one eye, whereas no subject was found in control group (p 0.001); in particular, 11 CD patients (34%) presented pachychoroid pigment epitheliopathy (PPE) and 1 CD patient (3%) presented polypoidal choroidal vasculopathy/aneurysmal type 1 neovascularization (PCV/AT1). In patients with CD, a significant positive association between SFCT and PSD was found (β: 0.010, 95% CI 0.001; 0.019).A chronic state of hypercortisolism may have direct implications on the choroid. Patients with CD had higher SFCT values and a significant change in the choriocapillary flow compared to healthy controls. Moreover, PSD was observed only in CD patients.

La profilassi con inibitore di pompa protonica (PPI) nei pazienti in concomitante trattamento steroideo o negli stati di ipercortisolismo e argomento ad oggi molto dibattuto in quanto, a differenza dell’accertato rischio trombotico correlato all’eccesso di glucocorticoidi, non ci sono dati certi sul rischio emorragico; pertanto, qualora quest’ultimo fosse assente, la profilassi con PPI, oltre a non apportare benefici gastroenterici, aumenterebbe anche il rischio di effetti collaterali correlati a questi farmaci.

ContextProlonged adrenal stimulation by corticotropin, as in long-standing Cushing disease (CD), leads to diffuse to nodular hyperplasia. Adrenal functional autonomy has been described in a subset of patients with CD, leading to the hypothesis of transition from ACTH-dependent to ACTH-independent hypercortisolism.ObjectiveWith the consideration that the catalytic α subunit of protein kinase A (PKA; PRKACA) somatic mutations are the most common finding in adrenal adenomas associated with ACTH-independent Cushing syndrome, our aim was to analyze PRKACA mutations in adrenals of patients with persistent/long-standing CD.DesignCross-sectional.SettingUniversity hospital.PatientsTwo patients with long-standing CD and suspicion of coexistence of autonomous adrenal hyperfunction, according to pre and postoperative evaluations, were selected for this study, following an intensive literature search and patient-chart reviewing.InterventionClinical data were analyzed. DNA was extracted from adrenal tissue for PRKACA sequencing. PKA activity was assayed.Main Outcome MeasurePRKACA somatic mutations.ResultsBoth patients showed mutations of PRKACA in the macronodule in the context of micronodular adrenal hyperplasia. One patient harbored the previously described p.Leu206Arg substitution, whereas a p.Ser213Arg missense variation was detected in the adrenal nodule of the second patient. No mutations were detected in the adjacent adrenal cortex of the second patient. In silico analysis predicts that p.Ser213Arg can interfere with the interaction between the regulatory and catalytic subunits of PKA.ConclusionsOur study shows that PRKACA somatic mutations can be found in adrenal nodules of patients with CD. These genetic alterations could represent a possible mechanism underlying adrenal nodule formation and autonomous cortisol hyperproduction in a subgroup of patients with long-standing CD.

BackgroundCushing’s syndrome (CS) is associated with numerous comorbidities, including diabetes mellitus (DM). Levoketoconazole, an orally administered ketoconazole stereoisomer, is in clinical trials for the treatment of CS.MethodsSONICS, a prospective, open-label, phase 3 study in adults with confirmed CS and mean 24-h urinary free cortisol (mUFC) ≥1.5× ULN, included dose-titration, 6-month maintenance, and 6-month extension phases. This subanalysis evaluated the efficacy of levoketoconazole in patients with DM (n = 28) or without DM (n = 49) who entered the maintenance phase. Safety was evaluated in the overall population (N = 94) during the dose-titration and maintenance phases.ResultsNormalization of mUFC at the end of maintenance phase (EoM), without a dose increase during maintenance (SONICS primary endpoint) was observed in 46% of patients with DM (95% CI, 28 to 66%; P = 0.0006 vs null hypothesis of ≤20%) and 33% of patients without DM (95% CI, 20 to 48%; P = 0.0209). At EoM, mean HbA1c decreased from 6.9% at baseline to 6.2% in patients with DM and from 5.5 to 5.3% in patients without DM. Mean fasting blood glucose decreased from 6.85 mmol/L (123.4 mg/dl) to 5.82 mmol/L (104.9 mg/dl) and from 5.11 mmol/L (92.1 mg/dl) to 4.66 mmol/L (84.0 mg/dl) in patients with and without DM, respectively. Adverse events that were more common in patients with DM included nausea (58.3%), vomiting (19.4%), and urinary tract infection (16.7%); none prompted study drug withdrawal.ConclusionsTreatment with levoketoconazole led to sustained normalization of mUFC and improvement in glycemic control that was more pronounced in patients with DM.Clinical Trial Registration(ClinicalTrials.gov), NCT01838551.

