Arginine or Hypertonic Saline-Stimulated Copeptin to Diagnose AVP Deficiency.

BACKGROUND: Distinguishing between arginine vasopressin (AVP) deficiency and primary polydipsia is challenging. Hypertonic saline-stimulated copeptin has been used to diagnose AVP deficiency with high accuracy but requires close sodium monitoring. Arginine-stimulated copeptin has shown similar diagnostic accuracy but with a simpler test protocol. However, data are lacking from a head-to-head comparison between arginine-stimulated copeptin and hypertonic saline-stimulated copeptin in the diagnosis of AVP deficiency. METHODS: In this international, noninferiority trial, we assigned adult patients with polydipsia and hypotonic polyuria or a known diagnosis of AVP deficiency to undergo diagnostic evaluation with hypertonic-saline stimulation on one day and with arginine stimulation on another day. Two endocrinologists independently made the final diagnosis of AVP deficiency or primary polydipsia with use of clinical information, treatment response, and the hypertonic-saline test results. The primary outcome was the overall diagnostic accuracy according to prespecified copeptin cutoff values of 3.8 pmol per liter after 60 minutes for arginine and 4.9 pmol per liter once the sodium level was more than 149 mmol per liter for hypertonic saline. RESULTS: Of the 158 patients who underwent the two tests, 69 (44%) received the diagnosis of AVP deficiency and 89 (56%) received the diagnosis of primary polydipsia. The diagnostic accuracy was 74.4% (95% confidence interval [CI], 67.0 to 80.6) for arginine-stimulated copeptin and 95.6% (95% CI, 91.1 to 97.8) for hypertonic saline-stimulated copeptin (estimated difference, -21.2 percentage points; 95% CI, -28.7 to -14.3). Adverse events were generally mild with the two tests. A total of 72% of the patients preferred testing with arginine as compared with hypertonic saline. Arginine-stimulated copeptin at a value of 3.0 pmol per liter or less led to a diagnosis of AVP deficiency with a specificity of 90.9% (95% CI, 81.7 to 95.7), whereas levels of more than 5.2 pmol per liter led to a diagnosis of primary polydipsia with a specificity of 91.4% (95% CI, 83.7 to 95.6). CONCLUSIONS: Among adult patients with polyuria polydipsia syndrome, AVP deficiency was more accurately diagnosed with hypertonic saline-stimulated copeptin than with arginine-stimulated copeptin. (Funded by the Swiss National Science Foundation; CARGOx ClinicalTrials.gov number, NCT03572166.).

The Novel SSTR3 Agonist ITF2984 Exerts Antimitotic and Proapoptotic Effects in Human Non-Functioning Pituitary Neuroendocrine Tumor (NF-PitNET) Cells.

Somatostatin receptor ligands (SRLs) with high affinity for somatostatin receptors 2 and 5 (SSTR2 and SSTR5) are poorly efficacious in NF-PitNETs, expressing high levels of SSTR3. ITF2984 is a pan-SSTR ligand with high affinity for SSTR3, able to induce SSTR3 activation and to exert antitumoral activity in the MENX rat model. The aim of this study was to test ITF2984's antiproliferative and proapoptotic effects in NF-PitNET primary cultured cells derived from surgically removed human tumors and to characterize their SSTR expression profile. We treated cells derived from 23 NF-PitNETs with ITF2984, and a subset of them with octreotide, pasireotide (SRLs with high affinity for SSTR2 or 5, respectively), or cabergoline (DRD2 agonist) and we measured cell proliferation and apoptosis. SSTR3, SSTR2, and SSTR5 expression in tumor tissues was analyzed by qRT-PCR and Western blot. We demonstrated that ITF2984 reduced cell proliferation (-40.8 (17.08)%, p < 0.001 vs. basal, n = 19 NF-PitNETs) and increased cell apoptosis (+41.4 (22.1)%, p < 0.001 vs. basal, n = 17 NF-PitNETs) in all tumors tested, whereas the other drugs were only effective in some tumors. In our model, SSTR3 expression levels did not correlate with ITF2984 antiproliferative nor proapoptotic effects. In conclusion, our data support a possible use of ITF2984 in the pharmacological treatment of NF-PitNET.

Predicting tumor consistency and extent of resection in non-functioning pituitary tumors.

