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Background: Adult growth hormone deficiency (GHD) has been recognized since the late 1980s. The clinical manifestations of adult GHD are often nonspecific, and diagnosis relies on GH stimulation tests, which are intricate, costly, time-consuming, and may carry the risk of adverse effects. Diagnosis is further complicated by factors like age, sex, and BMI, which affect GH response during testing. Therefore, GH replacement therapy remains challenging, requiring careful individualized evaluation of risks and benefits. The aim of this review is to provide an update on diagnosing and treating adult GHD, addressing current limitations and challenges based on recent studies. Methods: We conducted a comprehensive review of the literature regarding the diagnosis and management of adult GHD by searching PubMed and EMBASE. Only articles in English were included, and searches were conducted up to August 2024. Results: A review of guidelines and literature up to 2024 highlights the significant heterogeneity in the data and reveals various protocols for managing GHD, covering both diagnostic and therapeutic approaches. Conclusions: Despite diagnostic and treatment advances, managing adult GHD remains challenging due to variable presentation and the need for personalized GH therapy. Future efforts should aim to improve and standardize diagnostic and treatment protocols.

Hypothyroidism is a frequently diagnosed endocrine disorder. Common signs and symptoms include fatigue, cold intolerance, hoarseness, dry skin, constipation, a slow relaxation phase of deep tendon reflexes, and bradycardia. However, some patients may exhibit atypical signs and symptoms, which can result in diagnostic confusion. Pituitary hyperplasia resulting from longstanding primary hypothyroidism was first described by Niepce in 1851. It is usually asymptomatic, but sometimes, in addition to symptoms of overt hypothyroidism, patients may complain of headaches, hypopituitarism, visual field impairment, and hyperprolactinemia. Furthermore, on imaging, pituitary hyperplasia can be mistaken for a pituitary adenoma. Distinguishing between the two is crucial, as their management differs; the former often responds to thyroid hormone replacement therapy, while the latter might need treatment with surgery and/or radiotherapy. Here we describe a patient who developed pituitary hyperplasia in the setting of longstanding uncompensated primary hypothyroidism due to a lack of compliance with levothyroxine replacement therapy. We also review the clinical, laboratory, and radiologic findings of the case reports available in the literature up to now in order to improve the knowledge and the care of the disease.

Radiomic analysis has emerged as a valuable tool for extracting quantitative features from medical imaging data, providing in-depth insights into various contexts and diseases. By employing methods derived from advanced computational techniques, radiomics quantifies textural information through the evaluation of the spatial distribution of signal intensities and inter-voxel relationships. In recent years, these techniques have gained considerable attention also in the field of pituitary tumors, with promising results. Indeed, the extraction of radiomic features from pituitary magnetic resonance imaging (MRI) images has been shown to provide useful information on various relevant aspects of these diseases. Some of the key topics that have been explored in the existing literature include the association of radiomic parameters with histopathological and clinical data and their correlation with tumor invasiveness and aggressive behavior. Their prognostic value has also been evaluated, assessing their role in the prediction of post-surgical recurrence, response to medical treatments, and long-term outcomes. This review provides a comprehensive overview of the current knowledge and application of radiomics in pituitary tumors. It also examines the current limitations and future directions of radiomic analysis, highlighting the major challenges that need to be addressed before a consistent integration of these techniques into routine clinical practice.