PATRO adults is an ongoing, multicenter, observational, post-marketing surveillance study aimed at investigating the long-term safety (primary endpoint) and effectiveness (secondary endpoint) of the recombinant human growth hormone (rhGH) Omnitrope® during routine clinical practice. This report describes data from Italian participants in PATRO Adults with growth hormone deficiency (GHD), up to August 2017. Participants were adults (aged > 18 years) with GHD requiring rhGH therapy and were prescribed Omnitrope®, including those who had previously received another rhGH product. Adverse events (AEs) were evaluated in all study participants. Data were collected on insulin-like growth factor (IGF)-I levels and cardiovascular risk factors, including blood pressure, lipids, and anthropometric parameters. From September 2007 to August 2017, 88 patients (mean age 48.9 years, 58.0% male) were enrolled at 8 sites in Italy. The mean treatment duration with Omnitrope® was 51.5 ± 37 months. AEs occurred in 54 patients; the most common were asthenia (20.5%), headache (14.8%), and arthralgia (13.6%). Serious AEs occurred in 22 patients (25%), including pneumonia (n = 2) and renal failure (n = 2). Neoplasms (2 benign and 1 malignant) developed in three patients, but none were considered to be drug-related. There were no significant changes in fasting glucose or glycosylated hemoglobin (HbA1c) during the study period. Long-term Omnitrope® therapy showed slight positive effects on lipid profile, while no significant changes were observed in body weight and BMI during the study. This snapshot analysis of Italian participants in PATRO Adults confirmed the long-term safety and effectiveness of Omnitrope® in adults with GHD.

© 2021 European Society of Endocrinology, Adrenocortical carcinoma (ACC) is an orphan disease lacking effective systemic treatment options. The low incidence of the disease and high cost of clinical trials are major obstacles in the search for improved treatment strategies. As a novel approach, registry-based clinical trials have been introduced in clinical research, so allowing for significant cost reduction, but without compromising scientific benefit. Herein, we describe how the European Network for the Study of Adrenal Tumours (ENSAT) could transform its current registry into one fit for a clinical trial infrastructure. The rationale to perform randomized registry-based trials in ACC is outlined including an analysis of relevant limitations and challenges. We summarize a survey on this concept among ENSAT members who expressed a strong interest in the concept and rated its scientific potential as high. Legal aspects, including ethical approval of registry-based randomization were identified as potential obstacles. Finally, we describe three potential randomized registry-based clinical trials in an adjuvant setting and for advanced disease with a high potential to be executed within the framework of an advanced ENSAT registry. Thus we, therefore, provide the basis for future registry-based trials for ACC patients. This could ultimately provide proof-of-principle of how to perform more effective randomized trials for an orphan disease.

Background: COVID-19 is a novel threat to patients with adrenal insufficiency (AI), whose life expectancy and quality (QoL) are impaired by increased risk of infections and stress-triggered adrenal crises (AC). If infected, AI patients require prompt replacement tailoring. We interviewed a cohort of AI patients assessing: COVID-19 prevalence and clinical presentation; prevalence of AC and association with intercurrent COVID-19 or pandemic-related psychophysical stress; lockdown-induced emotional burden, and health-related QoL. Methods: In this monocentric (Ancona University Hospital, Italy), cross-sectional study covering February-April 2020, 121 (40 primary, 81 secondary) AI patients completed telematically the following three questionnaires: purpose-built “CORTI-COVID”, assessing medical history and concern for COVID-19-related global health, AI-specific personal health, occupational, economic, and social consequences; AddiQoL-30; Short-Form-36 (SF-36) Health Survey. Findings: COVID-19 occurred in one (0·8% prevalence) 48-year-old woman with primary AI, who promptly tailored her replacement. Dyspnea lasted three days, without requiring hospitalization. Secondary AI patients were not involved. No AC were experienced, but pandemic-related stress accounted for 6/14 glucocorticoid up-titrations. Mean CORTI-COVID was similar between groups, mainly depending on “personal health” in primary AI (ρ=0·888, p

Histological studies born in Ancona as morphological ultrastructural investigations. The ability to correlate structure and function concomitantly with the development of bio-molecular technologies was an important step forward for the scientific growth of the histological group. Starting from studies on tissue regeneration, which focused on cells, engineered material biocompatibility and appropriate biochemical factors interrelationship, researches were directed both to the study of wound healing and to deepen our knowledge on adult mesenchymal stem cells behaviour in normal and in pathological conditions. Knowledges of the group were important starting point for fruitful collaborations with clinicians.

