Cervicomediastinal Hematoma: Atypical Presentation of a Parathyroid Carcinoma.

Parathyroid carcinoma (PC) is a rare endocrine neoplasm that typically presents with osteopenia/osteoporosis, nephrolithiasis, asthenia, and neuropsychiatric symptoms. We describe the case of a 48-year-old woman, presenting with a large painful hematoma in the cervicomediastinal area. The neck ultrasound (US) demonstrated a solid lesion measuring 40 × 80 × 55 mm, markedly hypoechoic, which extended from the right thyroid lobe to the mediastinum. The blood tests showed elevated serum calcium and parathyroid hormone (PTH) concentrations, consistent with hypercalcemic primary hyperparathyroidism. The patient was rehydrated and treated with furosemide, cholecalciferol, and bisphosphonate, and underwent right lower parathyroidectomy, right hemithyroidectomy, and lymphadenectomy of the right VI cervical level. Histological examination was diagnostic for nonangioinvasive or neuroinvasive PC, and the thyroid lobe was the site of lymphocytic thyroiditis; all removed lymph nodes were benign. The postoperative course was regular. Postoperative neck US showed a hypoechoic left thyroid lobe without evidence of residual neoplasm in the right thyroid bed. Levothyroxine therapy of 50 mcg/day was started because of serum thyrotropin concentrations elevated at 18 mcIU/mL (normal reference range, 0.35-4.0 mIU/mL). Eight years after diagnosis, the patient is in good general condition, with no clinical, biochemical, or imaging evidence of disease persistence/recurrence.

Carotid intima-media thickness in surgically or conservatively managed patients with primary hyperparathyroidism.

CONTEXT: Current evidence of cardiovascular (CV) risk in primary hyperparathyroidism (PHPT) is still inconsistent. OBJECTIVE: To prospectively investigate changes of early atherosclerosis in patients with PHPT undergoing parathyroidectomy (PTx) or conservative management, according to Consensus criteria. METHODS: Biochemical parameters of PHPT, CV risk factors (systolic and diastolic blood pressure-BP-, total-, HDL- and LDL-cholesterol, triglyceride, glycosilated hemoglobin, and HOMA-IR), and carotid intima-media thickness (IMT) and plaque were assessed in 52 consecutive postmenopausal PHPT patients both at baseline and ≥24 months after surgery (PTx: n = 22) or conservative management (no-PTx: n = 30). RESULTS: At baseline, PTx and no-PTx showed comparable age, BMI, renal function, 25(OH)D levels, and did not differ for CV risk factors, IMT and plaques, nor for the prevalence of smoking, diabetes mellitus, antihypertensive or statin therapy, while differing for all parameters characterizing PHPT. Follow-up length in PTx was longer (p = 0.004) than in no-PTx. Parameters characterizing PHPT significantly improved ≥24 months after surgery, whereas in no-PTx serum phosphate slightly decreased and PTH increased. Systolic and diastolic BP increased at follow-up in both groups, while other CV risk factors did not significantly vary. In PTx IMT did not significantly vary after surgery (0.85 ± 0.14 to 0.89 ± 0.22 mm, p = 0.366), whereas it significantly increased in no-PHPT (0.80 ± 0.18 to 0.93 ± 0.23 mm, p = 0.008), even adjusting for BP values. Plaque prevalence and incidence did not significantly differ in the two groups. CONCLUSION: Our results suggest that in postmenopausal PHPT patients subclinical atherosclerosis could be halted by PTx, whereas it worsens over time in not operated patients with milder disease.

Increased Risk of Vertebral Fractures in Patients With Mild Autonomous Cortisol Secretion.

