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Objective This study aims to assess the feasibility and reliability of our endoscopic trans-nasal technique for the repair of cribriform and sellar high-flow cerebrospinal fluid (CSF) leaks. Methods A comparison between patients suffering from high-flow rhinorrhea and treated through a free grafting endoscopic technique or the “parachute” technique, our nasal packing proposal, was performed. Results Thirty-three patients were included. The mean age was 52 years (range: 36–68 years). The etiology of the CSF leaks was iatrogenic in 16 cases (48.5%), traumatic in 5 cases (15.2%), spontaneous in 11 cases (33.3%), and related to anterior skull base tumors in 1 case (3%). The bone defect affected the sphenoidal sinus in 20 cases (60.6%), the cribriform plate of the ethmoid in 10 cases (30.3%), and both the sphenoid and ethmoid in 3 cases (9.1%). The mean size of bone defects was 8.5 ± 3.9 mm. The median follow-up was 28 (64) months. A CSF leak recurrence occurred in no cases treated with the parachute technique and in 3 cases that underwent conventional endoscopic treatments. The CSF leak recurrences were associated with 2 iatrogenic and 1 post-traumatic fistula. All the CSF leak recurrences underwent the parachute technique, not showing second recurrences. Conclusions Our results suggest that the parachute technique is simple, safe, and effective. We recommend it as an alternative treatment to vascular flaps for the treatment of high-flow and recurrent fistulas.

The pharmacological treatment of pituitary tumours is based on the use of stable analogues of somatostatin and dopamine. The analogues bind to somatostatin receptor types 2 and 5 (SST2 and SST5) and dopamine receptor type 2 (DRD2), respectively, and generate signal transduction cascades in cancerous pituitary cells that culminate in the inhibition of hormone secretion, cell growth and invasion. Drug resistance occurs in a subset of patients and can involve different steps at different stages, such as following receptor activation by the agonist or during the final biological responses. Although the expression of somatostatin and dopamine receptors in cancer cells is a prerequisite for these drugs to reach a biological effect, their presence does not guarantee the success of the therapy. Successful therapy also requires the proper functioning of the machinery of signal transduction and the finely tuned regulation of receptor desensitization, internalization and intracellular trafficking. The present Review provides an updated overview of the molecular factors underlying the pharmacological resistance of pituitary tumours. The Review discusses the experimental evidence that supports a role for receptors and intracellular proteins in the function of SSTs and DRD2 and their clinical importance.

Objective Pseudohypoparathyroidism and related disorders belong to a group of heterogeneous rare diseases that share an impaired signaling downstream of Gsα-protein-coupled receptors. Affected patients may present with various combination of symptoms including resistance to PTH and/or to other hormones, ectopic ossifications, brachydactyly type E, early onset obesity, short stature and cognitive difficulties. Several years ago we proposed a novel nomenclature under the term of inactivating PTH/PTHrP signaling disorders (iPPSD). It is now of utmost importance to validate these criteria and/or improve the basis of this new classification. Design Retrospective study of a large international series of 459 probands and 85 relatives molecularly characterized. Methods Information on major and minor criteria associated with iPPSD and genetic results were retrieved from patient files. We compared the presence of each criteria according to the iPPSD subtype, age and gender of the patients. Results More than 98% of the probands met the proposed criteria for iPPSD classification. Noteworthy, most patients (85%) presented a combination of symptoms rather than a single sign suggestive of iPPSD and the overlap among the different genetic forms of iPPSD was confirmed. The clinical and molecular characterization of relatives identified familial history as an additional important criterion predictive of the disease. Conclusions The phenotypic analysis of this large cohort confirmed the utility of the major and minor criteria and their combination to diagnose iPPSD. This report shows the importance of having simple and easily recognizable signs to diagnose with confidence these rare disorders and supports a better management of patients.

Pseudohypoparathyroidism (PHP), the first known post-receptorial hormone resistance, derives from a partial deficiency of the α subunit of the stimulatory G protein (Gsα), a key component of the PTH/PTHrP signaling pathway. Since its first description, different studies unveiled, beside the molecular basis for PHP, the existence of different subtypes and of diseases in differential diagnosis associated with genetic alterations in other genes of the PTH/PTHrP pathway. The clinical and molecular overlap among PHP subtypes and with different but related disorders make both differential diagnosis and genetic counseling challenging. Recently, a proposal to group all these conditions under the novel term “inactivating PTH/PTHrP signaling disorders (iPPSD)” was promoted and, soon afterwards, the first international consensus statement on the diagnosis and management of these disorders has been published. This review will focus on the major and minor features characterizing PHP/iPPSDs as a group and on the specificities as well as the overlap associated with the most frequent subtypes.

Background Spindle cell oncocytomas are extremely rare neoplasms of the sellar, parasellar, and suprasellar regions that can frequently mimic pituitary adenomas. Fewer than 50 cases have been ever reported in the literature, and there is no consensus on best treatments to be provided. Case Description We hereby present a challenging case of sellar and suprasellar spindle cell oncocytoma in a patient of 64 years. The patient, who presented with hydrocephalus, hypopituitarism, and visual deficit, underwent urgent transsphenoidal (TNS) resection of the mass, which was aborted for massive life-threatening bleeding. The patient received ventriculoperitoneal shunt with relief of symptoms. An endovascular embolization of tumor feeders from the distal portion of the right internal maxillary artery, in particular the sphenopalatine artery, was then performed and a second-look TNS surgery was feasible. The patient was discharged in optimal clinical condition, recovered both endocrinologic and visual deficits, and is now in follow-up. Conclusions We found that the oncocytoma was radiologically and clinically comparable with a pituitary adenoma, except for higher representation of vasculature. According to our recent experience and review of the literature, we believe that surgery (transsphenoidal or transcranial approach) is the recommended treatment in those who are symptomatic and preoperative embolization might be a suitable option to reduce intraoperative bleeding and increase radicality.