Mitotane is the main option of treatment for advanced adrenocortical carcinoma (ACC). However, limited evidence is available regarding the impact of plasma mitotane levels on patient outcome. To address this question, we retrospectively analyzed patients with advanced ACC treated with mitotane for &ge, 3 months, with &ge, 3 measurements of plasma mitotane reported in the Lysosafe Online&reg, database (HRA Pharma, France), followed at 12 tertiary centers in Italy from 2005 to 2017. We identified 80 patients, initially treated with mitotane alone (56.2%) or plus chemotherapy (43.8%). The preference toward combination therapy was given to de novo stage IV ACC and younger patients. After the first line of treatment, 25% of valid cases experienced clinical benefit (14.5% objective response, 10.5% stabilization of disease) and 75% progression, without differences between the groups of treatment. Patients with progression had a lower time in the target range (TTR) of plasma mitotane and an unfavorable outcome. Death occurred in 76.2% of cases and multivariate analysis showed that clinical benefit after first treatment and longer TTR were favorable predictors of overall survival (OS). In conclusion, the present findings support the importance of mitotane monitoring and strengthen the concept of a therapeutic window for mitotane.

Background: Pituitary apoplexy is a life-threatening event with unspecific clinical background and no standardized treatment. Materials and Methods: The authors retrospectively analyzed seventeen patients affected by pituitary adenoma apoplexy and treated in a 10-year period. Thirteen patients underwent surgery through transsphenoidal route while four patients have been treated conservatively. Results: The endoscopic surgical procedure showed a better result in term of complete removal of the tumor while in the “conservative” group less frequent evidence of hormones' deficiency has been registered. Once a residual lesions was observed a strict radiological follow-up is mandatory. Conclusions: According to dedicated literature and pre- and post-operative evidence of personal series, the authors try to provide an algorithm that could help in the standardization of the diagnostic and therapeutic pathways in patients with pituitary adenoma apoplexy.

Introduction: During the 22-week core LINC 2 study, the oral 11β-hydroxylase inhibitor osilodrostat normalized mean urinary free cortisol (mUFC) in 79% (15/19) of patients with Cushing’s disease. This report describes long-term LINC 2 efficacy and safety results following an optional extension. Methods: Patients receiving clinical benefit at week 22 could enter the extension (that ran until Oct 22, 2019), continuing the same osilodrostat dose; dose adjustments were permitted based on efficacy and safety. Response rate (mUFC ≤ULN [controlled] or mUFC >ULN but ≥50% decrease from baseline [BL; partially controlled]) was assessed over time. Efficacy/safety were assessed for all patients from core BL until study end. Results: Of 19 enrolled patients (female:male 14:5; mean [SD] age 36.8 years [8.4]), 16 entered the optional extension and 8 of them remained on treatment until study end. Median (range) osilodrostat exposure was 282 weeks (2-351). Mean mUFC decreased from BL (9.9 x ULN) to ≤ULN by week 4 and remained stable throughout the study. All 19 patients achieved mUFC ≤ULN at least once during the study. At each assessment up to month 70 of the extension phase, 50-88% of ongoing patients were controlled, and up to 18% were partially controlled. Mean percentage change in clinical signs from BL (mean [SD]) to last assessment were: fasting plasma glucose, -10.8% (22.1) (from BL: 105.6 mg/dL [49.2]); HbA1c, -2.1% (9.0) (from BL: 5.7% [0.7]); systolic BP, -3.3% (12.6) (from BL: 132.6 mmHg [11.6]); diastolic BP, -2.0% (10.4) (from BL: 85.0 mmHg [6.5]); BMI, -5.9% (8.8) (from BL: 30.7 kg/m2 [7.0]). Overall, 9 patients discontinued treatment (n=2 core and n=7 extension), mostly because of AEs or no longer requiring treatment (n=3 each). The most common AEs during the entire treatment period were nausea (n=10), adrenal insufficiency, and headache (both n=9). AEs related to hypocortisolism and adrenal hormone precursor accumulation occurred in 11 (mostly adrenal insufficiency, n=9) and 12 patients (mostly hypertension, n=4), respectively; most were grade 1/2 and managed with dose adjustment/interruption and/or concomitant medication. Mean (SD) plasma ACTH increased from 1.8 x ULN (0.9) at BL to 7.1 x ULN (12.3) at week 22 and 6.9 x ULN (12.6) at last assessment. Mean (SD) 11-deoxycortisol increased from 1.2 x ULN (1.3) at BL to 13.6 x ULN (12.2) at week 22 and 3.6 x ULN (4.2) at last assessment. In females, mean (SD) testosterone increased from 0.8 x ULN (0.4) at BL to 2.4 x ULN (2.1) at week 22 and 1.0 x ULN (0.9) at last assessment. Two patients, both female, reported an AE of hirsutism. Conclusions: Rapid reductions in mUFC were sustained for up to 6 years of osilodrostat treatment and were accompanied by improvements in clinical signs of hypercortisolism. Osilodrostat was well tolerated, with no new safety signals during long-term treatment.

