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.

HypoparaNet: A Database of Chronic Hypoparathyroidism Based on Expert Medical-Surgical Centers in Italy.

Hypoparathyroidism is a rare disease characterized by low serum calcium levels and absent or deficient parathyroid hormone level. Regarding the epidemiology of chronic hypoparathyroidism, there are limited data in Italy and worldwide. Therefore, the purpose of this study was to build a unique database of patients with chronic hypoparathyroidism, derived from the databases of 16 referral centers for endocrinological diseases, affiliated with the Italian Society of Endocrinology, and four centers for endocrine surgery with expertise in hypoparathyroidism, to conduct an epidemiological analysis of chronic hypoparathyroidism in Italy. The study was approved by the Institutional Review Board. A total of 537 patients with chronic hypoparathyroidism were identified. The leading etiology was represented by postsurgical hypoparathyroidism (67.6%), followed by idiopathic hypoparathyroidism (14.6%), syndromic forms of genetic hypoparathyroidism (11%), forms of defective PTH action (5.2%), non-syndromic forms of genetic hypoparathyroidism (0.9%), and, finally, other forms of acquired hypoparathyroidism, due to infiltrative diseases, copper or iron overload, or ionizing radiation exposure (0.7%). This study represents one of the first large-scale epidemiological assessments of chronic hypoparathyroidism based on data collected at medical and/or surgical centers with expertise in hypoparathyroidism in Italy. Although the study presents some limitations, it introduces the possibility of a large-scale national survey, with the final aim of defining not only the prevalence of chronic hypoparathyroidism in Italy, but also standards for clinical and therapeutic approaches.

GH secretion reserve in subclinical hypercortisolism.

PURPOSE: In overt hypercortisolism, growth hormone (GH) secretion is decreased and normalizes after surgery. In subclinical hypercortisolism (SH), GH secretion has been scarcely investigated. We assessed GH reserve in patients with and without SH and, in the former, also after recovery. METHODS: We enrolled 24 patients with adrenal adenomas, 12 with SH (SH+, 8 females, 58.3 ± 6.5 years) and 12 without SH (SH-; 11 females, 61.8 ± 10.6 years). SH was diagnosed in the presence of ≥ 2 out of: 1 mg overnight dexamethasone suppression test >83 nmol/L, urinary free cortisol (UFC) >193 nmol/day and ACTH levels <2.2 pmol/L. GH secretion was assessed by GHRH + Arginine test (GHRH-ARG) and age-adjusted serum IGF-I levels, expressed as SDS (IGF-I SDS). Eight SH+ patients were re-evaluated after the recovery from SH. RESULTS: Age, gender, body mass index (BMI) and IGF-I SDS were comparable between SH+ and SH- patients. After GHRH-ARG the mean GH peak levels (GH-P) and GH response (as Area Under Curve, GH-AUC) were lower in SH+ than in SH- patients (15.2 ± 8.1 vs 44.5 ± 30.9 µg/L, P = 0.004 and 1,418 ± 803 vs 4,028 ± 2,476 µg/L/120 min, P = 0.002, respectively), after adjusting for age and BMI. The GH-AUC and GH-P levels were negatively associated with UFC after adjusting for age and BMI (ß = -0.39, P = 0.02 and ß = -0.4, P = 0.020 respectively). After recovery, GH-P levels and GH-AUC increased as compared to baseline (23.7 ± 16.3 vs 15.8 ± 10.2 µg/L, P = 0.036 and 2,549 ± 1,982 vs 1,618 ± 911 µg/L/120 min, P = 0.012, respectively). CONCLUSIONS: GH secretion reserve is decreased in SH patients and increases after the recovery.

Are comorbidities of patients with adrenal incidentaloma tied to sex?

