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Frontiers in Endocrinology 2022In recent years, vitamin D has become the protagonist in many studies. From cardiology to oncology the spotlight was on this vitamin. While in the past it was considered... (Review)
Review
In recent years, vitamin D has become the protagonist in many studies. From cardiology to oncology the spotlight was on this vitamin. While in the past it was considered for its important role in phospho-calcium metabolism and skeletal disorders; today by studying it better, thousands of scenarios and facets have opened up on this vitamin which is actually a hormone in all respects. There are authoritative studies that demonstrate its activity and on: carcinogenesis, inflammation, autoimmunity and endocrinopathies. Its role has been studied in type 1 and type 2 diabetes mellitus, in Hashimoto or Graves' thyroiditis and even in adrenal gland diseases. In fact, there are several studies that demonstrate the possible correlations between vitamin D and: Addison's disease, Cushing disease, hyperaldosteronism or adrenocortical tumors. Moreover, this fascinating hormone and adrenal gland even seem to be deeply connected by common genetic pathways. This review aimed to analyze the works that have tried to study the possible influence of vitamin D on adrenal diseases. In this review we analyze the works that have tried to study the possible influence of vita-min D on adrenal disease.
Topics: Humans; Vitamin D; Diabetes Mellitus, Type 2; Adrenal Glands; Hyperaldosteronism; Vitamins; Hormones
PubMed: 36313775
DOI: 10.3389/fendo.2022.1001065 -
BMC Endocrine Disorders Aug 2016The term "adrenal fatigue" ("AF") has been used by some doctors, healthcare providers, and the general media to describe an alleged condition caused by chronic exposure... (Review)
Review
BACKGROUND
The term "adrenal fatigue" ("AF") has been used by some doctors, healthcare providers, and the general media to describe an alleged condition caused by chronic exposure to stressful situations. Despite this, "AF" has not been recognized by any Endocrinology society, who claim there is no hard evidence for the existence. The aim of this systematic review is to verify whether there is substantiation for "AF".
METHODS
A systematic search was performed at PUBMED, MEDLINE (Ebsco) and Cochrane databases, from the beginning of the data until April 22nd, 2016. Searched key words were: "adrenal" + "fatigue", "adrenal" + "burnout", "adrenal" + "exhaustion", "hypoadrenia", "burnout" + "cortisol", "fatigue" + "cortisol", "clinical" + "burnout", "cortisol" + "vitalility", "adrenal" + "vitality", and "cortisol" + "exhaustion". Eligibility criteria were: (1) articles written in English, (2) cortisol profile and fatigue or energy status as the primary outcome, (3) performed tests for evaluating the adrenal axis, (4) absence of influence of corticosteroid therapy, and (5) absence of confounding diseases. Type of questionnaire to distinct fatigued subjects, population studied, tests performed of selected studies were analyzed.
RESULTS
From 3,470 articles found, 58 studies fulfilled the criteria: 33 were carried in healthy individuals, and 25 in symptomatic patients. The most assessed exams were "Direct Awakening Cortisol" (n = 29), "Cortisol Awakening Response" (n = 27) and "Salivary Cortisol Rhythm" (n = 26).
DISCUSSION
We found an almost systematic finding of conflicting results derived from most of the studies methods utilized, regardless of the validation and the quality of performed tests. Some limitations of the review include: (1) heterogeneity of the study design; (2) the descriptive nature of most studies; (3) the poor quality assessment of fatigue; (4) the use of an unsubstantiated methodology in terms of cortisol assessment (not endorsed by endocrinologists); (5) false premises leading to an incorrect sequence of research direction; and, (6) inappropriate/invalid conclusions regarding causality and association between different information.
CONCLUSION
This systematic review proves that there is no substantiation that "adrenal fatigue" is an actual medical condition. Therefore, adrenal fatigue is still a myth.
Topics: Adrenal Gland Diseases; Burnout, Professional; Circadian Rhythm; Fatigue; Fatigue Syndrome, Chronic; Female; Humans; Hydrocortisone; Male; Saliva; Stress, Psychological
PubMed: 27557747
DOI: 10.1186/s12902-016-0128-4 -
JAMA Oncology Feb 2018If not promptly recognized, endocrine dysfunction can be life threatening. The incidence and risk of developing such adverse events (AEs) following the use of immune... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
If not promptly recognized, endocrine dysfunction can be life threatening. The incidence and risk of developing such adverse events (AEs) following the use of immune checkpoint inhibitor (ICI) regimens are unknown.