Objective Patients with Cushing’s syndrome (CS) are at high risk of venous thromboembolism related to a hypercoagulability due to procoagulant imbalance. However, whether these alterations are reversible after disease remission is still unclear. The endogenous thrombin potential (ETP) measured with and without the addition of thrombomodulin provides a global representation of coagulation and previous data confirmed hypercoagulable profile in patients with active hypercortisolism. Aim of this study was to assess the short- and long-term modification of ETP in patients with CS after disease remission. Design and methods Nineteen patients with CS for whom surgical remission was achieved, were prospectively evaluated for clinical characteristics, cortisol secretion profile and ETP at different time points: (i) before surgical intervention; (ii) after 6 months and (iii) 5 years from the time of persistent remission. Nineteen healthy subjects matched for age and gender were also evaluated as control group. Results Before surgery, patients showed higher ETP-ratio (with/without thrombomodulin) than controls (0.62 ± 0.09-vs-0.56 ± 0.09, p = 0.034). No significant correlation between ETP-ratio and cortisol secretion was found. 6 months after remission, ETP-ratio was still significantly increased compared to controls (0.64 ± 0.09-vs-0.56 ± 0.09, p = 0.01), but was similar to baseline (0.64 ± 0.09-vs-0.62 ± 0.09, p = 0.87). At 5 years, ETP-ratio showed a significant decrease (0.55 ± 0.14-vs-0.62 ± 0.09, p = 0.02) and was comparable to controls (0.55 ± 0.14-vs-0.56 ± 0.09, p = 0.7). Conclusions Plasma hypercoagulability detected in patients with active hypercortisolism persists at short-term evaluation and seems to be completely reversible after long-term remission of disease. These data, as part of a whole evaluation of thrombotic risk, can contribute to make appropriate therapeutic choice in these patients.

Purpose: The aim of the present study is to assess the predictive value of the suprasellar volume (SSV) of nonfunctioning pituitary adenomas (NFPAs) for visual field (VF) impairment in order to guide clinical decision-making and improve neurosurgical management. Methods: Two independent samples of patients with NFPAs (exploratory population N = 50, testing population N = 98) were included in the present study. In the first phase, we determined the optimal cut-off value of the SSV correlating with VF deficits in the exploratory population. In the second phase, we then studied the accuracy of identified cut-off in predicting a VF deficit in the testing population. Results: In the exploratory population, the optimal cut-off value of the SSV to determine the presence of a VF deficit was 1.5mL. Sensitivity and specificity of the cut-off were 81.3 and 100%, respectively. The positive predictive value (PPV) and the negative predictive value (NPV) were 100 and 75%, respectively. When we checked the identified cut-off score on the testing population, we found a sensitivity of 71% and a specificity of 100%. The PPV and NPV were 100 and 59.2%, respectively. In six cases with VF defects and SSV inferior to 1.5mL, the displacement of optic chiasm was in superior position. Conclusion: The SSV may represent an accurate method in routinely clinical practice for predicting VF deficit in patients affected by NFPA.

Klinefelter syndrome (KS) is characterized by late adolescence/young adulthood onset of primary hypogonadism. Hypogonadotropic hypogonadism (HH), when congenital, is usually associated with absent/incomplete puberty and low/normal gonadotropins. We report the clinical and genetic features of two subjects with KS and an unexpected HH hormone profile. Magnetic resonance imaging (MRI) of hypothalamus-pituitary region and next generation sequencing (NGS) of congenital HH-associated genes were obtained. A narrative review of the literature was conducted. Patients were diagnosed with Klinefelter syndrome following karyotype analysis. Nevertheless, they showed unusual features: both had incomplete puberty, low gonadotropins and testosterone levels, and the first one was anosmic. Sellar lesions were excluded by MRI, and NGS was negative in both subjects. Our data add to those of the only 14 similar cases reported so far. Unexplained HH rarely occurs in KS and is variably associated with anosmia, other pituitary hormones deficiencies and heterogeneous karyotypes. However, most cases show an early, pre-pubertal onset of hypogonadism. If the causes behind this gonadotropins defect are largely unknown, hereby we provide the first review of the literature on this topic and propose some pathogenetic hypotheses, including the coexistence of KS and congenital HH as suggested by overlapping clinical features in some of these patients. HH is an exceptional occurrence in Klinefelter syndrome and is associated with heterogeneous phenotypes and, probably, aetiologies. Moreover, KS could underlie HH nonresponsive to gonadotropins. An exhaustive diagnostic workup and a tailored clinical management are advisable in these rare forms.

Purpose The current cut-offs for the diagnosis of adrenal insufficiency (AI) have been established using outdated immunoassays. We compared the cortisol concentrations measured with Roche Cortisol I (R1), the newly available Roche Cortisol II (R2), and liquid chromatography tandem mass spectrometry (LC-MS/MS), the gold standard procedure to measure steroids in patients undergoing the corticotropin (ACTH) test. Methods We enrolled 30 patients (age 47 ± 21 years) referred to undergo the ACTH test (1 or 250 μg). Cortisol was measured at 0, 30, and 60 min after stimulation with R1, R2, and LC-MS/MS. AI was diagnosed for R1-stimulated peak cortisol concentrations Results Mean cortisol concentrations measured with R2 and LC-MS/MS were comparable, while mean cortisol concentrations measured by R1 were higher than those of both R2 and LC-MS/MS (respectively, basal 411 ± 177, 287 ± 119, and 295 ± 119 nmol/L; at 30 min, 704 ± 204, 480 ± 132, and 500 ± 132 nmol/L; at 60 min, 737 ± 301, 502 ± 196, and 519 ± 201 nmol/L, p ≤ 0.01 for R1 vs. both R2 and LC-MS/MS at each point). Considering the 500 nmol/L cortisol peak cut-off, AI was diagnosed in 5/30 patients using R1 and in 12/30 using R2 (+ 140%). Based on the correlation between R1 and R2, the threshold of 500 nmol/L became 351 nmol/L (12.7 μg/dL) when cortisol was measured with R2, and 368 nmol/L (13.3 μg/dL) with LC-MS/MS. Conclusions The use of more specific cortisol assays results in lower cortisol concentrations. This could lead to misdiagnosis and overtreatment when assessing AI with the ACTH test if a different cut-off for cortisol peak is not adopted.