Context: Increase in drug frequency or dose is recommended for acromegaly patients with partial response to long-acting somatostatin receptor ligands (SRLs). However, the efficacy and safety data with lanreotide (LAN) Autogel (LAN-ATG) at high dose (HD) or high frequency (HF) are still scanty. Objective: To evaluate the biochemical efficacy and safety of HF and HD LAN-ATG in patients with active acromegaly. Design: Twenty-four-week prospective, multicenter, randomized, open-label trial. Patients and Interventions: Thirty patients with active acromegaly, partial responders to SRLs, were randomized to HF (120 mg/21 days; 15 patients) or HD (180 mg/28 days; 15 patients) LAN-ATG. Outcomes: Normalization of serum insulin-like growth factor-I (IGF-I) and reduction in random growth hormone (GH) values ,1.0 mg/L, reduction in serum IGF-I and GH from baseline, differences in biochemical response between HF and HD LAN-ATG, adverse events. Results: IGF-I decreased significantly (P = 0.007) during the 24-week treatment, with greater decrease in HD (P = 0.03) vs HF group (P = 0.08). Normalization in IGF-I values occurred in 27.6% of patients (P = 0.016 vs baseline), without a significant difference between HF and HD groups (P = 0.59). The decrease in serumIGF-I significantly correlated with serumLAN values (P = 0.04), and normalization of IGF-I was predicted by baseline IGF-I values (P = 0.02). Serum GH values did not change significantly (P = 0.22). Overall, 19 patients (63.3%) experienced adverse events, all being mild to moderate and transient, without differences between the two therapeutic arms. Conclusion: HF and HD LAN-ATG regimens are effective in normalizing IGF-I values in about onethird of patients with active acromegaly inadequately controlled by long-term conventional SRLs therapy.

L’anoressia nervosa e un disturbo del comportamento alimentare a chiara preponderanza femminile, con una prevalenza stimata nella popolazione generale pari a circa lo 0,3–0,9% nelle donne e meno dello 0,3% negli uomini. Secondo i criteri stabiliti dalla quinta edizione del Diagnostic and Statistical Manual of Mental Disorders (DSM-5) l’anoressia nervosa si caratterizza per una restrizione dell’introito calorico in rapporto ai fabbisogni, associata a intensa paura di acquisire peso e alterata percezione della propria immagine corporea. Tra le molteplici complicanze di questa patologia, oltre al grave calo ponderale, meritano notevole considerazione quelle endocrino-metaboliche, tra cui si annoverano la malnutrizione, con conseguente riduzione della massa grassa e della massa magra, l’ipogonadismo ipogonadotropo e l’amenorrea, la resistenza periferica all’azione del GH, l’ipercortisolismo, nonche la sindrome da bassa T3. Le suddette condizioni possono contribuire alle alterazioni del metabolismo osseo che si osservano in questa patologia. Nella presente rassegna verra presa in esame la relazione esistente tra anoressia nervosa e metabolismo osseo, con particolare riguardo all’osteoporosi, alla luce delle evidenze clinico-scientifiche piu recenti.