PURPOSE: To (1) identify a radiological parameter to predict non-functioning pituitary tumor (NFPT) consistency, (2) examine the relationship between NFPT consistency and extent of resection (EOR), (3) investigate if tumor consistency predictors can anticipate EOR. METHODS: The ratio (T2SIR) between the T2 min signal intensity (SI) of the tumor and the T2 mean SI of the CSF was the main radiological parameter, being determined through a radiomic-voxel analysis and calculated using the following formula: T2SIR = [(T2 tumor mean SI - SD)/T2 CSF SI]. The tumor consistency was pathologically estimated as collagen percentage (CP). EOR of NFPTs was evaluated by exploiting a volumetric technique and its relationship with the following explanatory variables was explored: CP, Knosp-grade, tumor volume, inter-carotid distance, sphenoidal sinus morphology, Hardy-grade, suprasellar tumor extension. RESULTS: A statistically significant inverse correlation between T2SIR and CP was demonstrated (p = 0.0001), with high diagnostic power of T2SIR in predicting NFPT consistency (ROC curve analysis' AUC = 0.88; p = 0.0001). The following predictors of EOR were identified in the univariate analysis: CP (p = 0.007), preoperative volume (p = 0.045), Knosp grade (p = 0.0001), tumor suprasellar extension (p = 0.044). The multivariate analysis demonstrated two variables as unique predictors of EOR: CP (p = 0.002) and Knosp grade (p = 0.001). The T2SIR was a significant predictor of EOR both in the univariate (p = 0.01) and multivariate model (p = 0.003). CONCLUSION: This study offers the potential to improve NFPT preoperative surgical planning and patient counseling by employing the T2SIR as a preoperative predictor of tumor consistency and EOR. Meanwhile, tumor consistency and Knosp grade were found to play an important role in predicting EOR.

High Filamin a Expression in Adrenocortical Carcinomas Is Associated with a Favourable Tumour Behaviour: A European Multicentric Study.

The insulin-like growth factor 2 (IGF2) promotes cell growth by overactivating the IGF system in an autocrine loop in adrenocortical carcinomas (ACCs). The cytoskeleton protein filamin A (FLNA) acts as a repressor of IGF2 mitogenic signalling in ACC cells. The aims of this study were to test FLNA expression by immunohistochemistry in 119 ACCs and 26 adrenocortical adenomas (ACAs) and to evaluate its relationship with clinicopathological features and outcome in ACCs. We found that 71.4% of ACCs did not express FLNA, whereas FLNA absence was a rare event in ACAs (15.4%, p < 0.001 vs. ACCs). In addition, the expression of FLNA was associated with a less aggressive tumour behaviour in ACCs. Indeed, the subgroup of ACCs with high FLNA showed a lower ENSAT stage, Weiss score, and S-GRAS score compared to ACCs with low FLNA expression (p < 0.05). Moreover, patients with high FLNA had a longer overall survival than those with low FLNA (p < 0.05). In conclusion, our data suggest that FLNA may represent a "protective" factor in ACCs, and the integration of FLNA immunohistochemical expression in ACC tissues along with other clinical and molecular markers could be helpful to improve diagnostic accuracy and prognosis prediction in ACCs.

Prognostic value of copeptin and mid-regional proadrenomedullin in COVID-19-hospitalized patients.