Gli analoghi della somatostatina (SA) rappresentano il trattamento d’elezione per l’acromegalia. Questi farmaci, legandosi ai recettori della somatostatina (SST) maggiormente espressi sulle cellule tumorali GH-secernenti, riducono la secrezione ormonale e la proliferazione cellulare. Tuttavia, la percentuale di pazienti che vengono adeguatamente controllati dagli SA varia significativamente nei diversi studi. Alcuni parametri clinici e specifiche caratteristiche istopatologiche del tumore sono stati associati alla diversa responsivita alla terapia con SA. Fra i biomarcatori molecolari, l’espressione del recettore della somatostatina di tipo 2 (SST2) trova riscontro nella maggior parte dei dati pubblicati. Sembrano inoltre fattori predittivi di responsivita al trattamento farmacologico alcune alterazioni post-recettoriali quali, ad esempio, quelle a carico di AIP, ZAC1, E-caderine, proteine del citoscheletro filamina A e cofilina, e $\beta $-arrestine. I dati attuali incoraggiano fortemente un orientamento verso una terapia di precisione in acromegalia e studi piu approfonditi consentiranno una maggiore efficacia del trattamento nel singolo paziente.

Pseudohypoparathyroidism (PHP), characterized by multihormone resistance and Albright’s hereditary osteodystrophy (AHO), is caused by GNAS mutations. Whole or partial gene deletions are rare. All disorders due to inactivating mutations of the GNAS gene are now classified as “inactivating PTH/PTHrP signaling disorder type 2” (iPPSD2). This study reports a family harboring a large GNAS gene deletion in order to improve the knowledge of genotype–phenotype correlation of this disease. An 18-year-old man with severe diffuse soft ossifications and multihormone resistance underwent to clinical, biochemical, radiological, and genetic studies. A review of the literature of other cases of iPPSD2 due to GNAS large deletions was performed focusing on clinical and biochemical features. The proband presented signs of hypocalcemia and marked AHO features. Laboratory tests revealed hypocalcemia, high levels of serum phosphate, PTH, TSH, and calcitonin despite therapy with calcium carbonate, calcitriol, and levothyroxine. Diffuse soft tissue ossifications and brain calcifications were shown by radiological exams. Family history was remarkable for hypocalcemia, neurocognitive impairment, and cerebral calcifications in his brother and AHO features in the maternal grandfather. The proband’s mother showed short stature, whereas physical examination of the father was unremarkable. Genetic analysis of the GNAS gene revealed an unreported large deletion encompassing exons 1–7 in the proband, brother, and mother. By reviewing the literature, only six other cases were described. We report a kindred harboring a large GNAS deletion. A genotype–phenotype correlation was observed in term of severity of tissue ossifications in the siblings but not in the mother.

Patients affected by pseudohypoparathyroidism (PHP) or related disorders are characterized by physical findings that may include brachydactyly, a short stature, a stocky build, early-onset obesity, ectopic ossifications, and neurodevelopmental deficits, as well as hormonal resistance most prominently to parathyroid hormone (PTH). In addition to these alterations, patients may develop other hormonal resistances, leading to overt or subclinical hypothyroidism, hypogonadism and growth hormone (GH) deficiency, impaired growth without measurable evidence for hormonal abnormalities, type 2 diabetes, and skeletal issues with potentially severe limitation of mobility. PHP and related disorders are primarily clinical diagnoses. Given the variability of the clinical, radiological, and biochemical presentation, establishment of the molecular diagnosis is of critical importance for patients. It facilitates management, including prevention of complications, screening and treatment of endocrine deficits, supportive measures, and appropriate genetic counselling. Based on the first international consensus statement for these disorders, this article provides an updated and ready-to-use tool to help physicians and patients outlining relevant interventions and their timing. A life-long coordinated and multidisciplinary approach is recommended, starting as far as possible in early infancy and continuing throughout adulthood with an appropriate and timely transition from pediatric to adult care.

First-line therapy of Cushing disease (CD) is transsphenoidal surgery (TSS) aimed to obtain a complete removal of the pituitary adenoma and remission of disease. To analyse the surgical outcome of patients with CD who underwent TSS in our Centre. Retrospective analysis on patients with CD who underwent TSS between 1990 and 2016. We analysed 102 TSS that included: 84 first TSS and 18 second and third TSS. The overall remission rate after surgery was 76.5%, with a significant higher percentage of remitted patients after the first TSS compared to the subsequent TSS (82% vs 50%, p = 0.014). The remission after the first TSS was significantly higher when performed by a dedicated surgical team (DST) (89.8% vs 71% p = 0.04) and when the immunohistochemical examination confirmed the adrenocorticotropic adenoma (87% vs 55%, p = 0.04). Neuroradiological findings influenced the surgical outcome in a non-significant manner. Post-TSS complications were reported in 32 patients, with no significant variation when TSS was performed by DST. In case of reintervention, remission of disease was obtained in 72.7% of microadenoma, while no remitted patients were observed in case of macroadenomas. The DST did not significantly improve the outcome. Cushing disease is characterized by a broad spectrum of neuroradiological presentation. Despite the availability of a DST make the TSS a safe and effective first-line treatment among all these patients, a precise pre-treatment evaluation is needed in order to define the aim of neurosurgery and to schedule the management of recurrent disease.