Cushing syndrome (CS), caused by glucocorticoid (GCs) excess, is strictly connected to onset of different metabolic diseases and impaired wound healing. The source of excessively high levels of GCs allows the identification of endogenous and exogenous (iatrogenic) CS. Iatrogenic patients usually receive also anti-metabolites serving as the foundation to modern steroid-sparing immunosuppressive therapy. Tissues mainly targeted by CS are bone and fat, both derived from progenitor cells named mesenchymal stem cells (MSCs). In addition, the pathogenic role of MSCs in other diseases sharing common properties with CS, such as an altered inflammatory profile and increased oxidative stress, has been identified. In this light, MSCs isolated from skin of control healthy subjects (C-MSCs), patients affected by endogenous CS (ENDO-MSCs), patients affected by iatrogenic CS (IATRO-MSCs) and patients affected by exogenous CS receiving steroid-sparing drugs (SS-MSCs), respectively, have been isolated and analyzed. ENDO- and IATRO-MSCs showed a reduced differentiative potential toward osteogenic and adipogenic lineages compared to C-MSCs, whereas SS-MSCs re-acquired the ability to differentiate, with a trend similar to control cells. In addition, MSCs from CS groups, compared to control MSCs, displayed a reduction in the secretion of cytokines (immune-suppression), a decreased expression of genes related to wound healing and a dysregulation of the enzymes/genes related to antioxidant capacity. In conclusion, our results suggest that the hallmarks of CS, such as wound healing impairment and immunosuppression, are already detectable in undifferentiated cells, which could be considered a potential therapeutic early target for control of CS.

Context: Glucocorticoid (GC) replacement therapy in patients with adrenal insufficiency (AI) is life saving. After over 50years of conventional GC treatment, novel formulations are now entering routine clinical practice. Methods: Given the spectrum of medications currently available and new insights into the understanding of AI, the authors reviewed relevant medical literature with emphasis on original studies, prospective observational data and randomized controlled trials performed in the past 35years. The Expert Opinion of a panel of selected endocrinologists was sought to answer specific clinical questions. The objective was to provide an evidence-supported guide, for the use of GC in various settings from university hospitals to outpatient clinics, that offers specific advice tailored to the individual patient. Results: The Panel reviewed available GC replacement therapies, comprising short-acting, intermediate and long-acting oral formulations, subcutaneous formulations and the novel modified-release hydrocortisone. Advantages and disadvantages of these formulations were reviewed. Conclusions: In the Panel’s opinion, achieving the optimal GC timing and dosing is needed to improve the outcome of AI. No-single formulation offers the best option for every patients. Recent data suggest that more emphasis should be given to the timing of intake. Tailoring of GS should be attempted in all patients—by experts—on a case-by-case basis. The Panel identified specific subgroups of AI patients that could be help by this process. Long-term studies areneeded to confirm the short-term benefits associated with the modified-release GCs. The impact of GC tailoring has yet to be proven in terms of hospitalization rate, morbidity and mortality.

Although polycystic ovary syndrome (PCOS) is the most common androgen excess disorder, screening for Cushing's Syndrome (CS) should be considered in women with PCOS phenotype, particularly if they are also affected by other disturbances that increase their pretest probability (e.g., osteoporosis/bone fractures). Approximately 70-80% of women with CS present menstrual abnormalities, and PCOS findings are found in 46% of these patients. Diagnostic efforts should strengthen if the clinical picture is severe or of rapid onset in order to ensure the earliest and most appropriate treatment. If the diagnosis of CS is challenging, its differentiation from PCOS is not outdone: isolated PCOS may be associated to hypothalamic-pituitary-adrenal axis disruption, leading to false-positive results in screening tests. Because of this overlap, the diagnosis of CS is initially missed or delayed. Diagnostic utility of serum androgen assessment is controversial, but the widespread use of high-performance liquid chromatography and gas chromatography-mass spectrometry for urinary steroid profiling is showing promising results. According to the role of adrenocorticotropic hormone (ACTH) in adrenal androgen secretion, it is not surprising that the levels of dehydroepiandrosterone, dehydroepiandrosterone-sulfate, and androstenedione (A4) are generally elevated or in the upper normal range in patients with ACTH-dependent CS. Conversely, adrenal androgens are generally low in patients with cortisol-secreting adrenocortical adenoma. However, androgen-secreting adrenal tumors (adenoma and carcinoma) can be also associated with severe hyperandrogenism. Regression of hypercortisolism after treatment causes disappearance of hyperandrogenism. However, signs of androgen excess may be detectable in well-controlled CS as a result of ACTH compensatory response to certain adrenal steroidogenesis inhibitors.