BACKGROUND: Biomarkers are used for diagnosis, risk stratification and medical decisions. Copeptin and mid-regional proadrenomedullin (MR-proADM) are markers of stress and endothelial function, respectively, which have been studied in pneumonia, sepsis and septic shock. This study aimed to assess whether copeptin and MR-proADM could predict coronavirus disease 2019 (COVID-19) in-hospital outcomes, that is multi-system complications, length of stay and mortality. METHODS: Copeptin and MR-proADM were assessed at admission in 116 patients hospitalized with COVID-19. Data were retrospectively extracted from an online database. The primary endpoint was in-hospital mortality. The secondary endpoints were in-hospital complications, the composite outcome 'death, or admission to intensive care unit, or in-hospital complications', and length of stay. The predictive power was expressed as area under the receiver operator characteristic curve (AUROC). RESULTS: Copeptin was increased in non-survivors (median 29.7 [interquartile range 13.0-106.2] pmol/L) compared to survivors (10.9 [5.9-25.3] pmol/L, p < 0.01). The AUROC for mortality was 0.71, with a hazard ratio of 3.67 (p < 0.01) for copeptin values > 25.3 pmol/L. MR-proADM differentiated survivors (0.8 [0.6-1.1] nmol/L) from non-survivors (1.5 [1.1-2.8] nmol/L, p < 0.001) and yielded a AUROC of 0.79 and a hazard ratio of 7.02 (p < 0.001) for MR-proADM values > 1.0 nmol/L. Copeptin and MR-proADM predicted sepsis (AUROC 0.95 and 0.96 respectively), acute kidney injury (0.87 and 0.90), the composite outcome (0.69 and 0.75) and length of stay (r = 0.42, p < 0.001, and r = 0.46, p < 0.001). CONCLUSIONS: Admission MR-proADM and copeptin may be implemented for early risk stratification in COVID-19-hospitalized patients to help identify those eligible for closer monitoring and care intensification.

Vertebral Fractures Associated with Spinal Sagittal Imbalance and Quality of Life in Acromegaly: A Radiographic Study with EOS 2D/3D Technology.

INTRODUCTION: Acromegaly is commonly complicated by arthropathy and skeletal fragility with high risk of vertebral fractures (VFs). OBJECTIVE: This study aimed to assess whether VFs may be associated with sagittal spine deformities, arthropathy, impaired quality of life (QoL), pain, and disability. METHODS: Thirty-eight patients with acromegaly (median age: 55 years, 20 males) and 38 matched control subjects were evaluated by a low-dose sagittal and coronal planes, X-ray imaging system (EOS®-2D/3D) for morphometric VFs, radiological signs of spine arthropathy, and spine deformities (Cobb thoracic index ≥40°, pelvic incidence minus lumbar lordosis ≥10°, pelvic tilt >20°, and sagittal vertical axis ≥4 cm) determining sagittal spine imbalance. Acromegalic patients were also evaluated by questionnaires for QoL (Acromegaly QoL Questionnaire [AcroQoL] and Short Form-36 [SF-36]) and pain and disability (Western Ontario and McMaster University [WOMAC]). RESULTS: Acromegalic patients showed higher prevalence of thoracic hyperkyphosis (i.e., Cobb thoracic index ≥40°; p = 0.04) and pelvic tilt >20° (p = 0.02) than control subjects. VFs were found in 34.2% of acromegalic patients (p = 0.003 vs. control subjects), in relationship with higher prevalence of hyperkyphosis (p = 0.03), pelvic tilt >20° (p = 0.04), sagittal vertical axis ≥4 cm (p = 0.03), and moderate/severe subchondral degeneration (p = 0.01). Moreover, patients with VFs had lower AcroQoL general health (p = 0.007) and SF-36 general health (p = 0.002) scores and higher WOMAC pain (p = 0.003) and global (p = 0.009) scores than patients who did not fracture. CONCLUSIONS: In acromegaly, VFs may be associated with spine deformities and sagittal imbalance, spine arthropathy, impaired QoL, and disability.

Central hypogonadism in Klinefelter syndrome: report of two cases and review of the literature.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Clinically Nonfunctioning Pituitary Incidentalomas: Characteristics and Natural History.

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 in-cidentalomas (CNFPIs). OBJECTIVE: To describe the charac-teristics 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.

The suprasellar volume of nonfunctioning pituitary adenomas: a useful tool for predicting visual field deficits.

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 1.5 mL. 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 1.5 mL, 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.

Recovery of Adrenal Function after Pituitary Surgery in Patients with Cushing Disease: Persistent Remission or Recurrence?