OBJECTIVE
To compare the incidence and risk of endocrine AEs following treatment with US Food and Drug Administration-approved ICI regimens.
DATA SOURCES
A PubMed search through July 18, 2016, using the following keywords was performed: "ipilimumab," "MDX-010," "nivolumab," "BMS-963558," "pembrolizumab," "MK-3475," "atezolizumab," "MPDL3280A," and "phase."
STUDY SELECTION
Thirty-eight randomized clinical trials evaluating the usage of these ICIs for treatment of advanced solid tumors were identified, resulting in a total of 7551 patients who were eligible for a meta-analysis. Regimens were categorized by class into monotherapy with a PD-1 (programmed cell death protein 1) inhibitor, a CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) inhibitor, or a PD-L1 (programmed cell death 1 ligand 1) inhibitor, and combination therapy with PD-1 plus CTLA-4 inhibitors.
DATA EXTRACTION AND SYNTHESIS
The data were extracted by 1 primary reviewer (R.B.-S.) and then independently reviewed by 2 secondary reviewers (W.T.B. and A.C.G.-C.) following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Inferences on the incidence of AEs were made using log-odds random effects models.
MAIN OUTCOMES AND MEASURES
Incidence of all-grade hypothyroidism, hyperthyroidism, hypophysitis, primary adrenal insufficiency, and insulin-deficient diabetes.
RESULTS
Overall, 38 randomized clinical trials comprising 7551 patients were included in this systematic review and meta-analysis. The incidence of both hypothyroidism and hyperthyroidism was highest in patients receiving combination therapy. Patients on the combination regimen were significantly more likely to experience hypothyroidism (odds ratio [OR], 3.81; 95% CI, 2.10-6.91, P < .001) and hyperthyroidism (OR, 4.27; 95% CI, 2.05-8.90; P = .001) than patients on ipilimumab. Compared with patients on ipilimumab, those on PD-1 inhibitors had a higher risk of developing hypothyroidism (OR, 1.89; 95% CI, 1.17-3.05; P = .03). The risk of hyperthyroidism, but not hypothyroidism, was significantly greater with PD-1 than with PD-L1 inhibitors (OR, 5.36; 95% CI, 2.04-14.08; P = .002). While patients who received PD-1 inhibitors were significantly less likely to experience hypophysitis than those receiving ipilimumab (OR, 0.29; 95% CI, 0.18-0.49; P < .001), those who received combination therapy were significantly more likely to develop it (OR, 2.2; 95% CI, 1.39-3.60; P = .001). For primary adrenal insufficiency and insulin-deficient diabetes no statistical inferences were made due to the smaller number of events.
CONCLUSIONS AND RELEVANCE
Our study provides more precise data on the incidence of endocrine dysfunctions among patients receiving ICI regimens. Patients on combination therapy are at increased risk of thyroid dysfunction and hypophysitis.
Topics: Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Cell Cycle Checkpoints; Endocrine Glands; Endocrine System Diseases; Humans; Immunotherapy; Incidence; Neoplasms; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic
PubMed: 28973656
DOI: 10.1001/jamaoncol.2017.3064 -
The Journal of Clinical Endocrinology... Aug 2023Adrenal medullary hyperplasia (AMH) is a rare, incompletely described disorder of the adrenal medulla that is associated with catecholamine excess. (Meta-Analysis)
Meta-Analysis
CONTEXT
Adrenal medullary hyperplasia (AMH) is a rare, incompletely described disorder of the adrenal medulla that is associated with catecholamine excess.
OBJECTIVE
To increase knowledge about AMH by reviewing the reported cases of this disorder.
DESIGN
Systematic review and meta-analysis of the genotype/phenotype relationship in all reported cases of AMH.
SETTING
Literature review and analysis.
PATIENTS OR OTHER PARTICIPANTS
All cases of AMH published to date.
MAIN OUTCOME MEASURE(S)
Characteristics of AMH cases and genotype-phenotype relationships.
RESULTS
A total of 66 patients, median age of 48 years, were identified from 29 reports. More than one-half were male (n = 39, 59%). The majority had unilateral (73%, n = 48) disease; 71% (n = 47) were sporadic and 23% (n = 15) were associated with the MEN2. Most (91%, n = 60) displayed signs and symptoms of excess catecholamine secretion, particularly hypertension. Elevated catecholamine concentrations (86%, n = 57) and adrenal abnormalities on imaging were common (80%, n = 53). More than one-half (58%, n = 38) had concurrent tumors: pheochromocytoma (42%, n = 16/38); medullary thyroid cancer (24%, n = 9/38); and adrenocortical adenoma (29%, n = 11/38). Most (88%, n = 58) underwent adrenalectomy with 45/58 achieving symptom resolution. Adrenalectomy was less common in patients under 40 years and those with bilateral disease (both P < .05).