Background: A recent cross-sectional study showed that both comorbidities and mortality in patients with adrenal incidentaloma (AI) are tied to sex. However, few longitudinal studies evaluated the development of arterial hypertension, hyperglycemia, dyslipidemia and bone impairment in patients with AI. The aim of this study is to analyze the impact of sex in the development of these comorbidities during long-term follow-up. Methods: We retrospectively evaluated 189 patients (120 females, 69 males) with AI, from four referral centers in Italy and Croatia. Clinical characteristics, comorbidities and cortisol after 1-mg dexamethasone suppression test (1-mg DST) were assessed at baseline and at last follow-up visit (LFUV). Median follow-up was 52 (Interquartile Range 25-86) months. Results: The rates of arterial hypertension and hyperglycemia increased over time both in females (65.8% at baseline versus 77.8% at LFUV, p=0.002; 23.7% at baseline versus 39.6% at LFUV, p<0.001; respectively) and males (58.0% at baseline versus 69.1% at LFUV, p=0.035; 33.8% at baseline versus 54.0% at LFUV, p<0.001; respectively). Patients were stratified in two groups using 1.8 µg/dl as cut-off of cortisol following 1-mg DST: non-functional adrenal tumors (NFAT) and tumors with mild autonomous cortisol secretion (MACS). In the NFAT group (99 patients, females 62.6%), at baseline, we did not observe any difference in clinical characteristics and comorbidities between males and females. At LFUV, males showed a higher frequency of hyperglycemia than females (57.6% versus 33.9%, p=0.03). In the MACS group (89 patients, females 64.0%), at baseline, the prevalence of hypertension, hyperglycemia and dyslipidemia was similar between sexes, despite females were younger (60, IQR 55-69 versus 67.5, IQR 61-73, years; p=0.01). Moreover, females presented higher rates of bone impairment (89.3% versus 54.5%, p=0.02) than males. At LFUV, a similar sex-related pattern was observed. Conclusion: Patients with AI frequently develop arterial hypertension and hyperglycemia and should be periodically checked for these comorbidities, regardless of sex. In patients with MACS, the lack of difference between sexes in the frequency of cardiometabolic comorbidities despite that females are younger, and the higher frequency of bone impairment in females, suggest a sex-specific effect of cortisol.

Prevalence and clinical features of armadillo repeat-containing 5 mutations carriers in a single center cohort of patients with bilateral adrenal incidentalomas.

OBJECTIVE: We aimed to evaluate the prevalence of armadillo repeat-containing 5 (ARMC5) genetic defects in our cohort of bilateral adrenal incidentaloma (BAI) patients and to evaluate the possible existence of genotype-phenotype correlations. DESIGN: Cross-sectional study. SETTING: Tertiary care center. PARTICIPANTS: 72 BAI patients. MAIN OUTCOME MEASURE(S): The following data have been collected: morning adrenocorticotropic hormone (ACTH) concentrations; cortisol levels after 1 mg overnight dexamethasone suppression test (F-1mgDST); urinary free cortisol (UFC) levels; diameter of the adrenal masses; and the association with overweight/obesity, arterial hypertension, diabetes mellitus, dyslipidemia, cardiovascular events, unrelated neoplasia, osteoporosis, thyroid nodular disease, and primary hyperparathyroidism. A search for ARMC5 germline and somatic pathogenic variants was performed in all patients and in the adrenal tissue of patients operated on, respectively. RESULTS: The prevalence of germline ARMC5 pathogenic variants among patients with mild autonomous cortisol secretion (MACS+, defined as F-1mgDST > 1.8 µg/dL) was 18.8%. No germline pathogenic variants were detected in patients without MACS. Moreover, somatic ARMC5 pathogenic variants were also found in the adrenal tissue of six patients without germline ARMC5 variants. The F-1mgDST levels >5 µg/dL predicted with a poor sensitivity but a 90.5% specificity in identifying the presence of ARMC5 germline pathogenic variants. We did not find any clinical parameter predictive of the ARMC5 mutation presence. CONCLUSIONS: In MACS+ BAI patients, germline ARMC5 gene pathogenic variants are frequent. Further studies are needed to elucidate the pathophysiological role of somatic ARMC5 pathogenic variants on adrenal tumor development in otherwise wild-type (WT) patients.