BACKGROUND: Cushing disease (CD) represents the principal cause of endogenous hypercortisolism. The first-line therapy of CD is surgical removal of the ACTH-secreting pituitary adenoma, which is generally followed by adrenal insufficiency (AI). OBJECTIVE: To analyze the recovery of AI in patients with CD after pituitary surgery in relation with recurrence and persistent remission of CD. PATIENTS AND METHODS: We performed a retrospective analysis of patients with CD who met the following inclusion criteria: adult age, presence of AI 2 months after the surgical intervention, and a minimum follow-up of 3 years after the surgical intervention. RESULTS: Sixty-one patients were followed for a median of 6 years. Ten (16.4%) patients recurred during follow-up. The patients who restored adrenal function did so after a median time of 19 months, with a significantly shorter time in the recurrence group (12.5 vs. 25 months, p = 0.008). All 10 patients who recurred recovered their adrenal function within 22 months. The recovery rate of AI in the persistent remission group was 37.3% (19/51) at 3 years and 55.8% (24/43) at 5 years. In all patients the duration of AI was negatively associated with disease recurrence. CONCLUSION: The duration of postsurgical AI in patients with recurrent CD is significantly shorter than that in patients with persistently remitted CD, and this parameter may be a useful predictor of recurrence. Patients showing a normal pituitary-adrenal axis within 2 years after surgery should be strictly monitored as they are at higher risk of disease relapse.

Multi Matrix System Mesalazine Plus Rectal Mesalazine in the Treatment of Mild to Moderately Active Ulcerative Proctitis.

BACKGROUND: Mesalazine 1 g suppository/die is used for mild to moderately active ulcerative proctitis (UP). Whether addiction of Multi Matrix System (MMX) mesalazine increases the remission rate of UP and prevents proximal extension of disease is unknown. METHODS: This is a retrospective study on 116 outpatients with UP who had been treated with one of the following regimens: (1) MMX mesalazine 1.2 g/die plus mesalazine suppositories for 8 ± 2 weeks and, subsequently, MMX mesalazine 1.2 g/die plus rectal mesalazine 1 g every other day for at least 6 months; (2) mesalazine 1 g suppositories/die alone for 8 ± 2 weeks and, subsequently, rectal mesalazine 1 g every other day for 6 more months. Patients were evaluated clinically at 2 months (±2 weeks) and endoscopically at 6 months (±2 weeks). For categorical variables, Pearson chi-square test was used. RESULTS: A total of 46 of 55 patients (84%) on combined therapy and 49 of 61 patients (80%) on rectal mesalazine reached clinical remission (p > 0.05; OR 0.79, 95% CI 0.30-2.07). At 6 months follow-up, proximal extension of disease was observed in 7 of 55 (14%) patients on combined therapy and in 18 of 61 (29%) patients on rectal mesalazine alone (p < 0.05; OR 2.87, 95% CI 1.09-7.53). CONCLUSIONS: Oral MMX mesalazine plus rectal mesalazine combined treatment is associated with prevention of proximal extension of the disease compared with rectal mesalazine alone.

Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation.

BACKGROUND: Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood. METHODS: We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly. RESULTS: We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. All the patients had disease onset during early childhood. Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years. Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein-coupled receptor, was overexpressed in patients' pituitary lesions. We identified a recurrent GPR101 mutation (p.E308D) in 11 of 248 patients with acromegaly, with the mutation found mostly in tumors. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone-producing cells. CONCLUSIONS: We describe a pediatric disorder (which we have termed X-linked acrogigantism [X-LAG]) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone. Duplication of GPR101 probably causes X-LAG. We also found a recurrent mutation in GPR101 in some adults with acromegaly. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).

Hypothalamic-Pituitary Axis in Non-Functioning Pituitary Adenomas: Focus on the Prevalence of Isolated Central Hypoadrenalism.

INTRODUCTION: Non-functioning pituitary adenomas (NFPA) account for about 40% of pituitary tumors. Pituitary deficiencies are present at diagnosis in 60-80% of NFPA, and, classically, growth hormone (GH) secretion is lost first, while adrenocorticotropic hormone is expected to disappear last. The aim of this study was to evaluate the incidence of multiple or isolated pituitary deficiencies in a large series of NFPA. MATERIALS AND METHODS: We retrospectively analyzed data on 218 NFPA cases (59% females, 59% with macroadenomas, average age: 50.2 ± 17 years) followed up at our center from 1990 to 2013. At diagnosis all patients had a complete evaluation of pituitary function in basal conditions and provocative tests for the hypothalamic-pituitary-adrenal axis, while tests for GH deficiency (GHD) were carried out in 38%. RESULTS: 52.3% of patients (65.6% of macroadenomas, 33.3% of microadenomas) presented at least 1 pituitary deficiency: isolated deficiency in 29.8%, multiple deficiencies in 30% and panhypopituitarism in 9%. Isolated deficiencies were hypogonadism in 11.5% of patients (8% in micro-, 14% in macroadenomas), hypoadrenalism in 10.1% (14% in micro-, 7% in macroadenomas) and GHD in 8.3% (8.9% in micro-, 7.8% in macroadenomas). About 30% of microadenomas had at least 1 pituitary deficiency at diagnosis, independently of tumor localization within the sellar region. CONCLUSIONS: The presence of isolated hypoadrenalism suggests that the order of appearance of hypopituitarism does not always follow the one expected. Given the relatively high prevalence of isolated hypoadrenalism even in microadenomas, we suggest a full assessment of basal and dynamic pituitary function in all NFPA regardless of tumor size.

