Vitamin D deficiency is very common and prescriptions of both assay and supplementation are increasing more and more. Health expenditure is exponentially increasing, thus it is timely and appropriate ...to establish rules. The Italian Association of Clinical Endocrinologists appointed a task force to review literature about vitamin D deficiency in adults. Four topics were identified as worthy for the practicing clinicians. For each topic recommendations based on scientific evidence and clinical practice were issued according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) System. (1) What cut-off defines vitamin D deficiency: even though 20 ng/mL (50 nmol/L) can be considered appropriate in the general population, we recommend to maintain levels above 30 ng/mL (75 nmol/L) in categories at risk. (2) Whom, when, and how to perform screening for vitamin D deficiency: categories at risk (patients with bone, liver, kidney diseases, obesity, malabsorption, during pregnancy and lactation, some elderly) but not healthy people should be screened by the 25-hydroxy-vitamin D assay. (3) Whom and how to treat vitamin D deficiency: beyond healthy lifestyle (mostly sun exposure), we recommend oral vitamin D (vitamin D2 or vitamin D3) supplementation in patients treated with bone active drugs and in those with demonstrated deficiency. Dosages, molecules and modalities of administration can be profitably individually tailored. (4) How to monitor the efficacy of treatment with vitamin D: no routine monitoring is suggested during vitamin D treatment due to its large therapeutic index. In particular conditions, 25-hydroxy-vitamin D can be assayed after at least a 6-month treatment. We are confident that this document will help practicing clinicians in their daily clinical practice.
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-βhydroxylase, 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.
Abstract
Context
Pathogenesis of autonomous steroid secretion and adrenocortical tumorigenesis remains partially obscure.
Objective
To investigate the relationship between transcriptome profile and ...genetic background in a large series of adrenocortical tumors and identify new potential pathogenetic mechanisms.
Design
Cross-sectional study.
Setting
University Hospitals of the European Network for the Study of Adrenal Tumors (ENSAT).
Patients
We collected snap-frozen tissue from patients with adrenocortical tumors (n = 59) with known genetic background: 26 adenomas with Cushing syndrome (CS- cortisol-producing adenoma CPA), 17 adenomas with mild autonomous cortisol secretion (MACS-CPAs), 9 endocrine-inactive adenomas (EIAs), and 7 adrenocortical carcinomas (ACCs).
Intervention
Ribonucleic acid (RNA) sequencing.
Main Outcome Measures
Gene expression, long noncoding RNA (lncRNA) expression, and gene fusions. Correlation with genetic background defined by targeted Sanger sequencing, targeted panel- or whole-exome sequencing.
Results
Transcriptome analysis identified 2 major clusters for adenomas: Cluster 1 (n = 32) mainly consisting of MACS-CPAs with CTNNB1 or without identified driver mutations (46.9% of cases) and 8/9 EIAs; Cluster 2 (n = 18) that comprised CP-CPAs with or without identified driver mutation in 83.3% of cases (including all CS-CPAs with PRKACA mutation). Two CS-CPAs, 1 with CTNNB1 and 1 with GNAS mutation, clustered separately and relatively close to ACC. lncRNA analysis well differentiate adenomas from ACCs. Novel gene fusions were found, including AKAP13-PDE8A in one CS-CPA sample with no driver mutation.
Conclusions
MACS-CPAs and EIAs showed a similar transcriptome profile, independently of the genetic background, whereas most CS-CPAs clustered together. Still unrevealed molecular alterations in the cAMP/PKA or Wnt/beta catenin pathways might be involved in the pathogenesis of adrenocortical tumors.
The existence of a common mesenchymal cell progenitor shared by bone, skeletal muscle, and adipocytes cell progenitors, makes the role of the skeleton in energy metabolism no longer surprising. Thus, ...bone fragility could also be seen as a consequence of a "poor" quality in nutrition. Ketogenic diet was originally proven to be effective in epilepsy, and long-term follow-up studies on epileptic children undergoing a ketogenic diet reported an increased incidence of bone fractures and decreased bone mineral density. However, the causes of such negative impacts on bone health have to be better defined. In these subjects, the concomitant use of antiepileptic drugs and the reduced mobilization may partly explain the negative effects on bone health, but little is known about the effects of diet itself, and/or generic alterations in vitamin D and/or impaired growth factor production. Despite these remarks, clinical studies were adequately designed to investigate bone health are scarce and bone health related aspects are not included among the various metabolic pathologies positively influenced by ketogenic diets. Here, we provide not only a narrative review on this issue, but also practical advice to design and implement clinical studies on ketogenic nutritional regimens and bone health outcomes. Perspectives on ketogenic regimens, microbiota, microRNAs, and bone health are also included.
...if in the presence of reduced BMD an increased risk of fracture has to be considered, then in the presence of normal BMD an increased risk of fractures could not be excluded 5. ...the fracture ...risk assessment algorithms, which are significantly based on BMD, are not accurate enough for identifying T2DM patients at risk for fractures 7, 8. In the first part of the review, the authors analysed the correct clinical approach for evaluating bone health in T2DM patients beyond dual X-ray densitometry, with particular attention to other imaging techniques that have been investigated in recent years, such as trabecular bone score, hip structural analysis, quantitative ultrasound, and peripheral quantitative computed tomography. ...the authors examined the role of microindentation and bone turnover markers in the evaluation of bone fragility in T2DM patients. ...the article by Zhao et al., entitled “Association between Uric Acid and Bone Mineral Density in Postmenopausal Women with Type 2 Diabetes Mellitus in China-A cross-sectional Inpatients Study,” retrospectively evaluated the association between uric acid levels and BMD in 262 postmenopausal women with T2DM.