Introduction: In type 2 diabetes mellitus (T2DM), the antidiuretic system participates in the adaptation to osmotic diuresis further increasing urinary osmolality by reducing the electrolyte-free water clearance. Sodium glucose co-transporter type 2 inhibitors (SGLT2i) emphasize this mechanism, promoting persistent glycosuria and natriuresis, but also induce a greater reduction of interstitial fluids than traditional diuretics. The preservation of osmotic homeostasis is the main task of the antidiuretic system and, in turn, intracellular dehydration the main drive to vasopressin (AVP) secretion. Copeptin is a stable fragment of the AVP precursor co-secreted with AVP in an equimolar amount., Aim: To investigate the copeptin adaptive response to SGLT2i, as well as the induced changes in body fluid distribution in T2DM patients., Methods: The GliRACo study was a prospective, multicenter, observational research. Twenty-six consecutive adult patients with T2DM were recruited and randomly assigned to empagliflozin or dapagliflozin treatment. Copeptin, plasma renin activity, aldosterone and natriuretic peptides were evaluated at baseline (T0) and then 30 (T30) and 90 days (T90) after SGLT2i starting. Bioelectrical impedance vector analysis (BIVA) and ambulatory blood pressure monitoring were performed at T0 and T90., Results: Among endocrine biomarkers, only copeptin increased at T30, showing subsequent stability (7.5 pmol/L at T0, 9.8 pmol/L at T30, 9.5 pmol/L at T90; p = 0.001). BIVA recorded an overall tendency to dehydration at T90 with a stable proportion between extra- and intracellular fluid volumes. Twelve patients (46.1%) had a BIVA overhydration pattern at baseline and 7 of them (58.3%) resolved this condition at T90. Total body water content, extra and intracellular fluid changes were significantly affected by the underlying overhydration condition ( p < 0.001), while copeptin did not., Conclusion: In patients with T2DM, SGLT2i promote the release of AVP, thus compensating for persistent osmotic diuresis. This mainly occurs because of a proportional dehydration process between intra and extracellular fluid (i.e., intracellular dehydration rather than extracellular dehydration). The extent of fluid reduction, but not the copeptin response, is affected by the patient's baseline volume conditions., Clinical Trial Registration: Clinicaltrials.gov, identifier NCT03917758., Competing Interests: AMB received fees from Thermo Fisher Diagnostics for previous editorial collaborations and oral presentations. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Berton, Parasiliti-Caprino, Prencipe, Bioletto, Lopez, Bona, Caputo, Rumbolo, Ponzetto, Settanni, Gasco, Mengozzi, Ghigo, Grottoli, Maccario and Benso.)

Hypopituitarism is defined as a complete or partial deficiency in one or more pituitary hormones. Anterior hypopituitarism includes secondary adrenal insufficiency, central hypothyroidism, hypogonadotropic hypogonadism, growth hormone deficiency and prolactin deficiency. Patients with hypopituitarism suffer from an increased disability and sick days, resulting in lower health status, higher cost of care and an increased mortality. In particular during adulthood, isolated pituitary deficits are not an uncommon finding; their clinical picture is represented by vague symptoms and unclear signs, which can be difficult to properly diagnose. This often becomes a challenge for the physician. Aim of this narrative review is to analyse, for each anterior pituitary deficit, the main related etiologies, the characteristic signs and symptoms, how to properly diagnose them (suggesting an easy and reproducible step-based approach), and eventually the treatment. In adulthood, the vast majority of isolated pituitary deficits are due to pituitary tumours, head trauma, pituitary surgery and brain radiotherapy. Immune-related dysfunctions represent a growing cause of isolated pituitary deficiencies, above all secondary to use of oncological drugs such as immune checkpoint inhibitors. The diagnosis of isolated pituitary deficiencies should be based on baseline hormonal assessments and/or dynamic tests. Establishing a proper diagnosis can be quite challenging: in fact, even if the diagnostic methods are becoming increasingly refined, a considerable proportion of isolated pituitary deficits still remains without a certain cause. While isolated ACTH and TSH deficiencies always require a prompt replacement treatment, gonadal replacement therapy requires a benefit-risk evaluation based on the presence of comorbidities, age and gender of the patient; finally, the need of growth hormone replacement therapies is still a matter of debate. On the other side, prolactin replacement therapy is still not available. In conclusion, our purpose is to offer a broad evaluation from causes to therapies of isolated anterior pituitary deficits in adulthood. This review will also include the evaluation of uncommon symptoms and main etiologies, the elements of suspicion of a genetic cause and protocols for diagnosis, follow-up and treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Prencipe, Marinelli, Varaldo, Cuboni, Berton, Bioletto, Bona, Gasco and Grottoli.)