CONTEXT: The risk of vertebral fractures (VFx) in patients with adrenal incidentalomas (AI) and mild autonomous cortisol secretion (MACS) is debated. OBJECTIVE: To evaluate the VFx prevalence and incidence in patients with AI and MACS. METHODS: This cross-sectional and longitudinal study using retrospective data from 4 Italian endocrinology units included 444 patients (cross-sectional arm) and 126 patients (longitudinal arm, 24.9 ± 5.3 months follow-up) to evaluate prevalent and incident VFx, respectively, in patients with MACS (MACS-yes) and without MACS (MACS-no). The main outcome measures were serum cortisol after a 1-mg dexamethasone test (F-1mgDST), bone mineral density (BMD) by dual-energy x-ray absorptiometry at spine (LS) and femur (FN), and VFx presence by x-ray. RESULTS: Cross-sectional arm: 214 and 230 patients were MACS-yes and MACS-no, respectively, based on F-1mgDST >1.8 µg/dL (50 nmol/L). Patients with MACS had higher VFx prevalence (62.6%) than those without MACS (22.9%, P < .001); MACS was associated with prevalent VFx (odds ratio, 5.203; 95% CI, 3.361-8.055; P < .001; relative risk [RR] 2.07), regardless of age, body mass index, gender distribution, LS-BMD, and presence of type 2 diabetes mellitus (T2D). Longitudinal arm: 66 and 60 patients were MACS-no and MACS-yes, respectively. Patients without MACS showed higher number of incident VFx (36.4%) than patients without MACS (10.0%, P < .001); MACS was associated with the presence of an incident VFx (RR 4.561; 95% CI, 1.600-13.003; P = .005) regardless of age, LS-BMD, gender distribution, presence of prevalent VFx, and T2D. Results were confirmed in women and men when separately evaluated. CONCLUSION: Women and men with AI and MACS are at higher risk of VFx.

Calcium-phosphate homeostasis and insulin resistance in men.

BACKGROUND AND AIMS: Data on P homeostasis in insulin resistance (IR) are still conflicting. We investigated calcium-phosphate homeostasis parameters in men with/without IR. METHODS AND RESULTS: 177 volunteers (aged 61.62 ± 12.11), whose body mass index (BMI) was 29.97 ± 6.35, were studied. On fasting blood and spot urine samples, we measured serum creatinine, sodium (sNa), potassium (sK), chloride (sCl), calcium (sCa), phosphate (sP), alkaline phosphatase total activity (ALP), glucose, insulin, parathyroid hormone (PTH), 25-hydroxy-vitamin D [25(OH)D], and urinary electrolytes corrected for creatinine (uNa/Cr, uK/Cr, uCl/Cr, uCa/Cr, and uP/Cr). Through the QUICKI index, we separated subjects with (IR+, n = 68) or without (IR-, n = 109) IR, and their parameters were compared. Associations were assessed by age-adjusted partial correlation, whose coefficients were compared by Fisher's transform. IR + had higher sP (3.54 ± 0.65 vs. 3.35 ± 0.47, p = 0.044) and lower uCa/Cr levels (0.073 ± 0.056 vs. 0.095 ± 0.072, p = 0.047) than IR-. BMI correlated with sP (r = 0.21, p < 0.05) and PTH (r = 0.29, p < 0.01). QUICKI negatively correlated with sCa (r = -0.22, p < 0.05) and positively with uCa/Cr (r = 0.21, p < 0.05), in turn correlating with uNa/Cr (r = 0.45, p < 0.001). In both groups, uCa/Cr correlated with eGFR and uNa/Cr (p < 0.05 to p < 0.001). In IR + only, sP correlated with BMI, PTH with insulin, and uP/Cr (p < 0.05 for all). IR+ and IR-coefficients differed (p < 0.05 to p < 0.001) for the correlation of sP with BMI and of PTH with insulin and uP/Cr. CONCLUSION: The higher sP and lower uCa/Cr levels found in men with IR + suggest that IR could modulate calcium-phosphate homeostasis, likely by affecting their renal handling.

Clinical and molecular description of the first Italian cohort of 33 subjects with hypophosphatasia.