CONCLUSION
AMH may be sporadic or associated with MEN2, most have catecholamine excess and imaging abnormalities. Unilateral involvement is more common. Most reported patients have been treated with adrenalectomy, which is usually curative with regard to catecholamine hypersecretion.
Topics: Male; Humans; Female; Hyperplasia; Adrenal Gland Neoplasms; Pheochromocytoma; Adrenal Medulla; Adrenalectomy; Catecholamines
PubMed: 36896586
DOI: 10.1210/clinem/dgad121 -
The Journal of Clinical Endocrinology... Jul 2020Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation and neural crest tumor (ROHHHAD[NET]) is a rare and potentially fatal...
CONTEXT
Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation and neural crest tumor (ROHHHAD[NET]) is a rare and potentially fatal disease. No specific diagnostic biomarker is currently available, making prompt diagnosis challenging. Since its first definition in 2007, a complete clinical analysis leading to specific diagnosis and follow-up recommendations is still missing.
OBJECTIVE
The purpose of this work is to describe the clinical timeline of symptoms of ROHHAD(NET) and propose recommendations for diagnosis and follow-up.
DESIGN
We conducted a systematic review of all ROHHAD(NET) case studies and report a new ROHHAD patient with early diagnosis and multidisciplinary care.
METHODS
All the articles that meet the definition of ROHHAD(NET) and provide chronological clinical data were reviewed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis individual patient data guidelines. The data were grouped into 7 categories: hypothalamic dysfunction, autonomic dysregulation, hypoventilation, NET, psychiatric symptoms, other clinical manifestations, and outcome.
RESULTS
Forty-three individual patient data descriptions were analyzed. The timeline of the disease shows rapid-onset obesity followed shortly by hypothalamic dysfunction. Dysautonomia was reported at a median age of 4.95 years and hypoventilation at 5.33 years, or 2.2 years after the initial obesity. A NET was reported in 56% of the patients, and 70% of these tumors were diagnosed within 2 years after initial weight gain.
CONCLUSION
Because early diagnosis improves the clinical management and the prognosis in ROHHAD(NET), this diagnosis should be considered for any child with rapid and early obesity. We propose guidance for systematic follow-up and advise multidisciplinary management with the aim of improving prognosis and life expectancy.
Topics: Adrenal Gland Neoplasms; Autonomic Nervous System Diseases; Ganglioneuroblastoma; Ganglioneuroma; Humans; Hypothalamic Diseases; Hypoventilation; Obesity; Prognosis; Syndrome
PubMed: 32407531
DOI: 10.1210/clinem/dgaa247 -
European Journal of Endocrinology Oct 2023To assess (1) comorbidities associated with and (2) treatment strategies for patients with adrenal incidentalomas and mild autonomous cortisol secretion (MACS; >... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To assess (1) comorbidities associated with and (2) treatment strategies for patients with adrenal incidentalomas and mild autonomous cortisol secretion (MACS; > 1.8 µg/dL (>50 nmol/L) cortisol level cut-off following the 1 mg dexamethasone suppression test).
DESIGN
Systematic review and meta-analysis.
METHODS
Seven databases were searched up to July 14, 2022. Eligible studies were (randomized) trials, cohort studies, and cross-sectional studies assessing comorbidities potentially attributable to cortisol excess or mortality in patients with adrenal incidentaloma with or without MACS or the effects of conservative or surgical management of MACS. Random-effects meta-analysis was performed to estimate pooled proportions (with 95% CIs).
RESULTS
In 30 cross-sectional and 16 cohort studies (n = 17 156 patients in total), patients with MACS had a higher prevalence of diabetes (relative risk [RR] 1.44 [1.23-1.69]), hypertension (RR = 1.24 [1.16-1.32]), and dyslipidemia (RR = 1.23 [1.13-1.34]). All-cause mortality (adjusted for confounders) in patients with MACS, assessed in 4 studies (n = 5921), was increased (hazard ratio [HR] = 1.54 [1.27-1.81]). Nine observational studies (n = 856) and 2 randomized trials (n = 107) suggest an improvement in glucometabolic control (RR = 7.99 [2.95-21.90]), hypertension (RR = 8.75 [3.99-19.18]), and dyslipidemia (RR = 3.24 [1.19-8.82]) following adrenalectomy.