Case Report: Multisystem inflammatory syndrome in children with associated proximal tubular injury.

Introduction: SARS-CoV-2 infection in the pediatric population can be associated with a multiorgan inflammatory syndrome called children's multisystem inflammatory syndrome (MIS-C). The kidneys can be affected by a broad spectrum of possible injuries, whose pathogenetic mechanisms are still unclear.Case report: We report the case of a 5-year-old boy with severe cardiac involvement in the context of MIS-C. After two weeks of hospitalization, an abdominal ultrasound showed massive bladder "debris", followed by the onset of normoglycemic glycosuria. Over time, there was a progressive increase in glycosuria, and the presence of a mat of amorphous phosphate crystals was evidenced on urinary sediment. Together with the findings of hypo-uricemia, increased urinary uric acid, and globally increased urinary amino acids, a clinical picture of kidney proximal tubular damage with secondary Fanconi-like syndrome took shape. Discussion: This case report describes the case of a patient with MIS-C with cardiac and kidney involvement characterized by proximal tubular damage, which slowly improved but still persisted at the 8-month follow-up. The pathogenesis of the damage is unclear and probably multifactorial.

Bisphosphonates after denosumab withdrawal reduce the vertebral fractures incidence.

OBJECTIVE: Several studies showed the occurrence of vertebral fracture (VFx) in patients discontinuing denosumab (Dmab), suggesting the need of bisphosphonate (BPs) therapy to mitigate this VFx risk increase. However, the morphometric VFx (morphoVFx) incidence after Dmab discontinuation and the BPs effect on VFx risk in this setting are still a matter of debate. DESIGN: Retrospective, monocentric study. METHODS: In 120 patients (111 females) discontinuing Dmab, 19 have not been treated (non-treated group: 16 females, aged 63.5 ± 15.0 years) and 101 patients have been treated (treated group: 95 females, aged 70.0 ± 10.6 years) with BPs (28 alendronate (ALN); 73 zoledronate ZOL), single infusion), respectively. We evaluated the incidence of both clinical VFx and morphoVFx in treated group and non-treated group. RESULTS: Patients in treated group showed a 5.5% VFx incidence (n = 6, three clinical, three morpho VFx), which was anyway lower than non-treated group patients (n = 4, 21.1%, four clinical, three multiple, P = 0.029), despite a comparable FRAX score at the time of Dmab initiation. The logistic regression analysis showed that the VFx incidence was independently associated with the lack of BPs treatment (odds ratio: 13.9, 95% CI 1.7-111.1, P = 0.014), but not with the number of Dmab injections, age, duration of BPs before Dmab initiation, the BMD at Dmab withdrawal, and the prevalence of VFx at Dmab withdrawal. CONCLUSIONS: The Dmab withdrawal is associated with an increased risk of clinical but not morphometric VFx. Therapy with ALN or with a single ZOL treatment is partially effective in reducing the increased VFx risk after Dmab withdrawal.

Case Report: Unusual Presentations of Loss-of-Function Mutations of the Calcium-Sensing Receptor.

BACKGROUND: In recent years, heterozygous loss-of-function mutations of the Calcium Sensing Receptor gene (CaSR) were implicated in different hypercalcemic syndromes besides familial hypocalciuric hypercalcemia (FHH), including neonatal severe primary hyperparathyroidism (NSHPT) and primary hyperparathyroidism (PHPT). CASES PRESENTATION: Here we describe two unusual presentations of heterozygous inactivating CaSR mutations. Case 1: a case of NSHPT due to a de novo, p.(ArgR185Gln) CaSR mutation and successfully treated with cinacalcet monotherapy for 8 years until definitive surgical resolution. Case 2: a 37 years-old woman with PHPT complicated with hypercalcemia and nephrocalcinosis with a novel heterozygous p.(Pro393Arg) CaSR mutation and cured with parathyroidectomy. CONCLUSIONS: These cases reinforce the fact that the clinical spectrum of inactivating mutations of the CaSR has widened and, although carrying a mutation suggestive of FHH, some patients may have different clinical phenotypes and complications requiring individualized therapies.