Introduction: Hypophosphatasia (HPP) is a rare genetic disease caused by inactivating variants of the ALPL gene. Few data are available on the clinical presentation in Italy and/or on Italian HPP surveys. Methods: There were 30 suspected HPP patients recruited from different Italian tertiary cares. Biological samples and related clinical, biochemical, and anamnestic data were collected and the ALPL gene sequenced. Search for large genomic deletions at the ALPL locus (1p36) was done. Phylogenetic conservation and modeling were applied to infer the effect of the variants on the protein structure. Results: There were 21 ALPL variants and one large genomic deletion found in 20 out of 30 patients. Unexpectedly, NGS-driven differential diagnosis allowed uncovering three hidden additional HPP cases, for a total of 33 HPP subjects. Eight out of 24 coding variants were novel and classified as "pathogenic", "likely pathogenic", and "variants of uncertain significance". Bioinformatic analysis confirmed that all the variants strongly destabilize the homodimer structure. There were 10 cases with low ALP and high VitB6 that resulted negative to genetic testing, whereas two positive cases have an unexpected normal ALP value. No association was evident with other biochemical/clinical parameters. Discussion: We present the survey of HPP Italian patients with the highest ALPL mutation rate so far reported and confirm the complexity of a prompt recognition of the syndrome, mostly for HPP in adults. Low ALP and high VitB6 values are mandatory for the genetic screening, this latter remaining the gold standard not only to confirm the clinical diagnosis but also to make differential diagnosis, to identify carriers, to avoid likely dangerous therapy in unrecognized cases.

The degree of cortisol secretion is associated with diabetes mellitus and hypertension in patients with nonfunctioning adrenal tumors.

BACKGROUND: Similarly to cortisol-secreting adrenal tumors, also non-functioning adrenal tumors (NFAT) may be associated with an increased cardiovascular risk. We assessed in NFAT patients: (i) the association between hypertension (HT), diabetes mellitus (DM), obesity (OB), dyslipidemia (DL) and cardiovascular events (CVE) and cortisol secretion; (ii) the cut-off of the cortisol secretion parameters for identifying NFAT patients with a worse cardiometabolic profile. PATIENTS AND METHODS: In 615 NFAT patients (with cortisol levels after 1 mg overnight dexamethasone suppression test, F-1mgDST < 1.8 µg/dL [50 nmol/L]) F-1mgDST and adrenocorticotroph hormone (ACTH) levels and data on HT, DM, OB, DL and CVEs prevalence were retrospectively collected. RESULTS: HT, DM and HT plus DM were associated with F-1mgDST levels (area under the ROC curve: 0.588 ± 0.023, 0.610 ± 0.028, 0.611 ± 0.033, respectively, p < 0.001 for all comparisons) but not with ACTH. The cut-off for identifying patients with either HT or DM or HT plus DM was set at ≥ 1.2 µg/dL (33 nmol/L). As compared with patients with F-1mgDST < 1.2 µg/dL (n = 289), patients with F-1mgDST 1.2-1.79 µg/dL (33-49.4 nmol/L) (n = 326) had lower ACTH levels (17.7 ± 11.9 vs 15.3 ± 10.1 pg/mL, respectively, p = 0.008), older age (57.5 ± 12.3 vs 62.5 ± 10.9 years, respectively, p < 0.001), and higher prevalence of HT (38.1% vs 52.5% respectively p < 0.001), DM (13.1% vs 23.3%, respectively, p = 0.001), HT plus DM (8.3% vs 16.9%, respectively, p < 0.002) and CVE (3.2% vs 7.3%, respectively, p = 0.028). F-1mgDST 1.2-1.79 µg/dL was associated with either HT (odd ratio, OR, 1.55, 95% confidence interval, 95% CI 1.08-2.23, p = 0.018) or DM (OR 1.60, 95% CI 1.01-2.57, p = 0.045) after adjusting for age, gender, OB, DL, and DM (for HT) or HT (for DM), and with the presence of HT plus DM (OR 1.96, 95% CI 1.12-3.41, p = 0.018) after adjusting for age, gender, OB and DL. CONCLUSIONS: In NFAT patients, F-1mgDST 1.2-1.79 µg/dL seems to be associated with a higher prevalence of HT and DM and a worse cardiometabolic profile, even if the poor accuracy of these associations suggests caution in interpreting these results.

Vitamin D Increases Irisin Serum Levels and the Expression of Its Precursor in Skeletal Muscle.