OBJECTIVESome studies have highlighted psychological and neuropsychological difficulties and a potential reduction in health-related quality of life (HRQOL) in patients with pituitary tumors, despite hormone deficits or excess. To the authors’ knowledge, this study is the first prospective longitudinal case-control study with the aim of simultaneously testing whether HRQOL and psychiatric and neuropsychological disabilities are related to neural dysfunction due to hypercortisolism per se, or tumor mass and/or surgery in patients with Cushing’s disease (CD). The authors evaluated a homogeneous cohort of patients with CD and nonfunctioning pituitary adenomas (NFPAs) before and after neurosurgery and compared these patients with healthy controls.METHODSTwenty patients (10 with NFPA and 10 with CD) were evaluated using 3 validated questionnaires (SF-36, Beck Depression Inventory–II [BDI-II], and Minnesota Multiphasic Personality Inventory–II [MMPI-II]) to assess HRQOL and psychological status preoperatively and 12 months after neurosurgery. Neuropsychological tests were assessed preoperatively, 3–7 days postoperatively, and 12 months postoperatively. Twenty healthy matched controls were recruited.RESULTSPreoperatively, the NFPA and CD subgroups had worse HRQOL scores than controls on the basis of SF-36 scores, although the NFPA subgroup experienced significant recovery 12 months postoperatively. Preoperatively, CD patients had depressive symptoms according to the BDI-II and MMPI-II that persisted 12 months postoperatively, together with social introversion and hypochondriasis; NFPA patients were similar to controls except for hypochondriasis scores that were clinically significant at all timepoints. Preoperatively and 3–7 days postoperatively, both subgroups showed significant neuropsychological disabilities compared with controls, but only the CD subgroup did not completely recover over time.CONCLUSIONSHRQOL and neuropsychological impairments were observed in all patients at early timepoints, independent of hypercortisolism, tumor mass, and successful surgery. Over time, CD patients showed persistent changes in HRQOL, in particular in social activities. In this light, CD seems to have a strong impact on HRQOL and to be associated with more psychological and neuropsychological comorbidities than NFPA.

Background Despite advances in endoscopic transnasal transsphenoidal surgery (ETNS) for pituitary adenomas (PAs), cerebrospinal fluid (CSF) leakage remains a life-threatening complication predisposing to major morbidity and mortality. In the current study we developed a supervised ML model able to predict the risk of intraoperative CSF leakage by comparing different machine learning (ML) methods and explaining the functioning and the rationale of the best performing algorithm. Methods A retrospective cohort of 238 patients treated via E-TNS for PAs was selected. A customized pipeline of several ML models was programmed and trained; the best five models were tested on a hold-out test and the best classifier was then prospectively validated on a cohort of 35 recently treated patients. Results Intraoperative CSF leak occurred in 54 (22,6%) of 238 patients. The most important risk's predictors were: non secreting status, older age, x-, y- and z-axes diameters, ostedural invasiveness, volume, ICD and R-ratio. The random forest (RF) classifier outperformed other models, with an AUC of 0.84, high sensitivity (86%) and specificity (88%). Positive predictive value and negative predictive value were 88% and 80% respectively. F1 score was 0.84. Prospective validation confirmed outstanding performance metrics: AUC (0,81), sensitivity (83%), specificity (79%), negative predictive value (95%) and F1 score (0,75). Conclusions The RF classifier showed the best performance across all models selected. RF models might predict surgical outcomes in heterogeneous multimorbid and fragile populations outperforming classical statistical analyses and other ML models (SVM, ANN etc.), improving patient management and reducing preventable morbidity and additional costs.

Aneurysmal bone cysts (ABCs) are rare benign pseudotumoral bone lesions with potential aggressive behavior due to the extensive destruction of surrounding bone. Traditionally, these tumors were treated with open surgery, but there is more and more a shift to less invasive procedures. In particular, treatment for spinal ABCs is generally unsatisfactory due to the risk of morbidity, neurological impairment and recurrence, and there is a need for innovative therapies. Denosumab has been reported as a useful treatment in giant cell tumors of bone (GCTB), so its efficacy has been tested also in other fibro-osseus lesions affecting children and adolescents, such as spinal aneurysmal bone cysts. The pediatric literature is limited to case reports and small series, all of which highlight the efficacy of this treatment on lesions growth and associated bone pain. Some of these reports have already reported well known side effects associated with denosumab, such as hypocalcemia at the beginning of the treatment, and rebound hypercalcemia at the discontinuation. The latter seems to be more frequent in children and adolescents than in adults, probably due to the higher baseline bone turnover in children. In addition, the use of denosumab in young patients could affect both bone modeling and remodeling, even if the consequences on the growing skeleton have not been reported in detail. Here we describe the case of a spinal ABC diagnosed in an 8-year old young boy which was not accessible to surgery but responded favorably to denosumab. Our aim is to describe the rapid changes in mineral and bone homeostasis in this patient, that required advice from the experts of the European Reference Network (ERN) for rare bone and endocrine diseases.

BackgroundEctopic adrenocorticotropic syndrome (EAS) is a rare cause of endogenous ACTH-dependent Cushing’s syndrome, usually associated with severe hypercortisolism as well as comorbidities. Tumor detection is still a challenge and often requires several imaging procedures. In this report, we describe a case of an ectopic ACTH secretion with a misleading localization of the responsible tumor due to a concomitant rectal carcinoma.Case presentationA 49-year-old man was referred to our Endocrinology Unit due to suspicion of Cushing’s syndrome. His medical history included metastatic rectal adenocarcinoma, diagnosed 5 years ago and treated with adjuvant chemotherapy, radiotherapy and surgical resection. During follow-up, a thoracic computed tomography scan revealed two pulmonary nodules located in the superior and middle lobes of the right lung with a diameter of 5 and 10 mm, respectively. However, these nodules remained radiologically stable thereafter and were not considered relevant. All biochemical tests were suggestive of EAS (basal ACTH levels: 88.2 ng/L, nv 0–46; basal cortisol levels: 44.2 µg/dl, nv 4.8–19.5; negative response to CRH test and high dose dexamethasone suppression test) and radiological localization of the ectopic ACTH-secreting tumor was scheduled. The CT scan revealed a dimensional increase of the right superior lung nodule (from 5 to 12 mm). [68Ga]-DOTA-TOC PET/CT scan was negative, while [18F]-FDG-PET/CT showed a tracer accumulation in the superior nodule. After a multidisciplinary consultation, the patient underwent thoracic surgery that started with two atypical wedge resections of nodules. Frozen section analyses showed a neuroendocrine tumor on the right middle lobe nodule and a metastatic colorectal adenocarcinoma on the superior lesion. Then, a right superior nodulectomy and a right middle lobectomy with mediastinal lymphadenectomy were performed. The final histopathological examination confirmed a typical carcinoid tumor, strongly positive for ACTH. A post-surgical follow-up showed a persistent remission of Cushing’s syndrome.ConclusionsThe present report describes a case of severe hypercortisolism due to EAS not detected by functional imaging methods, in which the localization of ACTH ectopic origin was puzzled by a concomitant metastatic rectal carcinoma. The multidisciplinary approach was crucial for the management of this rare disease.