Role of IGF1-(CA)19 promoter microsatellite in the clinical presentation of acromegaly.

BACKGROUND: A highly polymorphic Cytosine-Adenosine (CA) repeat sequence microsatellite has been identified in the promoter region of IGF1 gene. Several studies investigated the relationship between IGF1-(CA)n polymorphism and IGF1 levels, with conflicting results. Aim of this study was to investigate the influence of this polymorphism on clinical and biochemical characteristics of acromegalic patients. METHODS: Eighty-eight acromegalic patients and 104 normal subjects were included in the study. Blood DNA was extracted and analysed by microsatellite technique using capillary electrophoresis. Patients and controls were subdivided in 19/19 [homozygous for the (CA)19 allele], 19/X [heterozygous for the (CA)19 allele] and X/X (any other genotype). RESULTS: The genotype frequency was significantly different between patients and controls, the proportion of 19/19 being lower (28·4% vs. 50·0%) and 19/X and X/X higher in acromegalic patients than in controls (P = 0·004). There were no significant differences in age, gender, basal and nadir GH, IGF1-SDS, tumour size, metabolic parameters, outcome and treatment among the three groups. The different frequency of genotypes in acromegalic patients vs. controls, as well as the lack of relationship between IGF1-(CA)n polymorphism and clinical and biochemical data in acromegalic patients, was confirmed using an additional alternative genotyping considering (CA)19 and (CA)20 homozygotes and heterozygotes vs. alleles with more than 19 of 20 repeats or less. CONCLUSIONS: Our results do not support the hypothesis that IGF-(CA)n alleles may have a significant role in determining clinical, biochemical and outcome of patients with acromegaly. The possible role of IGF1 polymorphism on susceptibility to acromegaly remains to be investigated.

High prevalence of hypercalcitoninemia in a large cohort of adult and paediatric patients with PTH resistance syndromes.

BACKGROUND: Pseudohypoparathyroidism (PHP) refers to a group of rare hereditary disorders associated with resistance to parathormone (PTH) and other hormones now termed inactivating PTH/PTHrP disorders (iPPSD). Hypercalcitoninemia has been seldom reported in small series. Our aim was to investigate the characteristics of hypercalcitoninemia in paediatric and adult patients with PHP/iPPSD. METHODS: We retrospectively collected data from two cohorts from two European Endocrinology tertiary centers: the paediatric cohort comprised 88 children with available calcitonin (CT) measurements; the adult cohort included 43 individuals with simultaneous CT and PTH measurements. RESULTS: In the paediatric cohort 65.9% had hypercalcitoninemia (median CT 15 ng/L); in the adult cohort 53.5% (mean CT 21.6 ng/L). There was no difference between CT in paediatric and adult population; we observed stable CT levels over a median follow-up of 134.5 months in adults. Notably, no correlations were detected between CT and PTH levels. Other etiologies of hypercalcitoninemia were excluded, adult patients underwent regular thyroid ultrasound (US) to screen for medullary thyroid cancer (MTC). We performed 20 calcium stimulation tests in adult patients. While there was a significant difference in basal and peak CT between our patients, healthy subjects and subjects with MTC, there was no difference with patients with C-cell hyperplasia. CONCLUSIONS: This study underscores the common occurrence of hypercalcitoninemia in both paediatric and adult PHP/iPPSD patients, in particular with subtypes iPPSD2-iPPSD3. Furthermore, these patients show an hyperresponsiveness to calcium stimulation test falling between healthy subjects and patients with MTC. These findings contribute into the understanding of CT dynamics in the context of PHP/iPPSD.