Irisin is a myokine synthesized by skeletal muscle, which performs key actions on whole-body metabolism. Previous studies have hypothesized a relationship between irisin and vitamin D, but the pathway has not been thoroughly investigated. The purpose of the study was to evaluate whether vitamin D supplementation affected irisin serum levels in a cohort of 19 postmenopausal women with primary hyperparathyroidism (PHPT) treated with cholecalciferol for six months. In parallel, to understand the possible link between vitamin D and irisin, we analyzed the expression of the irisin precursor, Fndc5, in the C2C12 myoblast cell line treated with a biologically active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). Our results demonstrate that vitamin D supplementation resulted in a significant increase in irisin serum levels (p = 0.031) in PHPT patients. In vitro, we show that vitamin D treatment on myoblasts enhanced Fndc5 mRNA after 48 h (p = 0.013), while it increased mRNAs of sirtuin 1 (Sirt1) (p = 0.041) and peroxisome proliferator-activated receptor γ coactivator 1α (Pgc1α) (p = 0.017) over a shorter time course. Overall, our data suggest that vitamin-D-induced modulation of Fndc5/irisin occurs through up-regulation of Sirt1, which together with Pgc1α, is an important regulator of numerous metabolic processes in skeletal muscle.

Validation of the clinical consensus recommendations on the management of fracture risk in postmenopausal women with type 2 diabetes.

BACKGROUND AND AIMS: Bone fragility is recognized as a complication of type 2 diabetes (T2D). However, the fracture risk in T2D is underestimated using the classical assessment tools. An expert panel suggested the diagnostic approaches for the detection of T2D patients worthy of bone-active treatment. The aim of the study was to apply these algorithms to a cohort of T2D women to validate them in clinical practice. METHODS AND RESULTS: The presence of T2D-specific fracture risk factors (T2D ≥ 10 years, ≥1 T2D complications, insulin or thiazolidinedione use, poor glycaemic control) was assessed at baseline in 107 postmenopausal T2D women. In all patients at baseline and in 34 patients after a median follow-up of 60.2 months we retrospectively evaluated bone mineral density and clinical and morphometric vertebral fractures. No patient was treated with bone-active drug. Following the protocols, 34 (31.8%) and 73 (68.2%) patients would have been pharmacologically and conservatively treated, respectively. Among 49 patients without both clinical fractures and major T2D-related risk factors, who would have been, therefore, conservatively followed-up without vertebral fracture assessment, only one showed a prevalent vertebral fracture (sensitivity 90%, negative predictive value 98%). The two patients who experienced an incident fracture would have been pharmacologically treated at baseline. CONCLUSIONS: The clinical consensus recommendations showed a very good sensitivity in identifying T2D postmenopausal women at high fracture risk. Among those with treatment indication as many as 13% of patients experienced an incident fracture, and, conversely, among those without treatment indication no incident fractures were observed.

Tumor-induced Osteomalacia: A Comprehensive Review.

Tumor-induced osteomalacia (TIO) is an ultrarare paraneoplastic syndrome due to overproduction of fibroblast growth factor 23 (FGF23), with profound effects on patient morbidity. TIO is an underdiagnosed disease, whose awareness should be increased among physicians for timely and proper management of patients. Symptoms reported by patients with TIO are usually nonspecific, thus rendering the diagnosis elusive, with an initial misdiagnosis rate of more than 95%. Biochemical features of TIO are represented by hypophosphatemia, increased or inappropriately normal levels of FGF23, and low to low normal circulating 1,25-dihydroxyvitamin D (1,25(OH)2D). Phosphaturic mesenchymal tumors are the pathological entities underlying TIO in most affected patients. There is now evidence that FN1-FGFR1 and FN1-FGF1 fusion genes are present in about half of tumors causing this paraneoplastic syndrome. Tumors causing TIO are small and grow slowly. They can occur in all parts of the body from head to toe with similar prevalence in soft tissue and bone. There are a number of functional and anatomical imaging techniques used for tumor localization; 68Ga DOTA-based technologies have better sensitivity. Surgery is the treatment of choice; several medical treatments are now available in case of inability to locate the tumor or in case of incomplete excision.