Approach to patients with pseudo-Cushing's states.

The distinction between pseudo-Cushing's states (PCS) and Cushing's syndrome (CS) poses a significant clinical challenge even for expert endocrinologists. A patient's clinical history can sometimes help to distinguish between them (as in the case of alcoholic individuals), but the overlap in clinical and laboratory findings makes it difficult to arrive at a definitive diagnosis. We aim to describe the most common situations that can give rise to a condition resembling overt endogenous hypercortisolism and try to answer questions that physicians often face in clinical practice. It is important to know the relative prevalence of these different situations, bearing in mind that most of the conditions generating PCS are relatively common (such as metabolic syndrome and polycystic ovary syndrome), while CS is rare in the general population. Physicians should consider CS in the presence of additional features. Appropriate treatment of underlying conditions is essential as it can reverse the hormonal abnormalities associated with PCS. Close surveillance and a thorough assessment of a patient's hormone status will ultimately orient the diagnosis and treatment options over time.

Adrenal incidentaloma: differential diagnosis and management strategies.

Adrenal incidentaloma is a frequent clinical finding. Once an adrenal mass is detected, is mandatory to determine whether the lesion is malignant or benign and whether it is hormonally active or non-functioning, to estabilish an adequate treatement or follow-up. The European Society of Endocrinology and ENSAT Guideline recently provided the best recommendation based on the available literature. However, due to the retrospective design of the majority of the studies, the small number of patients included and the inadequate follow-up, some issues are still unresolved. In particular, there is a general consensus about the need of adrenalectomy in the presence of unilateral adrenal mass and clinically relevant hormone excess or radiological findings suspected for malignancy. On the other side, how to manage adrenal masses with indeterminate characteristics or subtle cortisol secretion, and how long the radiological and functional follow-up of benign adrenal mass should last in non-operated patients, are still open questions. Therefore, high-quality research for establish the adequate management of these patients and randomized clinical trials are needed to avoid unnecessary investigations and invasive procedures and ensure a clinically effective work-up.

Protective Effect of Denosumab on Bone in Older Women with Primary Hyperparathyroidism.

OBJECTIVES: To determine the effect of denosumab, which is used in primary osteoporosis (PO), in primary hyperparathyroidism (PHPT)-related osteoporosis. DESIGN: Retrospective, longitudinal study. SETTING: Outpatient osteoporosis clinic. PARTICIPANTS: Older women with PHPT (78.6 ± 5.5) (n = 25) and PO (78.8 ± 5.2) (n = 25) matched on age, body mass index, familial history of hip fracture, femoral bone mineral density (BMD), and personal history of fragility fractures. INTERVENTION: Twenty-four months of denosumab therapy. MEASUREMENTS: We assessed the calcium-phosphorus metabolism parameters; BMD at the lumbar spine (LS), femoral neck (FN), and total hip (TH) using dual X-ray absorptiometry; and morphometric vertebral fractures using radiographs in all subjects at baseline and after 24 months. Changes in BMD and total alkaline phosphatase (ALP) activity were considered significant if they were greater than the least significant change (LS 2.8%, FN 5.9%, TH 4.8%, ALP -22%) and were expressed as percentage difference between end of follow-up and baseline (Δ). RESULTS: After 24 months, women with PHPT had greater ΔALP (-30.6 ± 11.3), ΔFN (5.6 ± 4.8), and ΔTH (4.8 ± 4.4) than those with PO (ΔALP -21.4 ± 13.1, ΔFN 2.9 ± 4.8, ΔTH 1.2 ± 4.1, P < .05 for all comparisons). A significant increase in BMD was more frequent in women with PHPT (92%) than in those with PO (52%, P < .05) and it was 13.4 times as likely in women with PHPT as in those with PO (P = .02), regardless of possible confounders. Two subjects in each group had an incident fracture. CONCLUSIONS: Denosumab therapy is effective in older women with PHPT-related osteoporosis.