IntroductionSyndrome of inappropriate antidiuresis (SIAD) can be a complication of hypothalamus-pituitary surgery. The use of tolvaptan in this setting is not well established, hence the primary aim of this study was to assess the sodium correction rates attained with tolvaptan compared with standard treatments (fluid restriction and/or hypertonic saline). Furthermore, we compared the length of hospital stay in the two treatment groups and investigated the occurrence of overcorrection and side effects including osmotic demyelination syndrome.MethodsWe retrospectively reviewed 308 transsphenoidal surgical procedures performed between 2011 and 2019 at our hospital. We selected adult patients who developed post-operative SIAD and recorded sodium monitoring, treatment modalities and outcomes. Correction rates were adjusted based on pre-treatment sodium levels.ResultsTwenty-nine patients (9.4%) developed post-operative SIAD. Tolvaptan was administered to 14 patients (median dose 15 mg). Standard treatments were employed in 14 subjects (fluid restriction n=11, hypertonic saline n=1, fluid restriction and hypertonic saline n=2). Tolvaptan yielded higher adjusted sodium correction rates (12.0 mmolL-1/24h and 13.4 mmolL-1/48h) than standard treatments (1.8 mmolL-1/24h, p-1/48h, p=0.004, vs. tolvaptan). The correction rate exceeded 10 mmolL-1/24h or 18 mmolL-1/48h in 9/14 and 2/14 patients treated with tolvaptan, respectively, and in no patient who received standard treatments. No side effects including osmotic demyelination occurred. Tolvaptan was associated with a shorter hospital stay (11vs.15 days, p=0.01).ConclusionsTolvaptan is more effective than fluid restriction (with or without hypertonic saline) and allows for a shortened hospital stay in patients with SIAD after transsphenoidal surgery. However, its dose and duration should be carefully tailored, and close monitoring is recommended to allow prompt detection of overcorrection.

Introduction: Available data on pituitary incidentalomas mostly derive from small-scale studies, with heterogeneous inclusion criteria and limited follow-up. No paper has focused specifically on clinically nonfunctioning pituitary in­cidentalomas (CNFPIs). Objective: To describe the charac­teristics and the natural history of patients diagnosed with CNFPIs. Methods: Retrospective multicenter cohort study evaluating hormonal, imaging, and visual field characteristics at diagnosis and during follow-up of CNFPIs investigated in 2 Pituitary Centers. Results: Three hundred and seventy-one patients were included (50.9% microadenomas, 35.6% males). Men were older and more likely to have a macroadenoma (p < 0.01). Totally, 23.7% of patients presented secondary hormonal deficits (SHDs), related to tumor size (higher in macroadenomas; p < 0.001) and age (higher in older patients; p < 0.001). Hypogonadism was the most frequent SHD (15.6%). Two hundred and ninety-six patients had follow-up data, 29.1% required surgery after first evaluation, and 97 had at least 3 years of follow-up. In total, 15.3% adenomas grew (more macroadenomas), but only in microadenomas patients with longer follow-up showed a higher growth trend. Totally, 5.2% of patients developed new SHDs (micro- vs. macroadenomas p = 1.000), and in 60% of them this was not associated with an increase in tumor size. Thirteen additional patients required surgery during follow-up (1 microadenoma at diagnosis). Conclusions: Macroadenomas and age are risk factors for SHD in CNFPIs, which occur at diagnosis in a quarter of patients. During follow-up, macroadenomas tend to grow more often, but microadenomas display higher growth trend as follow-up increases. Deterioration of pituitary function is not always related to adenoma growth.

Selenium is frequently in nutraceuticals for pregnancy, given its role on fertility and thyroid metabolism. However, most evidence rise from non-controlled studies. We aimed to evaluate the protective effect of selenium against thyroid autoimmunity during and after pregnancy. A multicenter, randomized, double-blind, placebo-controlled trial was performed and promoted by the Young Italian Endocrinologists Group (EnGioI)—Italian Society of Endocrinology. Forty-five women with thyroiditis in pregnancy were enrolled and randomly assigned to L-selenomethionine (L-Se-Met) 83 mcg/day or placebo (PLB) and evaluated at 10 ± 2 (T1), 36 ± 2 weeks of gestation (T2) and 6 months after delivery (postpartum, PP). We measured a significant reduction of autoantibodies after pregnancy in L-Se-Met group [at PP: TgAb 19.86 (11.59–52.60), p

Pseudohypoparathyroidism type 1A (PHP1A) is usually diagnosed in childhood or early adulthood. We describe the case of a 64-year-old woman admitted to the Neurological Unit for recurrent episodes of loss of consciousness and seizures. Glycemia and ECG were normal, while hypocalcemia was noted. Clinical history revealed carpo-pedal spasm since the age of 30 years, cognitive impairment, hypothyroidism since early adulthood, and menopause at 30 years. She was taking oral calcium and cholecalciferol for chronic hypocalcemia. Physical features suggested Albright’s osteodystrophy. Blood calcium was confirmed low, with increased parathyroid hormone, moderate 25OH-vitamin D deficiency, and normal creatinine. Brain CT scan revealed calcifications of the basal ganglia, cortical and subcortical white matter, and cerebellum. Therapy was switched to oral calcitriol, with normalization of calcium levels; levetiracetam was started and no further seizures occurred. The clinical diagnosis of PHP1A was confirmed by molecular analysis, which demonstrated the heterozygous c.568_571del mutation of the GNAS gene. Our report illustrates the natural history of a patient with PHP1A, which went undiagnosed until the age of 64 years, with multi-hormonal resistance and clinical sequelae evolving throughout life, and underlines the importance of diagnosing this rare disease, which has a great impact on patients and their family life.