Background. Transition from ACTH-dependent to ACTH-independent hypercortisolism has been described in patients with long-standing Cushing´s disease (CD). The underlying molecular mechanisms are unknown. Clinical case.Case 1. A 41-years old woman was referred for Cushing’s syndrome (cortisol after 1-mg dexamethasone suppression test (DST) 410 nmol/L, urinary free cortisol (UFC) 2xULN, midnight cortisol 440 nmol/L). High-dose DST: no suppression. CRH test: no ACTH/cortisol increase. Basal ACTH: 18 pmol/L. Pituitary MRI showed a 7-mm adenoma. The inferior petrosal sinus sampling showed central source of ACTH. She was treated by trans-sphenoidal surgery (pituitary adenoma confirmed histologically) followed by clinical remission. Cushing’s syndrome recurred 1 year after. ACTH was undetectable and pituitary MRI normal. Abdominal CT-scan showed a left adrenal macronodule. Left adrenalectomy was performed, followed by glucocorticoid replacement therapy (1 year) and clinical/biochemical remission at last follow-up (15 years). Histopathology showed a 35-mm adrenal nodule and micronodular hyperplasia. We found a p.L206R missense mutation of PRKACA in the adrenal nodule. The functional implication of the mutation has been described (1). Case 2. A 31-years old woman was referred for Cushing´s syndrome (cortisol after 1-mg DST 579 nmol/L, UFC 4xULN, midnight cortisol 773 nmol/L). Basal ACTH: 18 pmol/L. CRH and desmopressin tests: indicative of CD. High-dose DST: no suppression. A pituitary MRI revealed a microadenoma, treated by trans-sphenoidal surgery (confirmed by histology). She had persistence of Cushing’s syndrome, undetectable basal ACTH and negative pituitary MRI. An abdominal CT-scan showed bilateral adrenal enlargement with a left nodule, treated by bilateral adrenalectomy. Histology showed a macronodule in micronodular hyperplasia. We found a p.S213R somatic missense mutation of PRKACA in the adrenal macronodule. Functional analyses showed that mutant cells had higher cAMP-independent PKA activity than wild-type, and similar to the L206R mutation. Conclusion. This is the first evidence showing that PRKACA somatic mutations can be found in adrenal nodules of patients with CD, possibly explaining the mechanism underlying transition from ACTH-dependent to ACTH-independent hypercortisolism. References. 1. Calebiro D et al. PKA catalytic subunit mutations in adrenocortical Cushing's adenoma impair association with the regulatory subunit. Nat Commun. 2014;5:5680.

Mitotane is used as a post-operative adjuvant treatment for patients with adrenocortical carcinoma. Monitoring of plasma mitotane concentrations is recommended, but we do not know what impact target concentrations have on patient outcome. To answer this question, we retrospectively analyzed patient records in the Lysosafe Online® database (HRA Pharma, France) for patients who were treated for ≥6 months and who had ≥3 measurements of plasma mitotane levels during follow-ups at 11 tertiary centers in Italy from 2005 to 2017. We identified 110 patients treated with adjuvant mitotane for a median of 46 months (IQR, interquartile range, 28−62) with a median maintenance dose of 2.0 g/day (IQR 1.5−2.5). Achievement of target mitotane concentrations (≥14 mg/L) required a median of 8 months (IQR 5−19). Female sex was associated inversely with the dose, while body mass index (BMI) was correlated positively. Multivariate analysis showed that the Ki67 index and time to achieve the target range of plasma mitotane were independent predictors of recurrence-free survival (RFS). In a separate multivariate model, considering only the maintenance phase (month 7 to month 36, M7−M36) of treatment, the time in the target range of plasma mitotane was associated with a significantly lower risk of recurrence (Hazard Ratio, HR = 0.93; 0.88−0.98, p < 0.01). The prognostic implications of the time in target range and the time needed to reach target mitotane concentrations support the use of mitotane monitoring and may inform practice.

