Background
The incidence of adrenal incidentalomas (AIs) has increased over the last 20 years, most of which are apparently non‐functioning adrenal adenomas. However, increased evidence supports the ...existence of an association between non‐functioning adrenal incidentalomas (NFAI) and an unfavourable cardio‐metabolic profile.
Methods
This study offers a comprehensive review of the available evidence supporting a higher cardiometabolic risk in NFAIs compared to controls without adrenal tumours. Moreover, it summarises the studies focused on the differential urinary metabolomic profile of NFAI and controls without adrenal lesions.
Results
This adverse metabolic profile of patients with NFAI includes a higher prevalence of insulin resistance, obesity, hypertension, hyperglycaemia, dyslipidaemia, and cardiovascular alterations and mortality compared to healthy controls without adrenal tumours. Although the pathophysiology that explains the association between NFAI and the parameters of metabolic syndrome and cardiovascular risk is a relatively unexplored field of study, some evidence supports that there are a series of incipient alterations in cortisol metabolism not detected with the classical tests that led to this detrimental profile. These alterations may be potentially detected by a comprehensive metabolomics approach. Several studies detected a shift towards an increase of urinary cortisol metabolites excretion in NFAIs compared to controls without adrenal tumours.
Conclusion
In view of the higher cardiometabolic risk in NFAI than in controls without adrenal tumours, and the detected alterations in metabolomics profile of NFAI, I propose that the term of NFAI should be changed for another term that best fits to its linked cardiometabolic profile.
Aim
To identify alterations in steroid metabolism in patients with nonfunctioning adrenal incidentalomas (NFAIs) through the analysis of their urinary steroid profile (USP).
Methods
Cross‐sectional ...study with one study group (NFAIs, cortisol post dexamethasone suppression test DST ≤ 1.8 µg/dl 49.7 nmol/L) and 2 control groups: patients with autonomous cortisol secretion (ACS group, cortisol post‐DST > 1.8 µg/dl (49.7 nmol/L) and patients without adrenal tumours (healthy‐adrenal group). Twenty‐four‐hour urine collections for USP measurement (total and free fraction of 51 24 h‐urine specimens) were obtained from 73 participants (24 with NFAIs, 24 without AIs, and 25 with ACS). USP was determined by gas chromatography coupled to mass spectrometry. Patients of the three groups were matched according to sex, age (±5 years‐old) and body mass index (±5 kg/m2).
Results
Compared to healthy‐adrenal controls, patients with NFAIs had a lower excretion of androgen metabolites (230.5 ± 190.12 vs. 388.7 ± 328.58 µg/24 h, p = .046) and a higher excretion of urinary free cortisol (UFC) (54.3 ± 66.07 vs. 25.4 ± 11.16 µg/24 h, p = .038). UFC was above the reference range in 20.8% of patients in the NFAI, compared to 0% in the healthy‐adrenal group (p = .018). Patients with ACS had a higher prevalence of hypertension, dyslipidemia, and diabetes than patients with NFAIs or the control group. A lower excretion of androgen metabolites (218.4 ± 204.24 vs. 231 ± 190 µg/24 h, p = .041) and a nonsignificant higher excretion of glucocorticoid metabolites (2129.6 ± 1195.96 vs. 1550.8 ± 810.03 µg/24 h, p = .180) was found in patients with ACS compared to patients with NFAIs.
Conclusion
NFAIs seem to secrete a subtle, yet clinically relevant, excess of glucocorticoids. Future studies are needed to confirm our findings; and to identify metabolic alterations associated with an increased cardiometabolic risk.
Cushing´s syndrome (CS) secondary to bilateral adrenal cortical disease may be caused by bilateral macronodular adrenal cortical disease (BMACD) or by bilateral micronodular adrenal cortical disease ...(miBACD). The size of adrenal nodules is a key factor for the differentiation between these two entities (>1cm, BMACD and <1cm; miBACD). BMACD can be associated with overt CS, but more commonly it presents with autonomous cortisol secretion (ACS). Surgical treatment of BMACD presenting with CS or with ACS and associated cardiometabolic comorbidities should be the resection of the largest adrenal gland, since it leads to hypercortisolism remission in up to 95% of the cases. Medical treatment focused on the blockade of aberrant receptors may lead to hypercortisolism control, although cortisol response is frequently transient. miBACD is mainly divided in primary pigmented nodular adrenocortical disease (PPNAD) and isolated micronodular adrenocortical disease (i-MAD). miBACD can present at an early age, representing one of the main causes of CS at a young age. The high-dose dexamethasone suppression test can be useful in identifying a paradoxical increase in 24h-urinary free cortisol, that is a quite specific in PPNAD. Bilateral adrenalectomy is generally the treatment of choice in patients with overt CS in miBACD, but unilateral adrenalectomy could be considered in cases with asymmetric disease and mild hypercortisolism. This article will discuss the clinical presentation, genetic background, hormonal and imaging features and treatment of the main causes of primary bilateral adrenal hyperplasia associated with hypercortisolism.
Prolactin (PRL) and growth hormone (GH) are peptide hormones that bind to the class 1 cytokine receptor superfamily, a highly conserved cell surface class of receptors. Both hormones control their ...own secretion via a negative autocrine loop in their own mammosomatotroph, lactotroph or somatotroph. In this regard, GH and PRL are regulated by similar signaling pathways involving cell growth and hormone secretion. Thus, GH and PRL dysregulation and pituitary neuroendocrine tumor (PitNET) development may have common pathogenic pathways. Based on cell linage, lactotroph and somatotroph PitNETs come from pituitary-specific POU-class homeodomain transcription factor (Pit-1). Mammosomatotroph and plurihormonal PitNETs are a unique subtype of PitNETs that arise from a single-cell population of Pit-1 lineage. In contrast, mixed somatotroph–lactotroph PitNETs are composed of two distinct cell populations: somatotrophs and lactotrophs. Morphologic features that distinguish indolent PitNETs from locally aggressive ones are still unidentified, and no single prognostic parameter can predict tumor aggressiveness or treatment response. In this review, we aim to explore the latest research on lactotroph and somatotroph PitNETs, the molecular mechanisms involved in PRL and GH axis regulation and the signaling pathways involved in their aggressiveness, particularly focused on mammosomatotroph and mixed subtypes. Finally, we summarize epidemiological, clinical, and radiological features of these exceptional tumors. We aim to shed light, from basic to clinical settings, on new perspectives and scientific gaps in this field.