A population-based study of cancer incidence in solid organ transplants from donors at various risk of neoplasia.

A population-based cohort study of recipients of organs from donors with a recognized history or active cancer has been conducted by linking the Italian National Registry of Transplanted Patients and the National Registry of Donors with Neoplasia Risk. Between 2002 and 2004, 8,198 solid organ transplants have been performed in Italy, 108 of them with organs from 59 cadaveric donors with various risk of neoplasia. There were two reported cases of nonmelanoma skin cancer during the follow up of the transplanted patients, which lasted 27.6+/-11.3 months (234 patient-years). In our study, recipients of organs from donors with various degree of neoplasia risk are exposed to a low risk of cancer transmission.

Primary aldosteronism as a cause of secondary osteoporosis.

OBJECTIVE: Patients with primary aldosteronism (PA) have a high prevalence of osteoporosis (OP) and fractures (Fx). We evaluated the presence of PA in patients admitted to our metabolic bone disease outpatient clinic. DESIGN: Study conducted on an in- and outpatient basis in a referral Italian endocrinology unit. METHODS: A total of 2632 patients were evaluated. 2310 were excluded because they were taking drugs known to affect bone or mineralocorticoids metabolism or were diagnosed to have a secondary cause of osteoporosis. The remaining 322 subjects (304 females, 18 males) took part in the study. Bone mineral density (BMD) and thoracic and lumbar spine vertebral morphometry were performed by dual X-ray absorptiometry. All patients were screened for PA with aldosterone-to-renin ratio. In those who had positive results, confirmatory tests were performed. RESULTS: Among 322 subjects, 213 were osteoporotics and 109 were not. PA was diagnosed in eleven out of 213 osteoporotic patients (5.2%) and one out of 109 non-osteoporotic subjects (0.9%, P = 0.066). PA was observed in the 26.1% of patients with the concomitant presence of osteoporosis, hypertension and hypercalciuria. Compared with patients without PA, patients with PA had mean values of urinary calcium excretion, 4.8 ± 2.5 mmol/day vs 7.6 ± 3.2 mmol/day, P < 0.001 and serum PTH levels, 5.4 pmol/L vs 7.3 pmol/L, P < 0.01, significantly higher. CONCLUSIONS: PA should be considered among the causes of secondary OP.

Cardiovascular events in patients with mild autonomous cortisol secretion: analysis with artificial neural networks.

BACKGROUND: The independent role of mild autonomous cortisol secretion (ACS) in influencing the cardiovascular event (CVE) occurrence is a topic of interest. We investigated the role of mild ACS in the CVE occurrence in patients with adrenal incidentaloma (AI) by standard statistics and artificial neural networks (ANNs). METHODS: We analyzed a retrospective record of 518 AI patients. Data regarding cortisol levels after 1 mg dexamethasone suppression (1 mg DST) and the presence of obesity (OB), hypertension (AH), type-2 diabetes (T2DM), dyslipidemia (DL), familial CVE history, smoking habit and CVE were collected. RESULTS: The receiver-operating characteristic curve analysis suggested that 1 mg DST, at a cut-off of 1.8 µg/dL, had the best accuracy for detecting patients with increased CVE risk. In patients with 1 mg-DST ≥1.8 µg/dL (DST+, n = 223), age and prevalence of AH, T2DM, DL and CVE (66 years, 74.5, 25.9, 41.4 and 26.8% respectively) were higher than that of patients with 1 mg-DST ≤1.8 µg/dL (61.9 years, 60.7, 18.5, 32.9 and 10%, respectively, P < 0.05 for all). The CVE were associated with DST+ (OR: 2.46, 95% CI: 1.5-4.1, P = 0.01), regardless of T2DM, AH, DL, smoking habit, gender, observation period and age. The presence of at least two among AH, T2DM, DL and OB plus DST+ had 61.1% sensitivity in detecting patients with CVE. By using the variables selected by ANNs (familial CVE history, age, T2DM, AH, DL and DST+) 78.7% sensitivity was reached. CONCLUSIONS: Cortisol after 1 mg-DST is independently associated with the CVE occurrence. The ANNs might help for assessing the CVE risk in AI patients.