Although polycystic ovary syndrome (PCOS) is the most common androgen excess disorder, screening for Cushing's Syndrome (CS) should be considered in women with PCOS phenotype, particularly if they are also affected by other disturbances that increase their pretest probability (e.g., osteoporosis/bone fractures). Approximately 70-80% of women with CS present menstrual abnormalities, and PCOS findings are found in 46% of these patients. Diagnostic efforts should strengthen if the clinical picture is severe or of rapid onset in order to ensure the earliest and most appropriate treatment. If the diagnosis of CS is challenging, its differentiation from PCOS is not outdone: isolated PCOS may be associated to hypothalamic-pituitary-adrenal axis disruption, leading to false-positive results in screening tests. Because of this overlap, the diagnosis of CS is initially missed or delayed. Diagnostic utility of serum androgen assessment is controversial, but the widespread use of high-performance liquid chromatography and gas chromatography-mass spectrometry for urinary steroid profiling is showing promising results. According to the role of adrenocorticotropic hormone (ACTH) in adrenal androgen secretion, it is not surprising that the levels of dehydroepiandrosterone, dehydroepiandrosterone-sulfate, and androstenedione (A4) are generally elevated or in the upper normal range in patients with ACTH-dependent CS. Conversely, adrenal androgens are generally low in patients with cortisol-secreting adrenocortical adenoma. However, androgen-secreting adrenal tumors (adenoma and carcinoma) can be also associated with severe hyperandrogenism. Regression of hypercortisolism after treatment causes disappearance of hyperandrogenism. However, signs of androgen excess may be detectable in well-controlled CS as a result of ACTH compensatory response to certain adrenal steroidogenesis inhibitors.

A phase III study has demonstrated that 6-month pasireotide treatment induced disease control with good safety in 15–26% of patients with Cushing’s disease (CD). The aim of the current study was to evaluate the 6-month efficacy and safety of pasireotide treatment according to the real-world evidence. Thirty-two CD patients started pasireotide at the dose of 600 µg twice a day (bid) and with the chance of up-titration to 900 µg bid, or down-titration to 450 or 300 µg bid, on the basis of urinary cortisol (UC) levels or safety. Hormonal, clinical and metabolic parameters were measured at baseline and at 3-month and 6-month follow-up, whereas tumour size was evaluated at baseline and at 6-month follow-up. At baseline, 31 patients had very mild to moderate disease and 1 patient had very severe disease. Five (15.6%) patients discontinued treatment for adverse events; the remaining 27 patients (26 with very mild to moderate disease and 1 with very severe disease), reached 6-month follow-up. Considering the group of patients with very mild to moderate disease, responsiveness, defined by the normalization (1 and ≤1.1 ULN) of UC levels, was registered in 21 patients (full control in 19 and near control in 2), corresponding to 67.7% and 80.8% according to an “intention-to-treat” or “per-protocol” methodological approach, respectively. Weight, body mass index, waist circumference, as well as total and LDL-cholesterol significantly decreased, whereas fasting plasma glucose and glycated haemoglobin significantly increased. Hyperglycaemia was documented in 81.2%, whereas gastrointestinal disturbances in 40.6% of patients. In conclusion, in the real-life clinical practice, pasireotide treatment normalizes or nearly normalizes UC in at least 68% of patients with very mild to moderate disease, with consequent improvement in weight, visceral adiposity and lipid profile, despite the occurrence or deterioration of diabetes in the majority of cases, confirming the usefulness of this treatment in patients with milder disease and without uncontrolled diabetes.

Several hormones contribute to ensure penile erection, a neurovascular phenomenon in which nitric oxide plays a major role. Erectile dysfunction (ED), which is defined as the persistent inability to obtain or maintain penile erection sufficient for a satisfactory sexual performance, may be due to arteriogenic, neurogenic, iatrogenic, but also endocrinological causes. The hypothalamus–pituitary axis plays a central role in the endocrine system and represents a fundamental link between the brain and peripheral glands, including gonads. Therefore, the hormonal production of the hypothalamic–pituitary axis can control various aspects of sexual function and its dysregulation can compromise erectile function. In addition, excess and deficiency of pituitary hormones or metabolic alterations that are associated with some pituitary diseases (e.g., Cushing’s disease and acromegaly, hypopituitarism) can determine the development of ED with different mechanisms. Thus, the present review aimed to explore the relationship between hypothalamic and pituitary diseases based on the most recent clinical and experimental evidence.