Italian Guidelines for the Management of Sporadic Primary Hyperparathyroidism.

AIM: This guideline (GL) is aimed at providing a clinical practice reference for the management of sporadic primary hyperparathyroidism (PHPT) in adults. PHPT management in pregnancy was not considered. METHODS: This GL has been developed following the methods described in the Manual of the Italian National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinology (AME) and Società Italiana dell'Osteoporosi, del Metabolismo Minerale e delle Malattie dello Scheletro (SIOMMMS) identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence. Those classified as "critical" were considered for the clinical practice recommendations. RESULTS: The present GL provides recommendations about the roles of pharmacological and surgical treatment for the clinical management of sporadic PHPT. Parathyroidectomy is recommended in comparison to surveillance or pharmacologic treatment in any adult (outside of pregnancy) or elderly subject diagnosed with sporadic PHPT who is symptomatic or meets any of the following criteria: • Serum calcium levels >1 mg/dL above the upper limit of normal range. • Urinary calcium levels >4 mg/kg/day. • Osteoporosis disclosed by DXA examination and/or any fragility fracture. • Renal function impairment (eGFR <60 mL/min). • Clinic or silent nephrolithiasis. • Age ≤50 years. Monitoring and treatment of any comorbidity or complication of PHPT at bone, kidney, or cardiovascular level are suggested for patients who do not meet the criteria for surgery or are not operated on for any reason. Sixteen indications for good clinical practice are provided in addition to the recommendations. CONCLUSION: The present GL is directed to endocrinologists and surgeons - working in hospitals, territorial services or private practice - and to general practitioners and patients. The recommendations should also consider the patient's preferences and the available resources and expertise.

Adrenalectomy Improves Blood Pressure and Metabolic Control in Patients With Possible Autonomous Cortisol Secretion: Results of a RCT.

Objective: The best approach to patients with adrenal incidentaloma (AI) and possible autonomous cortisol secretion (PACS) is debated. The aim of this study was to assess the metabolic effect of adrenalectomy in AI patients with PACS in relation to cortisol secretion parameters, peripheral activation, and glucocorticoid sensitivity. Design: This is a multicenter randomized study (NCT number: NCT04860180). Methods: Sixty-two AI outpatients (40-75 years) with AI >1 cm and cortisol after overnight dexamethasone suppression test (F-1mgDST) between 50 and 138 nmol/L were randomized to adrenalectomy (Arm A) or a conservative approach (Arm B). Fifty-five patients completed the 6-month follow-up, 25 patients in Arm A (17 female patients, aged 62.5 ± 10.4 years) and 30 patients in Arm B (24 female patients, 66.1 ± 9.1 years). Plasma adrenocorticotroph hormone (ACTH), 24-h urinary free cortisol, 24-h urinary free cortisone, F-1mgDST, glucose, lipids, glycated hemoglobin (HbA1c) levels, blood pressure (BP), body weight, and treatment variations were assessed. The 24-h urinary free cortisol/cortisone ratio (an 11-beta hydroxysteroid dehydrogenase type 2 activity marker), BclI, and the N363S variants of glucocorticoid receptor (GR) polymorphisms were also evaluated. Results: BP control improved in 68% and 13% of the subjects in Arm A and Arm B, respectively (p = 0.001), and the glycometabolic control improved in 28% and 3.3% of the subjects in Arm A and Arm B patients, respectively (p = 0.02). Arm A subjects more rarely showed the BP and/or glycometabolic control worsening than Arm B patients (12% and 40%, respectively, p = 0.03). The surgical approach was independently associated with BP amelioration (OR 3.0, 95% CI 3.8-108.3, p < 0.001) but not with age, F-1mgDST levels, BMI, and hypertension and diabetes mellitus presence at baseline. The 24-h urinary free cortisol/cortisone ratio and the presence of sensitizing GR polymorphisms were not associated with the surgical outcome. The receiver operating characteristic (ROC) curve analysis showed that the BP control amelioration was associated with F-1mgDST [area under the curve (AUC), 0.82 ± 0.09 p = 0.012]. The F-1mgDST cutoff with the best compromise in predicting the BP amelioration was set at 75 nmol/L (sensitivity 77%, specificity 75%). Conclusions: AI patients with PACS benefit from surgery in terms of BP and glycometabolic control.