The activity of 11ß-hydroxysteroid dehydrogenase type 2 enzyme and cortisol secretion in patients with adrenal incidentalomas.

In adrenal incidentaloma (AI) patients, beside the cortisol secretion, a different 11ß-hydroxysteroid dehydrogenase type 2 (HSD11B2) activity, measurable by 24-h urinary cortisol/cortisone ratio (R-UFF/UFE) (the higher R-UFF/UFE the lower HSD11B2 activity), could influence the occurrence of the subclinical hypercortisolism (SH)-related complications (hypertension, type 2 diabetes, obesity). We evaluated whether in AI patients, UFF levels are associated to UFE levels, and the HSD11B2 activity to the complications presence. In 156 AI patients (93F, age 65.2 ± 9.5 years), the following were measured: serum cortisol after 1 mg-dexamethasone test (1 mg-DST), ACTH, UFF, UFE levels, and R-UFF/UFE (by liquid chromatography-tandem mass spectrometry), the latter was also evaluated in 63 matched-controls. We diagnosed SH (n = 22) in the presence of ≥2 among ACTH <2.2 pmol/L, increased UFF levels, and 1 mg-DST >83 nmol/L. Patients showed higher UFF levels and R-UFF/UFE than controls (75.9 ± 43.1 vs 54.4 ± 22.9 nmol/24 h and 0.26 ± 0.12 vs 0.20 ± 0.07, p < 0.005, respectively) but comparable UFE levels (291 ± 91.1 vs 268 ± 61.5, p = 0.069). The R-UFF/UFE was higher in patients with high (h-UFF, n = 28, 0.41 ± 0.20) than in those with normal (n-UFF, 0.22 ± 0.10, p < 0.005) UFF levels and in patients with SH than in those without SH (0.30 ± 0.12 vs 0.25 ± 0.12, p = 0.04). UFF levels were associated with R-UFF/UFE (r = 0.849, p < 0.001) in n-UFF, but not in h-UFF patients. Among h-UFF patients, the complications prevalence was not associated with R-UFF/UFE values. In AI patients, the UFF increase is not associated with a UFE increase. The HSD11B2 activity is inversely associated with UFF levels in n-UFF patients but not in h-UFF patients, and it is not associated with the SH complications.

Adrenalectomy reduces the risk of vertebral fractures in patients with monolateral adrenal incidentalomas and subclinical hypercortisolism.

OBJECTIVE: Subclinical hypercortisolism (SH) is associated with increased risk of vertebral fractures (VFx). The effect on bone following recovery from SH is unknown. DESIGN: Of the 605 subjects consecutively referred for monolateral adrenal incidentalomas (AIs) to our outpatient clinics, 55 SH patients (recruited on the basis of the exclusion criteria) were enrolled. We suggested to all patients to undergo adrenalectomy, which was accepted by 32 patients (surgical group, age 61.3±8.1 years) and refused by 23 patients, who were followed with a conservative management (non-surgical group, age 65.4±7.1 years). METHODS: We diagnosed SH in patients with serum cortisol after 1  mg dexamethasone suppression test (1  mg-DST) >5.0  µg/dl or with greater than or equal to two criteria among 1  mg-DST >3.0  µg/dl, urinary free cortisol >70  µg/24  h and ACTH <10  pg/ml. We assessed: bone mineral density (BMD) at lumbar spine (LS) and femoral neck (as Z-score) by dual-energy X-ray absorptiometry and the VFx presence by X-ray at baseline and at the end of follow up (surgical group 39.9±20.9 months and non-surgical group 27.7±11.1 months). RESULTS: The LS Z-score (ΔZ-score/year) tended to increase in the surgical group (0.10±0.20) compared with the non-surgical group (-0.01±0.27, P=0.08) and in the former, the percentage of patients with new VFx was lower (9.4%) than in the latter (52.2%, P<0.0001). Surgery in AI patients with SH was associated with a 30% VFx risk reduction (odds ratio 0.7, 95% CI 0.01-0.05, P=0.008) regardless of age, gender, follow up duration, 1  mg-DST, LS BMD, and presence of VFx at baseline. CONCLUSION: In patients with monolateral AI and SH, adrenalectomy reduces the risk of VFx.