CONCLUSIONS
The present systematic review and meta-analysis highlight the relevance of MACS, since both cardiometabolic morbidities and mortality appeared to have increased in patients with MACS compared to patients with non-functioning incidentalomas. However, due to heterogeneous definitions, various outcomes, selective reporting, and missing data, the reported pooled estimates need to be interpreted with caution. The small number of patients in randomized trials prevents any strong conclusion on the causality between MACS and these comorbidities.
Topics: Humans; Adrenal Gland Neoplasms; Hydrocortisone; Cross-Sectional Studies; Hypertension; Dyslipidemias
PubMed: 37801655
DOI: 10.1093/ejendo/lvad134 -
The Journal of Clinical Endocrinology... Jun 2023Adrenal hyperfunction is associated with an increased risk of cardiometabolic complications in subjects with adrenal incidentaloma (AI). Reliable prevalence estimates of... (Meta-Analysis)
Meta-Analysis
CONTEXT
Adrenal hyperfunction is associated with an increased risk of cardiometabolic complications in subjects with adrenal incidentaloma (AI). Reliable prevalence estimates of functioning AIs are important to direct resources allocations.
OBJECTIVE
To assess the prevalence of autonomous/possible autonomous cortisol secretion (ACS), primary aldosteronism (PA), pheochromocytoma (PHEO), and Cushing syndrome (CS) in patients with AI.
METHODS
We performed a comprehensive search of multiple databases (PubMed, Ovid MEDLINE, Web of Science) for potentially relevant studies without language restriction, up to February 2022. Of the 1661 publications evaluated at title and abstract levels, 161 were examined as full text and 36 were included. Study level clinical data were extracted by 3 independent reviewers.
RESULTS
The overall prevalence of functioning AIs was 27.5% (95% CI 23.0, 32.5). ACS/possible ACS, with a prevalence of 11.7% (95% CI 8.6, 15.7), was the most frequent hormonal alteration, while PA occurred in 4.4% of the patients (95% CI 3.1, 6.2). Subgroup analysis showed that PA was more prevalent in patients from Asia than in patients from Europe/America; in contrast, ACS/possible ACS had a lower prevalence in Asian countries. At meta-regression analysis, the prevalence of ACS/possible ACS was influenced by the proportion of female patients, while the prevalence of PA was positively associated with the proportion of patients with hypertension and the publication year. Finally, PHEO and CS prevalence were 3.8% (95% CI 2.8, 5.0) and 3.1% (95% CI 2.3, 4.3) respectively.
CONCLUSION
This meta-analysis provides extensive data on the prevalence of functioning AIs and the factors affecting heterogeneity in prevalence estimates.
Topics: Humans; Female; Adrenal Gland Neoplasms; Prevalence; Cushing Syndrome; Hypertension; Pheochromocytoma; Hydrocortisone
PubMed: 36718682
DOI: 10.1210/clinem/dgad044 -
The Journal of Clinical Endocrinology... Oct 2019This mini-review offers an update on the rare autoimmune polyendocrinopathy (AP) syndrome with a synopsis of recent developments.
CONTEXT
This mini-review offers an update on the rare autoimmune polyendocrinopathy (AP) syndrome with a synopsis of recent developments.
DESIGN AND RESULTS
Systematic search for studies related to pathogenesis, immunogenetics, screening, diagnosis, clinical spectrum, and epidemiology of AP. AP (orphan code ORPHA 282196) is defined as the autoimmune-induced failure of at least two glands. AP is divided into the rare juvenile type I and the adult types II to IV. The prevalence is 1:100,000 and 1:20,000 for types I and types II to IV, respectively. Whereas type I (ORPHA 3453) is a monogenetic syndrome with an autosomal recessive transmission related to mutations in the autoimmune regulator (AIRE) gene, types II to IV are genetically complex multifactorial syndromes that are strongly associated with certain alleles of HLA genes within the major histocompatibility complex located on chromosome 6, as well as the cytotoxic T lymphocyte antigen 4 and the protein tyrosine phosphatase nonreceptor type 22 genes. Addison disease is the major endocrine component of type II (ORPHA 3143), whereas the coexistence of type 1 diabetes and autoimmune thyroid disease is characteristic for type III (ORPHA 227982). Genetic screening for the AIRE gene is useful in patients with suspected type I, whereas serological screening (i.e., diabetes/adrenal antibodies) is required in patients with monoglandular autoimmunity and suspected AP. If positive, functional endocrine testing of the antibody-positive patients as well as serological screening of their first-degree relatives is recommended.