Pathophysiology of Mild Hypercortisolism: From the Bench to the Bedside.

Mild hypercortisolism is defined as biochemical evidence of abnormal cortisol secretion without the classical detectable manifestations of overt Cushing's syndrome and, above all, lacking catabolic characteristics such as central muscle weakness, adipose tissue redistribution, skin fragility and unusual infections. Mild hypercortisolism is frequently discovered in patients with adrenal incidentalomas, with a prevalence ranging between 5 and 50%. This high variability is mainly due to the different criteria used for defining this condition. This subtle cortisol excess has also been described in patients with incidentally discovered pituitary tumors with an estimated prevalence of 5%. To date, the mechanisms responsible for the pathogenesis of mild hypercortisolism of pituitary origin are still not well clarified. At variance, recent advances have been made in understanding the genetic background of bilateral and unilateral adrenal adenomas causing mild hypercortisolism. Some recent data suggest that the clinical effects of glucocorticoid (GC) exposure on peripheral tissues are determined not only by the amount of the adrenal GC production but also by the peripheral GC metabolism and by the GC sensitivity. Indeed, in subjects with normal cortisol secretion, the combined estimate of cortisol secretion, cortisone-to-cortisol peripheral activation by the 11 beta-hydroxysteroid dehydrogenase enzyme and GC receptor sensitizing variants have been suggested to be associated with the presence of hypertension, diabetes and bone fragility, which are three well-known consequences of hypercortisolism. This review focuses on the pathophysiologic mechanism underlying both the different sources of mild hypercortisolism and their clinical consequences (bone fragility, arterial hypertension, subclinical atherosclerosis, cardiovascular remodeling, dyslipidemia, glucose metabolism impairment, visceral adiposity, infections, muscle damage, mood disorders and coagulation).

Novel Glial Cells Missing-2 (GCM2) variants in parathyroid disorders.

OBJECTIVE: The aim of this study was to analyze variants of the gene glial cells missing-2 (GCM2), encoding a parathyroid cell-specific transcription factor, in familial hypoparathyroidism and in familial isolated hyperparathyroidism (FIHP) without and with parathyroid carcinoma. DESIGN: We characterized 2 families with hypoparathyroidism and 19 with FIHP in which we examined the mechanism of action of GCM2 variants. METHODS: Leukocyte DNA of hypoparathyroid individuals was Sanger sequenced for CASR, PTH, GNA11 and GCM2 mutations. DNA of hyperparathyroid individuals underwent MEN1, CDKN1B, CDC73, CASR, RET and GCM2 sequencing. The actions of identified GCM2 variants were evaluated by in vitro functional analyses. RESULTS: A novel homozygous p.R67C GCM2 mutation which failed to stimulate transcriptional activity in a luciferase assay was identified in affected members of two hypoparathyroid families. Oligonucleotide pull-down assay and in silico structural modeling indicated that this mutant had lost the ability to bind the consensus GCM recognition sequence of DNA. Two novel (p.I383M and p.T386S) and one previously reported (p.Y394S) heterozygous GCM2 variants that lie within a C-terminal conserved inhibitory domain were identified in three affected individuals of the hyperparathyroid families. One family member, heterozygous for p.I138M, had parathyroid carcinoma (PC), and a heterozygous p.V382M variant was found in another patient affected by sporadic PC. These variants exerted significantly enhanced in vitrotranscriptional activity, including increased stimulation of the PTH promoter. CONCLUSIONS: We provide evidence that two novel GCM2 R67C inactivating mutations with an inability to bind DNA are causative of hypoparathyroidism. Additionally, we provide evidence that two novel GCM2 variants increased transactivation of the PTH promoter in vitro and are associated with FIHP. Furthermore, our studies suggest that activating GCM2 variants may contribute to facilitating more aggressive parathyroid disease.