Prediction of Vertebral Fractures in Patients With Monolateral Adrenal Incidentalomas.

CONTEXT: Subtle hypercortisolism is associated with an increased risk of vertebral fracture (VFx). OBJECTIVE: The objective was to determine the best parameters of cortisol secretion for detecting the VFx risk in patients with adrenal incidentalomas (AI). DESIGN: This was a retrospective (cross-sectional arm) and prospective (longitudinal arm) design. In the cross-sectional arm, we assessed the accuracy of the cortisol secretion indexes in identifying the patients with VFx (prevalent VFx). In the longitudinal arm, we tested the cortisol secretion parameters, which were able to identify the prevalent VFx, for the prediction of the occurrence of a new VFx (incident VFx) in AI patients followed-up for at least 2 years. SETTING: Four referral Italian endocrinology units participated in this study. PATIENTS: A total of 444 and 126 AI patients without symptoms of hypercortisolism enrolled in the cross-sectional arm and longitudinal arm, respectively. MAIN OUTCOME MEASURES: Serum cortisol after a 1-mg dexamethasone suppression test (1 mg DST), urinary free cortisol, ACTH, bone mineral density at lumbar spine and femoral neck (by dual-energy x-ray absorptiometry), and the VFx presence (by x-ray). RESULTS: The cortisol levels after 1 mg DST that were greater than 2.0 µg/dl (55 nmol/liter) were the best criteria for detecting patients with both prevalent (73.6% sensitivity, 70.5% specificity) and incident VFx (80% sensitivity, 68.8% specificity) and were associated with a 10-fold increased risk of a new VFx (odds ratio,10.27; 95% confidence interval, 3.39-31.12; P < .0001), regardless of age, gender, bone mineral density at lumbar spine, and prevalent VFx. CONCLUSIONS: In AI patients without symptoms of overt hypercortisolism, the cortisol levels after 1 mg DST greater than 2.0 µg/dl (55 nmol/liter) represent the best criterion for detecting prevalent and incident VFx.

Hypercalciuria May Persist After Successful Parathyroid Surgery and It Is Associated With Parathyroid Hyperplasia.