CONCLUSION
Timely diagnosis, genetic counseling, and optimal long-term management of AP is best offered in specialized centers.
Topics: Adult; Autoimmunity; Child; Comorbidity; Genetic Counseling; Genetic Testing; Humans; Long-Term Care; Polyendocrinopathies, Autoimmune; Prevalence
PubMed: 31127843
DOI: 10.1210/jc.2019-00602 -
European Journal of Endocrinology May 2016Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours. Standard treatment is surgical resection. Following complete resection of the primary... (Review)
Review
Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours. Standard treatment is surgical resection. Following complete resection of the primary tumour, patients with PPGL are at risk of developing new tumoural events. The present guideline aims to propose standardised clinical care of long-term follow-up in patients operated on for a PPGL. The guideline has been developed by The European Society of Endocrinology and based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) principles. We performed a systematic review of the literature and analysed the European Network for the Study of Adrenal Tumours (ENS@T) database. The risk of new events persisted in the long term and was higher for patients with genetic or syndromic diseases. Follow-up in the published cohorts and in the ENS@T database was neither standardised nor exhaustive, resulting in a risk of follow-up bias and in low statistical power beyond 10 years after complete surgery. To inform patients and care providers in this context of low-quality evidence, the Guideline Working Group therefore prepared recommendations on the basis of expert consensus. Key recommendations are the following: we recommend that all patients with PPGL be considered for genetic testing; we recommend assaying plasma or urinary metanephrines every year to screen for local or metastatic recurrences or new tumours; and we suggest follow-up for at least 10 years in all patients operated on for a PPGL. High-risk patients (young patients and those with a genetic disease, a large tumour and/or a paraganglioma) should be offered lifelong annual follow-up.
Topics: Adrenal Gland Neoplasms; Endocrinology; Europe; Humans; Paraganglioma; Pheochromocytoma; Practice Guidelines as Topic; Societies, Medical
PubMed: 27048283
DOI: 10.1530/EJE-16-0033 -
Clinical Endocrinology Jul 2021To describe the presentation and outcomes of patients with adrenal ganglioneuromas (AGNs).
OBJECTIVE
To describe the presentation and outcomes of patients with adrenal ganglioneuromas (AGNs).
DESIGN
Single-centre retrospective cohort study (1 January 1995 to 31 December 2019) and systematic review of literature (1 January 1980 to 19 November 2019).
PATIENTS
Diagnosed with histologically confirmed AGN.
MEASUREMENTS
Baseline clinical, imaging and biochemical characteristics, recurrence rates and mortality. Subgroup analysis was performed on tumours with histologic elements of ganglioneuroma and pheochromocytoma (ie composite tumours).
RESULTS
The cohort study included 45 patients with AGN, 20 (44%) of which had composite tumours. Compared to pure AGN, patients with composite tumour were older (median age, 62.5 vs. 35 years, p < .001), had smaller tumours (median size, 3.9 vs. 5.7 cm, p = .016) and were discovered incidentally less frequently (65% vs. 84%, p = .009). No recurrences or ganglioneuroma-specific mortality occurred during follow-up (range, 0-266 months). The systematic review included 14 additional studies and 421 patients. The mean age of diagnosis was 39 years, and 47% were women. AGNs were discovered incidentally in 72% of patients, were predominantly unilateral (99%) and had a mean diameter of 5.8 cm and an unenhanced computed tomography (CT) attenuation of -118 to 49 Hounsfield units (HU). On imaging, 69% of AGNs were homogenous, 41% demonstrated calcifications, and 40% were lobulated.
CONCLUSIONS
AGNs are rare benign tumours that present with variable imaging features including large size, unenhanced CT attenuation >20 HU, calcifications and lobulated shape. Imaging characteristics can assist in establishing a diagnosis and avoiding an unnecessary adrenalectomy. The association of pheochromocytomas with AGNs is frequent. Diagnosis should include biochemical testing.
Topics: Adrenal Gland Neoplasms; Adult; Cohort Studies; Female; Ganglioneuroma; Humans; Middle Aged; Neoplasm Recurrence, Local; Retrospective Studies
PubMed: 33721367
DOI: 10.1111/cen.14460