Gene mutations encoding transcription factors, including SOX2 , have been associated with growth hormone deficiency (GHD) and abnormal pituitary development. Guidelines on GHD management in the transition period state that patients with genetic-based childhood-onset GHD can skip retesting due to a high likelihood of permanent GHD. We describe a case of septo-optic-dysplasia due to SOX2 mutation characterised by childhood-onset GHD, which showed a normal somatotropic function at the transition period. This case raises the opportunity to retest for GHD during the transition period, even in patients with a known genetic cause, in order to avoid inappropriate GH treatment., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Adult GH deficiency (GHD) has been described as a heterogeneous condition characterized by many clinical modifications, such as metabolic alterations, impaired quality of life, and increased mortality. The clinical relevance of cardiac involvement remains, however, only partially elucidated., Methods: PubMed/Medline, EMBASE, Cochrane library, OVID and CINAHL databases were systematically searched until February 2022 for studies evaluating cardiac function and morphology by magnetic resonance imaging in adult patients with GHD. Effect sizes were pooled through a random-effect model., Results: Four studies were considered in the meta-analysis. With respect to the left ventricle, GHD patients were characterized by a lower stroke-volume-index (-3.6 ml/m 2 , standardized mean difference (SMD) -0.60, 95%CI [-1.15,-0.05], p=0.03), lower end-diastolic-volume-index (-6.2 ml/m 2 , SMD -0.54, 95%CI [-0.97,-0.10], p=0.02) and, after accounting for possible biases, lower mass-index (-15.0 g/m 2 , SMD -1.03, 95%CI [-1.89,-0.16], p=0.02). With respect to the right ventricle, a lower end-diastolic-volume-index (-16.6 ml/m 2 , SMD -1.04, 95%CI [-2.04,-0.03], p=0.04) and a borderline-significant lower stroke-volume-index (-5.0 ml/m 2 , SMD -0.84, 95%CI [-1.77,0.08], p=0.07) could be observed. Data about the effect of GH replacement therapy highlighted a significant increase in left ventricular mass-index after treatment initiation (+3.7 g/m 2 , 95%CI [1.6,5.7], p<0.01)., Conclusion: With respect to the left ventricle, our results confirmed those retrieved by echocardiographic studies. In addition, significant alterations were demonstrated also for the right ventricle, for which echocardiographic data are nearly absent. This supports the thesis of a biventricular cardiac involvement in patients with GHD, with a similar pattern of morphological and functional alterations in both ventricles., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bioletto, Prencipe, Berton, Bona, Parasiliti-Caprino, Faletti, Ghigo, Grottoli and Gasco.)

A reliable prediction of the recurrence risk of pheochromocytoma after radical surgery would be a key element for the tailoring/personalization of post-surgical follow-up. Recently, our group developed a multivariable continuous model that quantifies this risk based on genetic, histopathological, and clinical data. The aim of the present study was to simplify this tool to a discrete score for easier clinical use. Data from our previous study were retrieved, which encompassed 177 radically operated pheochromocytoma patients; supervised regression and machine-learning techniques were used for score development. After Cox regression, the variables independently associated with recurrence were tumor size, positive genetic testing, age, and PASS. In order to derive a simpler scoring system, continuous variables were dichotomized, using > 50 mm for tumor size, ≤ 35 years for age, and ≥ 3 for PASS as cut-points. A novel prognostic score was created on an 8-point scale by assigning 1 point for tumor size > 50 mm, 3 points for positive genetic testing, 1 point for age ≤ 35 years, and 3 points for PASS ≥ 3; its predictive performance, as assessed using Somers’ D, was equal to 0.577 and was significantly higher than the performance of any of the four dichotomized predictors alone. In conclusion, this simple scoring system may be of value as an easy-to-use tool to stratify recurrence risk and tailor post-surgical follow-up in radically operated pheochromocytoma patients.

Background: The diagnosis of adult GH deficiency (GHD) relies on a reduced GH response to provocative tests. Their diagnostic accuracy, however, is not perfect, and a reliable estimation of pre-test GHD probability could be helpful for a better interpretation of their results., Methods: Eighty patients showing concordant GH response to two provocative tests, i.e. the insulin tolerance test and the GHRH + arginine test, were enrolled. Data on IGF-I values and on the presence/absence of other pituitary deficits were collected and integrated for the estimation of GHD probability prior to stimulation tests., Results: An independent statistically significant association with the diagnosis of GHD was found both for IGF-I SDS (OR 0.34, 95%-CI 0.18-0.65, p=0.001) and for the presence of other pituitary deficits (OR 6.55, 95%-CI 2.06-20.83, p=0.001). A low (<25%) pre-test GHD probability could be predicted when IGF-I SDS > +0.91 in the presence of other pituitary deficits or IGF-I SDS > -0.52 in the absence of other pituitary deficits. A high (>75%) pre-test GHD probability could be predicted when IGF-I SDS < -0.82 in the presence of other pituitary deficits or IGF-I SDS < -2.26 in the absence of other pituitary deficits., Conclusion: This is the first study that proposes a quantitative estimation of GHD probability prior to stimulation tests. Our risk class stratification represents a simple tool that could be adopted for a Bayesian interpretation of stimulation test results, selecting patients who may benefit from a second stimulation test and possibly reducing the risk of wrong GHD diagnosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bioletto, Parasiliti-Caprino, Berton, Prencipe, Cambria, Ghigo, Grottoli and Gasco.)