CONTEXT: Hypercalciuria is frequently found in primary hyperparathyroidism (1HPT) and, although it generally normalizes after successful parathyroidectomy, may persist in some patients. The factors associated with persistent calcium renal leak (cRL) have not been clarified. OBJECTIVE: The purpose of this study was to determine the prevalence of cRL in our 1HPT population and investigate cRL-related factors. DESIGN: This was a retrospective longitudinal study. SETTING: The study was conducted in an outpatient setting. PATIENTS/INTERVENTION: The participants were 95 patients with 1HPT successfully operated on who had a normal estimated glomerular filtration rate. MAIN OUTCOME MEASURES: The biochemical parameters of calcium metabolism and bone mineral density (BMD) measured by dual-X-ray absorptiometry before and 24 months after surgery were assessed. All histological findings were recorded. RESULTS: The prevalence of hypercalciuria before and after surgery was 74% and 32%, respectively. Before, surgery patients with cRL showed lower calcium and higher phosphate levels than those without cRL (10.9 ± 0.6 vs 11.4 ± 0.8 mg/dL [2.7 ± 0.2 vs 2.8 ± 0.2 mmol/L], P = .01 and 2.6 ± 0.5 vs 2.4 ± 0.4 mg/dL [0.84 ± 0.2 vs 0.77 ± 0.1 mmol/L], P = .04, respectively), whereas 24-h calciuria levels and the prevalence of 1HPT complications (osteoporosis, renal stones, and hypertension) were comparable. After surgery, serum calcium, phosphate, and PTH levels were comparable between patients with and without cRL. The prevalence of the histological finding of parathyroid hyperplasia was higher in patients with cRL (50%) than in patients without cRL (22%) (P = .01). The presence of cRL was independently associated with presurgery hypercalciuria (odds ratio, 4.71; 95% confidence interval, 1.18-18.8; P = .03) and parathyroid hyperplasia (odds ratio, 3.52; 95% confidence interval, 1.31-9.43; P = .01). Only patients without cRL had improved BMD at the spine (P = .04), total femur (P = .01), and femoral neck (P = .01). CONCLUSIONS: cRL is present in 30% of patients with 1HPT after successful surgery, and it is associated with parathyroid hyperplasia before surgery and the lack of improvement in BMD after surgery.

In postmenopausal female subjects with type 2 diabetes mellitus, vertebral fractures are independently associated with cortisol secretion and sensitivity.

CONTEXT: In type 2 diabetes (T2D), the vertebral fracture (VFx) prevalence and cortisol secretion are increased. OBJECTIVE: The objective of this study was to evaluate the role of glucocorticoid secretion and sensitivity in T2D-related osteoporosis. DESIGN AND SETTING: This was a case-control study in an outpatient setting. PATIENTS: The patients were ninety-nine well-compensated T2D postmenopausal women (age, 65.7 ± 7.3 y) and 107 controls (age, 64.5 ± 8.2 y). MAIN OUTCOME MEASURES: We assessed osteocalcin, C-terminal telopeptide of type I collagen, ACTH, cortisol after the dexamethasone suppression test (F-1mgDST), BclI and N363S single-nucleotide polymorphisms (SNPs) of glucocorticoid receptor, lumbar spine and femoral neck bone mineral density by dual x-ray absorptiometry, and VFx by radiography. RESULTS: Compared with controls, T2D subjects had increased VFx prevalence (20 vs 34.3%, respectively; P = .031), bone mineral density (Z-scores, lumbar spine, 0.16 ± 1.28 vs 0.78 ± 1.43, P = .001; femoral neck, -0.03 ± 0.87 vs 0.32 ± 0.98, P = .008, respectively), and F-1mgDST (1.06 ± 0.42 vs 1.21 ± 0.44 µg/dL, 29.2 ± 1.2 vs 33.3 ± 1.2 nmol/L, respectively; P = .01), and decreased osteocalcin (10.6 ± 6.4 vs 4.9 ± 3.2 ng/mL, 10.6 ± 6.4 vs 4.9 ± 3.2 µg/L, respectively; P < .0001) and C-terminal telopeptide of type I collagen (0.28 ± 0.12 vs 0.14 ± 0.08 ng/mL, 0.28 ± 0.12 vs 0.14 ± 0.08 mcg/L, respectively; P < .0001). Fractured controls or T2D patients had increased sensitizing N363S SNP prevalence (20 and 17.6%, respectively) compared to non-fractured subjects (3.4 and 3.1%, respectively; P = .02 for both comparisons), and similar BclI SNP prevalence. The VFx presence was associated with the sensitizing variant of N363S SNPs in controls (odds ratio [OR] = 10.6; 95% confidence interval [CI], 1.8-63.3; P = .01) and in T2D patients (OR = 12.5; 95% CI, 1.8-88.7; P = .01), and with the F-1mgDST levels (OR = 2.1; 95% CI, 1.1-4.1; P = .03) only in T2D patients. CONCLUSIONS: In postmenopausal T2D women, VFx are associated with cortisol secretion and the sensitizing variant of N363S SNPs.