Context:
Adrenocortical adenomas (ACAs) are among the most frequent human neoplasias. Genetic alterations affecting the cAMP/protein kinase A signaling pathway are common in cortisol-producing ACAs, ...whereas activating mutations in the gene encoding β-catenin (CTNNB1) have been reported in a subset of both benign and malignant adrenocortical tumors. However, the molecular pathogenesis of most ACAs is still largely unclear.
Objective:
The aim of the study was to define the genetic landscape of sporadic unilateral ACAs.
Design and Setting:
Next-generation whole-exome sequencing was performed on fresh-frozen tumor samples and corresponding normal tissue samples.
Patients:
Ninety-nine patients with ACAs (74 cortisol-producing and 25 endocrine inactive) negative for p.Leu206Arg PRKACA mutation.
Main Outcome Measures:
Identification of known and/or new genetic alterations potentially involved in adrenocortical tumorigenesis and autonomous hormone secretion, genotype-phenotype correlation.
Results:
A total of 706 somatic protein-altering mutations were detected in 88 of 99 tumors (median, six per tumor). We identified several mutations in genes of the cAMP/protein kinase A pathway, including three novel mutations in PRKACA, associated with female sex and Cushing's syndrome. We also found genetic alterations in different genes involved in the Wnt/β-catenin pathway, associated with larger tumors and endocrine inactivity, and notably, in many genes of the Ca2+-signaling pathway. Finally, by comparison of our genetic data with those available in the literature, we describe a comprehensive genetic landscape of unilateral ACAs.
Conclusions:
This study provides the largest sequencing effort on ACAs to date. We thereby identified somatic alterations affecting known and novel pathways potentially involved in adrenal tumorigenesis.
This study provides the largest DNA sequencing effort in adrenocortical adenomas up to now. Somatic alterations in known and novel pathways potentially involved in adrenal tumorigenesis are reported.
Objective
Experimental studies proposed a direct effect of follicle-stimulating hormone (FSH) on the skeletal metabolism, but results of human studies mainly conducted in females are controversial. ...The present study aims to investigate the possible role of FSH excess in male bone health, by comparing for the first time primary and central hypogonadism.
Design and Methods
119 men were enrolled in this cross-sectional observational study at the time of the first diagnosis of hypogonadism. All participants had spontaneous pubertal development. Regarding patients with hypergonadotropic hypogonadism (Hyper-H), Klinefelter syndrome (KS) patients were distinguished from the other forms (non-KS-Hyper-H) based on the onset of FSH elevation. Bone mineral density (BMD) at both lumbar spine (LS) and femoral neck (FN), as well as the prevalence of morphometric vertebral fractures (VFx), were assessed.
Results
Across the whole cohort, higher LS and FN BMD were associated with older age at diagnosis and higher body mass index (BMI), respectively. After adjusting for potential confounders (age at diagnosis, BMI, smoking habits, degree of hypogonadism defined by calculated free testosterone, and 25OH vitamin D levels), non-KS-Hyper-H patients showed significantly lower LS BMD and tended to show lower FN BMD values, as compared to those with hypogonadotropic hypogonadism (Hypo-H). In KS men, LS BMD was significantly lower than in those with non-KS-Hyper-H. No significant differences in the prevalence of VFx were found between the groups.
Conclusions
These findings suggest a potential negative effect of FSH excess on the male bone mass, especially at spine. The duration of high FSH levels may also contribute to these findings.
In these recent years many people are adopting a vegetarian type diet due to the numerous positive health effects of this regimen such as the reduction of the incidence of many chronic disorders like ...diabetes, hypertension, obesity and cancer. However this diet is quite restrictive and so it could be possible to have a deficiency in some specific nutrients, increasing the risk of osteoporosis and fractures. Although there are conflicting results on the effects of the vegetarian diet on bone health and fracture incidence, it is always recommendable in vegetarian people to have an adequate intake of calcium and vitamin D, through an increased intake of supplements, natural and fortified foods, an adequate intake of protein, fruit, vegetables, as well as vitamin B12. The aim of this literature review is to revise the actual knowledge of the effect of some nutrients and vegetarian diets on bone health.
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).
Purpose
It has been hypothesized that specific early-life stress (ES) procedures on CD-1 male mice produce diabetes-like alterations due to the failure of negative feedback of glucocorticoid hormone ...in the pituitary. The aim of this study is to investigate the possible mechanism that leads to this pathological model, framing it in a more specific clinical condition.
Methods
Metabolic and hypothalamic–pituitary–adrenal-related hormones of stressed mice (SM) have been analyzed immediately after stress procedures (21 postnatal days, PND) and after 70 days of a peaceful (unstressed) period (90 PND). These data have been compared to parameters from age-matched controls (CTR), and mice treated during ES procedures with oligonucleotide antisense for pro-opiomelanocortin (AS-POMC).
Results
At 21 PND, SM presented an increased secretion of hypothalamic
CRH
and pituitary
POMC
-
derived
peptides, as well as higher plasmatic levels of
ACTH
and
corticosterone
vs. CTR. At 90 PND, SM showed hyperglycemia, with suppression of hypothalamic
CRH
, while pituitary and plasmatic
ACTH
levels, as well as plasma corticosterone, were constantly higher than in CTR. These values are accompanied by a progressive acceleration in gaining total body weight, which became significant vs. CTR at 90 PND together with a higher pituitary weight. Treatment with AS-POMC prevented all hormonal and metabolic alterations observed in SM, both at 21 and 90 PND.
Conclusions
These findings show that these specific ES procedures affect the negative glucocorticoid feedback in the pituitary, but not in the hypothalamus, suggesting a novel model of ACTH-dependent hypercortisolism that can be prevented by silencing the
POMC
gene.
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