Testosterone therapy does not affect coagulation in male hypogonadism: a longitudinal study based on thrombin generation.

CONTEXT: Testosterone therapy has been variably associated with increased thrombotic risk but investigations of global coagulation in this setting are lacking. OBJECTIVE: To compare global coagulation of hypogonadal men before (T0) and 6 months after (T1) starting testosterone replacement therapy (TRT), and healthy controls. DESIGN: Observational prospective cohort study. SETTING: Two tertiary endocrinological ambulatory care centers. PATIENTS: Thirty-eight men with hypogonadism (mean age 55, SD 13) and 38 age-matched healthy controls. INTERVENTIONS: Thrombin generation assay (TGA) was performed at T0 and T1 in hypogonadal men and in controls. TGA is an in vitro procedure based on the continuous registration of thrombin generation and decay under conditions mimicking the process that occurs in vivo. MAIN OUTCOME MEASURES: The following TGA parameters were recorded: lag-time; thrombin-peak concentration; time-to-reach the peak, velocity index and endogenous thrombin potential (ETP), the latter representing the total amount of thrombin generated under the driving forces of procoagulants opposed by the anticoagulants. PC, antithrombin, factor (F)VIII, and fibrinogen were assessed. RESULTS: No changes of TGA parameters were observed between T0 and T1. Hypogonadal men displayed significantly higher ETP, fibrinogen, and significantly lower antithrombin levels both at T0 and T1 compared to controls. Thrombin-peak of hypogonadal men was significantly higher than controls at T0 but not at T1. ETP and antithrombin were correlated with testosterone levels. CONCLUSIONS: Hypogonadal men display a procoagulant imbalance detected by increased thrombin generation. Short-term TRT does not worsen global coagulation, suggesting that the treatment can be safely prescribed to men diagnosed with hypogonadism.

DXA-derived lumbar bone strain index corrected for kyphosis is associated with vertebral fractures and trabecular bone score in acromegaly.

PURPOSE: The bone strain index (BSI) is a marker of bone deformation based on a finite element analysis inferred from dual X-ray absorptiometry (DXA) scans, that has been proposed as a predictor of fractures in osteoporosis (i.e., higher BSI indicates a lower bone's resistance to loads with consequent higher risk of fractures). We aimed to investigate the association between lumbar BSI and vertebral fractures (VFs) in acromegaly. METHODS: Twenty-three patients with acromegaly (13 males, mean age 58 years; three with active disease) were evaluated for morphometric VFs, trabecular bone score (TBS), bone mineral density (BMD) and BSI at lumbar spine, the latter being corrected for the kyphosis as measured by low-dose X-ray imaging system (EOS®-2D/3D). RESULTS: Lumbar BSI was significantly higher in patients with VFs as compared to those without fractures (2.90 ± 1.46 vs. 1.78 ± 0.33, p = 0.041). BSI was inversely associated with TBS (rho -0.44; p = 0.034), without significant associations with BMD (p = 0.151), age (p = 0.500), BMI (p = 0.957), serum IGF-I (p = 0.889), duration of active disease (p = 0.434) and sex (p = 0.563). CONCLUSIONS: Lumbar BSI corrected for kyphosis could be proposed as integrated parameter of spine arthropathy and osteopathy in acromegaly helping the clinicians in identifying patients with skeletal fragility possibly predisposed to VFs.

A pharmacoeconomic analysis from Italian guidelines for the management of prolactinomas.

Background: Prolactinoma, the most common pituitary adenoma, is usually treated with dopamine agonist (DA) therapy like cabergoline. Surgery is second-line therapy, and radiotherapy is used if surgical treatment fails or in relapsing macroprolactinoma. Objective: This study aimed to provide economic evidence for the management of prolactinoma in Italy, using a cost-of-illness and cost-utility analysis that considered various treatment options, including cabergoline, bromocriptine, temozolomide, radiation therapy, and surgical strategies. Methods: The researchers conducted a systematic literature review for each research question on scientific databases and surveyed a panel of experts for each therapeutic procedure's specific drivers that contributed to its total cost. Results: The average cost of the first year of treatment was €2,558.91 and €3,287.40 for subjects with microprolactinoma and macroprolactinoma, respectively. Follow-up costs from the second to the fifth year after initial treatment were €798.13 and €1,084.59 per year in both groups. Cabergoline had an adequate cost-utility profile, with an incremental cost-effectiveness ratio (ICER) of €3,201.15 compared to bromocriptine, based on a willingness-to-pay of €40,000 per quality-adjusted life year (QALY) in the reference economy. Endoscopic surgery was more cost-effective than cabergoline, with an ICER of €44,846.64. Considering a willingness-to-pay of €40,000/QALY, the baseline findings show cabergoline to have high cost utility and endoscopic surgery just a tad above that. Conclusions: Due to the favorable cost-utility profile and safety of surgical treatment, pituitary surgery should be considered more frequently as the initial therapeutic approach. This management choice could lead to better outcomes and an appropriate allocation of healthcare resources.