Summary Pseudohypoparathyroidism (PHP) is a heterogeneous group of rare endocrine disorders characterised by normal renal function and renal resistance to the action of the parathyroid hormone. Type 1A (PHP1A), which is the most common variant, also include developmental and skeletal defects named as Albright hereditary osteodystrophy (AHO). We present two cases, a 54- and a 33-year-old male diagnosed with PHP who were referred to us for persistently high levels of serum calcitonin. AHO and multinodular goitre were present in the 54-year-old male, while the second patient was free of skeletal deformities and his thyroid gland was of normal size and without nodular appearance. We performed GNAS molecular analysis (methylation status and copy number analysis by MS-MLPA) in genomic DNA samples for both patients. The analysis revealed a novel missense variant c.131T>G p.(Leu44Pro) affecting GNAS exon 1, in the patient with the clinical diagnosis of PHP1A. This amino acid change appears to be in accordance with the clinical diagnosis of the patient. The genomic DNA analysis of the second patient revealed the presence of the recurrent 3-kb deletion affecting the imprinting control region localised in the STX16 region associated with the loss of methylation (LOM) at the GNAS A/B differentially methylated region and consistent with the diagnosis of an autosomal dominant form of PHP type 1B (PHP1B). In conclusion, hypercalcitoninaemia may be encountered in PHP1A and PHP1B even in the absence of thyroid pathology. Learning points: We describe a novel missense variant c.131T>G p.(Leu44Pro) affecting GNAS exon 1 as the cause of PHP1A. Hypercalcitoninaemia in PHP1A is considered an associated resistance to calcitonin, as suggested by the generalised impairment of Gsα-mediated hormone signalling. GNAS methylation defects, as in type PHP1B, without thyroid pathology can also present with hypercalcitoninaemia.

Objective High insulin-like growth factor 1 (IGF-1) and unsuppressed growth hormone (GH) levels after glucose load confirm the diagnosis of acromegaly. Management of patients with conflicting results could be challenging. Our aim was to evaluate the clinical and hormonal evolution over a long follow-up in patients with high IGF-1 but normal GH nadir (GHn < 0.4 μg/L according to the latest guidelines). Design Retrospective cohort study. Methods We enrolled 53 patients presenting high IGF-1 and GHn < 0.4 μg/L, assessed because of clinical suspicion of acromegaly or in other endocrinological contexts (e.g. pituitary incidentaloma). Clinical and hormonal data collected at the first and last visit were analyzed. Results At the first evaluation, the mean age was 54.1 ± 15.4 years, 34/53 were females, median IGF-1 and GHn were +3.1 SDS and 0.06 μg/L, respectively. In the whole group, over a median time of 6 years, IGF-1 and GHn levels did not significantly change (IGF-1 mean of differences: −0.58, P = 0.15; GHn +0.03, P = 0.29). In patients with clinical features of acromegaly, the prevalence of acromegalic comorbidities was higher than in the others (median of 3 vs 1 comorbidities per patient, P = 0.005), especially malignancies (36% vs 6%, P = 0.03), and the clinical worsening overtime was more pronounced (4 vs 1 comorbidities at the last visit). Conclusions In patients presenting high IGF-1 but GHn < 0.4 μg/L, a hormonal progression is improbable, likely excluding classical acromegaly in its early stage. However, despite persistently low GH nadir values, patients with acromegalic features present more acromegalic comorbidities whose rate increases over time. Close clinical surveillance of this group is advised.

BackgroundHypoparathyroidism (HypoPT) or pseudo-hypoparathyroidism (pseudo-HypoPT) during pregnancy may cause maternal and fetal/neonatal complications. In this regard, only a few case reports or case series of pregnant or lactating women have been published. The purpose of this study was to describe clinical and biochemical course, pharmacological management, and potential adverse events during pregnancy and post-partum in pregnant women with HypoPT or pseudo-HypoPT. This was a retrospective, observational, multicenter, study involving nine Italian referral centers for endocrine diseases affiliated with the Italian Society of Endocrinology and involved in “Hypoparathyroidism Working Group”.ResultsThis study identified a cohort of 28 women (followed between 2005 and 2018) with HypoPT (n = 25, 84% postsurgical, 16% idiopathic/autoimmune) and pseudo-HypoPT (n = 3). In HypoPT women, the mean calcium carbonate dose tended to increase gradually from the first to third trimester (+ 12.6%) in pregnancy. This average increase in the third trimester was significantly greater compared to the pre-pregnancy period (pvalue = 0.03). However, analyzing the individual cases, in 44% the mean calcium dosage remained unchanged throughout gestation. Mean calcitriol doses tended to increase during pregnancy, with a statistically significant increase between the third trimester and the pre-pregnancy period (pvalue = 0.02). Nevertheless, analyzing the individual cases, in the third trimester most women with HypoPT (64%) maintained the same dosage of calcitriol compared to the first trimester. Both mean calcium carbonate and calcitriol doses tended to decrease from the third trimester to the post-partum six months. Most identified women (~ 70%) did not display maternal complications and (~ 90%) maintained mean serum albumin-corrected total calcium levels within the low-to-mid normal reference range (8.5 ± 0.8 mg/dl) during pregnancy. The main complications related to pregnancy period included: preterm birth (n = 3 HypoPT women), and history of miscarriages (n = 6 HypoPT women and n = 2 pseudo-HypoPT women).ConclusionThis study shows that mean serum albumin-corrected total calcium levels were carefully monitored during pregnancy and post-pregnancy, with limited evaluation of other biochemical parameters, such as serum phosphate, 24 h urinary calcium, 25-OH vitamin D, and creatinine clearance. To avoid complications in mothers affected by (HypoPT) or (pseudo-HypoPT) and offspring, intense biochemical, clinical and pharmacological monitoring during pregnancy and breastfeeding is highly recommended.