Management of Osteoporosis in Men: A Narrative Review.

Male osteoporosis is a still largely underdiagnosed pathological condition. As a consequence, bone fragility in men remains undertreated mainly due to the low screening frequency and to controversies in the bone mineral density (BMD) testing standards. Up to the 40% of overall osteoporotic fractures affect men, in spite of the fact that women have a significant higher prevalence of osteoporosis. In addition, in males, hip fractures are associated with increased morbidity and mortality as compared to women. Importantly, male fractures occur about 10 years later in life than women, and, therefore, due to the advanced age, men may have more comorbidities and, consequently, their mortality is about twice the rate in women. Gender differences, which begin during puberty, lead to wider bones in males as compared with females. In men, follicle-stimulating hormones, testosterone, estrogens, and sex hormone-binding levels, together with genetic factors, interact in determining the peak of bone mass, BMD maintenance, and lifetime decrease. As compared with women, men are more frequently affected by secondary osteoporosis. Therefore, in all osteoporotic men, a complete clinical history should be collected and a careful physical examination should be done, in order to find clues of a possible underlying diseases and, ultimately, to guide laboratory testing. Currently, the pharmacological therapy of male osteoporosis includes aminobisphosphonates, denosumab, and teriparatide. Hypogonadal patients may be treated with testosterone replacement therapy. Given that the fractures related to mortality are higher in men than in women, treating male subjects with osteoporosis is of the utmost importance in clinical practice, as it may impact on mortality even more than in women.

Management and Medical Therapy of Mild Hypercortisolism.

Mild hypercortisolism (mHC) is defined as an excessive cortisol secretion, without the classical manifestations of clinically overt Cushing's syndrome. This condition increases the risk of bone fragility, neuropsychological alterations, hypertension, diabetes, cardiovascular events and mortality. At variance with Cushing's syndrome, mHC is not rare, with it estimated to be present in up to 2% of individuals older than 60 years, with higher prevalence (up to 10%) in individuals with uncontrolled hypertension and/or diabetes or with unexplainable bone fragility. Measuring cortisol after a 1 mg overnight dexamethasone suppression test is the first-line test for searching for mHC, and the degree of cortisol suppression is associated with the presence of cortisol-related consequences and mortality. Among the additional tests used for diagnosing mHC in doubtful cases, the basal morning plasma adrenocorticotroph hormone, 24-h urinary free cortisol and/or late-night salivary cortisol could be measured, particularly in patients with possible cortisol-related complications, such as hypertension and diabetes. Surgery is considered as a possible therapeutic option in patients with munilateral adrenal incidentalomas and mHC since it improves diabetes and hypertension and reduces the fracture risk. In patients with mHC and bilateral adrenal adenomas, in whom surgery would lead to persistent hypocortisolism, and in patients refusing surgery or in whom surgery is not feasible, medical therapy is needed. Currently, promising though scarce data have been provided on the possible use of pituitary-directed agents, such as the multi-ligand somatostatin analog pasireotide or the dopamine agonist cabergoline for the-nowadays-rare patients with pituitary mHC. In the more frequently adrenal mHC, encouraging data are available for metyrapone, a steroidogenesis inhibitor acting mainly against the adrenal 11-ßhydroxylase, while data on osilodrostat and levoketoconazole, other new steroidogenesis inhibitors, are still needed in patients with mHC. Finally, on the basis of promising data with mifepristone, a non-selective glucocorticoid receptor antagonist, in patients with mild cortisol hypersecretion, a randomized placebo-controlled study is ongoing for assessing the efficacy and safety of relacorilant, a selective glucocorticoid receptor antagonist, for patients with mild adrenal hypercortisolism and diabetes mellitus/impaired glucose tolerance and/or uncontrolled systolic hypertension.

When to Suspect Hidden Hypercortisolism in Type 2 Diabetes: A Meta-Analysis.