The association of hypogonadism with depression and its treatments.

According to World Health Organization estimates, 5% of the adult population worldwide suffers from depression. In addition to the affective, psychomotor and cognitive symptoms which characterize this mood disorder, sexual dysfunction has been frequently reported among men suffering from depression. The most common sexual manifestations are decreased libido, erectile dysfunction and orgasmic disorder. In addition, epidemiological studies have documented a reduction of testosterone concentrations in men with depression and, for these reasons, depressive disorders appear as one possible cause of male functional hypogonadism. Moreover, some largely used antidepressant medications can cause or worsen sexual complaints, thus depression and its treatments rise several andrological-relevant issues. The other way round, men with hypogonadism can manifest depressed mood, anxiety, insomnia, memory impairment which, if mild, may respond to testosterone replacement therapy (TRT). However, the prevalence of functional hypogonadism in depression, and of depressive symptoms in hypogonadal men, is not known. Severe depressive symptoms do not respond to TRT, while the effect of treating major depression on functional hypogonadism, has not been investigated. Overall, the clinical relevance of each condition to the other, as well as the physiopathological underpinnings of their relationship, are still to be clarified. The present review summarizes current evidence on the influence of testosterone on mood and of depression on the hypothalamic-pituitary-testis axis; the clinical association between male hypogonadism and depression; and the reciprocal effects of respective treatments.

Effects of the therapy shift from cortisone acetate to modified-release hydrocortisone in a group of patients with adrenal insufficiency.

Objective: Patients with adrenal insufficiency (AI) may be exposed to supraphysiological glucocorticoids levels during standard treatment with cortisone acetate (CA) or immediate-release hydrocortisone (IR-HC). Recent studies, predominantly including patients in IR-HC treatment, suggested that modified-release hydrocortisone (MRH) provide a more physiological cortisol rhythm, improving metabolic control and quality of life. Our primary aim was to assess clinical and biochemical modifications in patients shifted from CA to MRH. Design/Methods: We designed a retrospective longitudinal study, enrolling 45 AI patients (22 primary and 23 secondary AI) treated exclusively with CA thrice daily, shifted to MRH once daily; 29/45 patients concluded at least 18-months follow-up (MRH-group). We recruited 35 AI patients continuing CA as a control group (CA-group). Biochemical and clinical data, including metabolic parameters, bone quality, and symptoms of under- or overtreatment were collected. In 24 patients, a daily salivary cortisol curve (SCC) performed before and one month after shifting to MRH was compared to healthy subjects (HS). Results: No significant changes in glycometabolic and bone parameters were observed both in MRH and CA-groups during a median follow-up of 35 months. A more frequent decrease in blood pressure values (23.1% vs 2.8%, p=0.04) and improvement of under- or overtreatment symptoms were observed in MRH vs CA-group. The SCC showed a significant steroid overexposure in both CA and MRH-groups compared to HS [AUC (area under the curve) = 74.4 ± 38.1 nmol×hr/L and 94.6 ± 62.5 nmol×hr/L respectively, vs 44.1 ± 8.4 nmol×hr/L, p<0.01 for both comparisons], although SCC profile was more similar to HS in MRH-group. Conclusions: In our experience, patients shifted from CA to equivalent doses of MRH do not show significant glycometabolic modifications but blood pressure control and symptoms of over-or undertreatment may improve. The lack of amelioration in glucose metabolism and total cortisol daily exposure could suggest the need for a dose reduction when shifting from CA to MRH, due to their different pharmacokinetics.