Purpose A long-lasting remission of acromegaly after somatostatin analogues (SAs) withdrawal has been described in some series. Our aim was to update the disease evolution after SAs withdrawal in a cohort of acromegalic patients. Methods We retrospectively evaluated 21 acromegalic patients previously included in a multicentre study (Ronchi et al. 2008), updating data at the last follow-up. We added further 8 patients selected for SAs withdrawal between 2008–2018. Pituitary irradiation represented an exclusion criterion. The withdrawal was suggested after at least 9 months of clinical and hormonal disease control. Clinical and biochemical data prior and after SAs withdrawal were analysed. Results In the whole cohort (29 patients) mean age was 50 ± 14.9 years and 72.4% were females. In 69% pituitary surgery was previously performed. Overall, the median time of treatment before SAs withdrawal was 53 months (IQR = 24–84). At the last follow up in 2019, 23/29 patients (79.3%) had a disease relapse after a median time of 6 months (interquartile range or IQR = 3–12) from the drug suspension, while 6/29 (20.7%) were still on remission after 120 months (IQR = 66–150). IGF-1 levels were significantly lower before withdrawal in patients with persistent remission compared to relapsing ones (IGF-1 SDS: -1.5 ± 0.6 vs -0.11 ± 1, p = 0.01). We did not observe any other difference between patients with and without relapse, including SAs formulation, dosage and treatment duration. Conclusion A successful withdrawal of SAs is possible in a subset of well-controlled acromegalic patients and it challenges the concept that medical therapy is a lifelong requirement.

Context Pseudohypoparathyroidism (PHP) is a group of disorders characterized by hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH) levels as a result of end-organ resistance to PTH. Objective To describe a cohort of 26 patients with PHP followed in a single tertiary center. Methods Clinical, biochemical, radiological, and genetic analysis of the GNAS gene in 26 patients recruited since 2002. Results Ten patients harbored a GNAS mutation, 15 epigenetic abnormalities at the GNAS locus, and 1 did not show genetic or epigenetic abnormalities. According to clinical, biochemical, and genetic features, patients were classified as PHP1A, PHP1B, and pseudopseudohypoparathyroidism. Patients with PHP1A had an earlier diagnosis and more cases with family history, Albright hereditary osteodystrophy (AHO) features, hormonal resistance, and hypertension. Obesity was a common feature. No difference in biochemical values was present among PHP1A and PHP1B. Intracerebral calcification occurred in 72% of patients with no difference among PHP1A and PHP1B subgroups. No significant difference was observed between patients with and without intracerebral calcification for the time-weighted average values of total serum calcium, phosphate, calcium–phosphate product, and PTH fold increase. A borderline association between cerebral calcification and age at the time of diagnosis (P = .04) was found in the whole cohort of patients. No renal calcifications were found in the overall cohort. Conclusion Patients with PHP1A more frequently have AHO features as well as hypertension than patients with PHP1B. Patients with PHP presented a high rate of intracerebral calcification with no significant difference between subgroups. No increased risk of renal calcifications was also found in the entire cohort.

BackgroundThe impact of the Covid-19 infection on patients with chronic endocrine disease is not fully known. We describe here the first case of a pregnant woman with Covid-19 acute infection and non-classical congenital adrenal hyperplasia (NCAH).Case descriptionA woman at 36 weeks of gestation was referred to our Maternity Hospital for premature rupture of membranes (PROM). Her medical history was positive for NCAH on chronic steroid replacement till the age of 17 years (cortisone acetate and dexamethasone, both in the morning). At admission, her naso-oro-pharyngeal swab resulted positive for SARS-CoV-2. Due to hyperpyrexia and late preterm PROM, cesarean section was planned, and she was started on a 100 mg-bolus of hydrocortisone, followed by continuous infusion of 200 mg/24 h. A female neonate in good clinical condition and with a negative nasopharyngeal Covid-19 swab was delivered. On secondpostpartumday, the mother was in good condition and was switched to oral steroid therapy. On thirdpostpartumday she worsened, with radiological signs of acute pulmonary embolism. Oro-tracheal intubation and mechanical ventilation were started, and she was switched back to intravenous steroid therapy. On April 30, pulmonary embolism was resolved, and on May 13th she was discharged in good condition.ConclusionsWe report the first case of Covid-19 acute infection that occurred in late-pregnancy in a woman with NCAH on chronic steroid replacement. The management of the patient in a reference center with early involvement of a multidisciplinary team granted prompt care and adequate protection for all the involved sanitary operators.

Context Acromegalic patients have an increased vertebral fracture (VFx) risk due to bone quality reduction, independently of bone mineral density (BMD). Objective The aim of the study is to describe bone quality in acromegaly, measured by trabecular bone score (TBS), a noninvasive index for assessing bone microarchitecture. Methods We collected data from 18 patients (13 female, age 56.2 ± 15 years) newly diagnosed with acromegaly. Thirty-six age- and sex-matched healthy controls were also recruited. Pituitary function, bone and calcium-phosphorous metabolism, and BMD at spine and femur and TBS (by dual-energy x-ray absorptiometry) were assessed in acromegalic patients at diagnosis and 12 months after the achievement of insulin-like growth factor 1 (IGF-1) normalization. Results At diagnosis, BMD and the VFx prevalence were comparable between patients and controls (28.3 ± 5.9 vs 27.6 ± 3.7 and 11% vs 8.3%), whereas TBS was significantly lower in acromegalic patients (1.20 ± 0.13 vs 1.30 ± 0.06; P Conclusion Acromegalic patients have impaired bone quality despite normal density. Achieving normal growth hormone secretion rapidly leads to the normalization of bone turnover.