OBJECTIVE: To investigate whether the available literature helps to identify the characteristics of patients with type 2 diabetes (T2D) more frequently associated with hidden hypercortisolism (HidHyCo). METHODS: A meta-analysis was performed using studies that assessed both the prevalence of HidHyCo in patients with T2D and the characteristics of these patients with and without HidHyCo. The DerSimonian and Laird (DSL) and Hartung-Knapp-Sidik-Jonkman (HKSJ) methods were utilized. RESULTS: Among the 18 available studies, 6 provided the necessary data. The association between HidHyCo and advanced T2D (based on the patients' description given in each study in the presence of microvascular/macrovascular complications or insulin treatment plus hypertension or hypertension treated with 2 or more drugs), hypertension, insulin treatment, and dyslipidemia was reported in 5 (2184 patients), 6 (2283 patients), 3 (1440 patients), and 3 (987 patients) studies, respectively. HidHyCo was associated with advanced T2D as assessed by both the DSL (odds ratio [OR], 3.4; 95% confidence interval [95% CI], 2.12-5.67) and HKSJ (OR, 3.60; 95% CI, 2.03-6.41) methods and with the prevalence of hypertension or insulin treatment as assessed by the DSL method (OR, 1.92; 95% CI, 1.05-3.50 and OR, 2.29; 95% CI, 1.07-4.91, respectively) but not as assessed by the HKSJ method. CONCLUSION: Patients with advanced T2D have a higher prevalence of HidHyCo. These data inform about the selection of patients with T2D for HidHyCo screening.

Management of bone fragility in type 2 diabetes: Perspective from an interdisciplinary expert panel.

AIM: Bone fragility is increasingly recognized as a relevant complication of type 2 diabetes (T2D) and diabetic patients with fragility fractures have higher mortality rates than non diabetic individuals or diabetic patients without fractures. However, current diagnostic approaches for fracture risk stratification, such as bone mineral density measurement or the use of risk assessment algorithms, largely underestimate fracture risk in T2D patients. A multidisciplinary expert panel was established in order to in order to formulate clinical consensus recommendations on bone health assessment and management of fracture risk in patients with T2D. DATA SYNTHESIS: The following key questions were addressed: a) which are the risk factors for bone fragility in T2D?, b) which diagnostic procedures can be currently used to stratify fracture risk in T2D patients?, c) which are the effects of antidiabetic treatments on bone?, and d) how to prevent and treat bone fragility in T2D patients? Based on the available data members of this panel suggest that the stratification of fracture risk in patients with diabetes should firstly rely on the presence of a previous fragility fracture and on the individual risk profile, with the inclusion of T2D-specific risk factors (namely T2D duration above 10 yrs, presence of chronic T2D complications, use of insulin or thiazolidinediones and persistent HbA1c levels above 8% for at least 1 year). Two independent diagnostic approaches were then suggested in the presence or the absence of a prevalent fragility fracture, respectively. CONCLUSIONS: Clinical trials in T2D patients at risk for fragility fractures are needed to determine the efficacy and safety of available antiresorptive and anabolic agents in this specific setting.

Cardiovascular complications of mild autonomous cortisol secretion.

Adrenal incidentalomas (AI) may be associated with a mild autonomous cortisol secretion (MACS) in up to one third of cases. There is growing evidence that MACS patients actually present increased risk of cardiovascular disease and higher mortality rate, driven by increased prevalence of known cardiovascular risk factors, as well as accelerated cardiovascular remodelling. Adrenalectomy seems to have cardiometabolic beneficial effects in MACS patients but their management is still a debated topic due to the lack of high-quality studies. Several studies suggested that so called "non-functioning" AI may be actually "functioning" with an associated increased cardiovascular risk. Although the individual cortisol sensitivity and peripheral activation have been recently suggested to play a role in influencing the cardiovascular risk even in apparently eucortisolemic patients, to date the degree of cortisol secretion, as mirrored by the cortisol levels after dexamethasone suppression test remains the best predictor of an increased cardiovascular risk in AI patients. However, whether or not the currently used cut-off set at 50 nmol/L for cortisol levels after dexamethasone suppression could be considered completely reliable in ruling out hypercortisolism remains unclear.