No research has explored the role of catecholamine metabolites in the stratification of cardiovascular risk. We aimed to evaluate the relationship between urine metanephrines and cardiometabolic risk/complications. In this retrospective cross-sectional study, we collected the data of 1374 patients submitted to the evaluation of urine metanephrines at the City of Health and Science University Hospital of Turin between 2007 and 2015, mainly for investigating the suspicion of secondary hypertension or the secretion of an adrenal lesion. The univariate analysis showed associations between metanephrines and cardiometabolic variables/parameters, particularly considering noradrenaline metabolite. At univariate regression, normetanephrine was associated with hypertensive cardiomyopathy (OR = 1.18, 95% CI 1.11-1.25; p < 0.001) and metabolic syndrome (OR = 1.11, 95% CI 1.03-1.20; p = 0.004), while metanephrine was associated with hypertensive cardiomyopathy (OR = 1.23, 95% CI 1.06-1.43; p = 0.006) and microalbuminuria (OR = 1.30, 95% CI 1.03-1.60; p = 0.018). At multivariate regression, considering all major cardiovascular risk factors as possible confounders, normetanephrine retained a significant association with hypertensive cardiomyopathy (OR = 1.14, 95% CI 1.07-1.22; p < 0.001) and metabolic syndrome (OR = 1.10, 95% CI 1.02-1.19; p = 0.017). Moreover, metanephrine retained a significant association with the presence of hypertensive cardiomyopathy (OR = 1.18, 95% CI 1.01-1.41; p = 0.049) and microalbuminuria (OR = 1.34, 95% CI 1.03-1.69; p = 0.019). The study showed a strong relationship between metanephrines and cardiovascular complications/metabolic alterations. Individuals with high levels of these indirect markers of sympathetic activity should be carefully monitored, and they may benefit from an aggressive treatment to reduce the cardiometabolic risk.

Traumatic brain injury (TBI)-related hypopituitarism has been recognized as a clinical entity for more than a century, with the first case being reported in 1918. However, during the 20 th century hypopituitarism was considered only a rare sequela of TBI. Since 2000 several studies strongly suggest that TBI-mediated pituitary hormones deficiency may be more frequent than previously thought. Growth hormone deficiency (GHD) is the most common abnormality, followed by hypogonadism, hypothyroidism, hypocortisolism, and diabetes insipidus. The pathophysiological mechanisms underlying pituitary damage in TBI patients include a primary injury that may lead to the direct trauma of the hypothalamus or pituitary gland; on the other hand, secondary injuries are mainly related to an interplay of a complex and ongoing cascade of specific molecular/biochemical events. The available data describe the importance of GHD after TBI and its influence in promoting neurocognitive and behavioral deficits. The poor outcomes that are seen with long standing GHD in post TBI patients could be improved by GH treatment, but to date literature data on the possible beneficial effects of GH replacement therapy in post-TBI GHD patients are currently scarce and fragmented. More studies are needed to further characterize this clinical syndrome with the purpose of establishing appropriate standards of care. The purpose of this review is to summarize the current state of knowledge about post-traumatic GH deficiency., Competing Interests: The authors declare the absence of any commercial or financial relationship that could be construed as a potential conflict of interest., (Copyright © 2021 Gasco, Cambria, Bioletto, Ghigo and Grottoli.)

Dopamine-agonist cabergoline (CB) reduces prolactin (PRL) secretion and tumor size in 80% of patients with prolactin-secreting adenomas (PRL-omas) by binding type 2 dopamine receptor (DRD2). The mechanisms responsible for resistance to CB remain largely unknown. To assess the association of DRD2 with sensitivity to CB, TaqI-A1/A2, TaqI-B1/B2, HphI-G/T and NcoI-C/T genotypes were determined in a cross-sectional retrospective study, including 203 patients with PRL-oma. DRD2 alleles frequencies did not differ between patients and 212 healthy subjects. Conversely, NcoI-T allele frequency was higher in resistant rather than responsive patients, considering both PRL normalization (56.6 vs 45.3%, P=0.038) and tumor shrinkage (70.4 vs 41.4%, P=0.006). Finally, [TaqI A1-/TaqI B1-/HphI T-/NcoI T-] haplotype was found in 34.5% of patients normalizing PRL with < or =3 mg/week of CB vs 11.3% of resistants (P=0.021). In conclusion, resistance to CB was associated with DRD2 NcoI-T+ allele, consistent with evidence suggesting that this variant may lead to reduction and instability of DRD2 mRNA or protein.