Pituitary neuroendocrine tumors (PitNETs) are the most common intracranial neoplasms. Although generally benign, they can show a clinically aggressive course, with local invasion, recurrences, and resistance to medical treatment. No universally accepted biomarkers of aggressiveness are available yet, and predicting clinical behavior of PitNETs remains a challenge. In rare cases, the presence of germline mutations in specific genes predisposes to PitNET formation, as part of syndromic diseases or familial isolated pituitary adenomas, and associates to more aggressive, invasive, and drug-resistant tumors. The vast majority of cases is represented by sporadic PitNETs. Somatic mutations in the α subunit of the stimulatory G protein gene (gsp) and in the ubiquitin-specific protease 8 (USP8) gene have been recognized as pathogenetic factors in sporadic GH- and ACTH-secreting PitNETs, respectively, without an association with a worse clinical phenotype. Other molecular factors have been found to significantly affect PitNET drug responsiveness and invasive behavior. These molecules are cytoskeleton and/or scaffold proteins whose alterations prevent proper functioning of the somatostatin and dopamine receptors, targets of medical therapy, or promote the ability of tumor cells to invade surrounding tissues. The aim of the present review is to provide an overview of the genetic and molecular alterations that can contribute to determine PitNET clinical behavior. Understanding subcellular mechanisms underlying pituitary tumorigenesis and PitNET clinical phenotype will hopefully lead to identification of new potential therapeutic targets and new markers predicting the behavior and the response to therapeutic treatments of PitNETs.

The identification of hyperandrogenism in polycystic ovary syndrome (PCOS) is concerning because of the poor accuracy of the androgen immunoassays (IA) and controversies regarding which androgens should be measured. The aim of our study was to evaluate the impact of the assessment of testosterone (T) and androstenedione (A) by liquid chromatography in tandem with mass spectrometry (LC/MS-MS), in the diagnosis of PCOS. We evaluated 131 patients referred for suspected PCOS. Fourteen patients in total were excluded, some because of other diagnosis (n = 7) or incomplete diagnostic workup (n = 7). We measured T and A both by IA and LC-MS/MS in the 117 subjects included. We calculated free T (fT) by the Vermeulen formula and recorded clinical and metabolic data. 73 healthy females served as controls to derive immunoassays (IA) and LC-MS/MS reference intervals for T, fT and A. PCOS was confirmed in 90 subjects by IA and in 93 (+3.3%) by LC-MS/MS. The prevalence of biochemical hyperandrogenism in PCOS by LC-MS/MS increased from 81.7% to 89.2% if A was also considered. The most frequently elevated androgens were fT (73.1%) and A (64.5%) and they had similar levels of accuracy in differentiating PCOS and controls (0.34 ng/dL, Sn 91% Sp 89%, 1.16 ng/mL, Sn 91% Sp 88%, respectively). Free testosterone correlated with body mass index (BMI), homeostatic model assessment (HOMA)-index, glycated hemoglobin (HbA1c), and sex-binding globulin (SHBG). The results confirm that LC-MS/MS is slightly more sensitive than IA in the diagnosis of PCOS with LC-MS/MS detecting higher levels of fT and A. Moreover, assessment of fT and A by LC-MS/MS had a similar level of accuracy in discriminating between PCOs and control subjects. Lastly, fT by LC-MS/MS correlates with adverse metabolic parameters.

Background: Despite advances in endoscopic transnasal transsphenoidal surgery (E-TNS) for pituitary adenomas (PAs), cerebrospinal fluid (CSF) leakage remains a life-threatening complication as it predisposes to meningitis and tension pneumocephalus. The purpose of the current study is to develop an accurate supervised ML model able to predict the risk of intraoperative CSF leakage by comparing different machine learning (ML) methods. Methods: A cohort of patients consecutively treated via E-TNS for PAs was selected. Clinical, radiological and endocrinological preoperative data were reviewed and elaborated through a features selecting algorithm. A customized pipeline of several ML models was programmed and trained in parallel; the best five models were included for further analyses. Selected risk factors were then used for training and hyperparameters optimization. Results: Intraoperative CSF leak occurred in 54 (22,6%) of 238 patients. Best risk’s predictors were: non secreting status, older age, x-, y- and z-axes diameters, ICD and R ratio. The random forest (RF) classifier outperformed other models, with an AUC of 0,84, high sensitivity (87%) and specificity (82%). Positive predictive value and negative predictive value were 69% and 93% respectively. F1 score was 0,87. Conclusion: A supervised machine learning prediction model able to identify patients at higher risk of intraoperative CSF leakage was trained and internally validated. The random forest classifier showed the best performance across all models selected by the authors. RF models might predict surgical outcomes in heterogeneous multimorbid and fragile populations outperforming classical statistical analyses and other machine learning models.

TNM 8th edition introduces changes in the staging of patients with differentiated thyroid carcinoma (DTC). This study aims at assessing the value of TNM 8th edition in predicting response to therapy and structural recurrence of DTC. Four hundred and eighty DTC patients were retrospectively evaluated by 7th and 8th editions of TNM staging system in relationship with risk stratification, response to therapy and recurrence of disease as defined by 2015 ATA guidelines. As compared to the 7th edition, TNM 8th led to downstage 136 patients (28.3%), with 97.5% of patients falling into lower stages (I–II) and only 2.5% remaining in higher stages (III–IV) (P th were classified more frequently at intermediate-high risk (P P = 0.009) and had higher risk of structural recurrence (P = 0.002) as compared to patients who were in the same TNM stages but were not downstaged. Specifically, the risk of structural recurrence was significantly higher in patients in whom the downstaging was induced by changes in tumour classification (hazard ratio (HR) 6.18, 95% CI 2.20–17.40; P = 0.001) but not in those who were downstaged for the increase in age cut-off (HR 2.80, 95% CI 0.86–9.19; P = 0.09). In conclusion, TNM 8th edition did not show reliability in predicting aggressiveness of DTC. In fact, the downstaging of DTC patients especially when performed due to changes in tumour classification may overlook patients predisposed to structural recurrence, potentially causing uncertainty in the therapeutic decision-making at the time of disease’s diagnosis.