To evaluate which radiological classification, Knosp, revised-Knosp, or Hardy-Wilson classification, is better for the prediction of surgical outcomes in the endoscopic endonasal transsphenoidal ...(EET) surgery of pituitary adenomas (PAs).
This is a retrospective study of patients with PAs who underwent EET PA resection for the first time between January 2009 and December 2020. Radiological cavernous sinus invasiveness was defined as a Knosp or revised-Knosp grade >2 or a grade E in the Hardy-Wilson classification.
A total of 228 patients with PAs were included. Cavernous sinus invasion was evident in 35.1% and suprasellar extension was evident in 74.6%. Overall, surgical cure was achieved in 64.3% of patients. Surgical cure was lower in invasive PAs than in non-invasive PAs (28.8% vs. 83.1%,
< 0.0001), and the risk of major complications was higher (13.8% vs. 3.4%,
= 0.003). The rate of surgical cure decreased as the grade of Knosp increased (
< 0.001), whereas the risk of complications increased (
< 0.001). Patients with Knosp 3B PAs tended to achieve surgical cure less commonly than Knosp 3A PAs (30.0% vs. 56.0%,
= 0.164). Similar results were observed based on the invasion and extension of Hardy-Wilson classification (stage A-C 83.1% vs. E 28.8%
< 0.0001, grade 0-II 81.1% vs. III-IV 59.7%
= 0.008). The Knosp classification offered the greatest diagnostic accuracy for the prediction of surgical cure (AUC 0.820), whereas the invasion Hardy-Wilson classification lacked utility for this purpose (AUC 0.654).
The Knosp classifications offer a good orientation for the estimation of surgical cure and the risk of complications in patients with PAs submitted to EET surgery. However, the invasion Hardy-Wilson scale lacks utility for this purpose.
Mild autonomous cortisol secretion (MACS) is associated with a higher cardiometabolic risk than that observed in patients with nonfunctioning adrenal adenomas and in the general population. In ...patients with MACS, the excess of glucocorticoids affects various metabolic pathways, leading to different manifestations of metabolic syndrome and other comorbidities. Hypertension and diabetes mellitus are two of the most common cardiometabolic comorbidities associated with MACS, reaching a prevalence of up to 80% and up to 40%, respectively. In addition, they are the comorbidities that experienced a greater improvement after adrenalectomy in patients with MACS. Hypertension pathogenesis is multifactorial, including the coexistence of comorbidities such as obesity or diabetes and the role of the different polymorphisms of the glucocorticoid receptor gene, among others. Glucocorticoid-induced diabetes mellitus is mainly related to the detrimental effects of glucocorticoids on insulin-dependent glucose uptake in peripheral tissues, gluconeogenesis and insulin secretion. There are no specific recommendations for hypertension and diabetes treatment in patients with MACS. Thus, considering the similar underlying pathogenesis of hypertension and diabetes mellitus in overt and mild hypercortisolism, our recommendation is to follow this general stepwise approach: surgically remove the adrenal culprit lesion to induce remission from hypercortisolism; control hypercortisolism with steroidogenesis inhibitors; and treat elevated blood pressure or high glucose levels using carefully selected anti-hypertensives and glucose-lowering medications if blood pressure and glucose levels remain uncontrolled, respectively. In this review, we summarize the epidemiology, physiopathology and management of diabetes mellitus and hypertension in patients with MACS.
Age-related macular degeneration (AMD) is a chronic progressive ocular disease and the main cause of severe visual impairment in the elderly. Vitamin D deficiency may be a risk factor for AMD. ...Additionally, current evidence suggests dietary advice of increasing consumption of polyphenols, which may have antioxidant and anti-inflammatory properties. The aim of this review was to describe the roles of vitamin D levels and polyphenols in the management of AMD. The results of this review showed mixed evidence regarding the protective effect of vitamin D against AMD. Polyphenols (flavonoids group, curcumin and resveratrol) seem to play an important role as angiogenesis inhibitors, but their effect on AMD is still unclear. Vitamin D and polyphenols may both play an important role as nutritional modifiable protective factors that reduce the risk of AMD progression. However, more research is necessary to better understand the roles of vitamin D and polyphenols in different stages of the disease.
Background
Two types of ectopic Cushing syndrome (ECS) are described: ECS associated with aggressive neoplasms, and ECS with indolent and occult tumors, however, there is a lack of studies that ...thoroughly review their characteristics.
Methods
A systematic review was carried out on PUBMED of all the papers about the ECS, in order to better define the types of this subcategory of Cushing’s syndrome, highlighting the differential aspects between these subgroups.
Results
It was found that in 50% of cases the prototypic “aggressive” ECS is caused by small cell lung carcinomas (SCLC). In these cases, the clinical presentation may be atypical, predominating the signs and symptoms derived from the protein catabolism. Cortisol and ACTH levels are extremely high, the clinical presentation is abrupt (< 3–6 months) and the tumor is usually advanced, being impossible a curative treatment. On the other hand, “indolent” ECS is mainly represented by carcinoid tumors (CT). In these cases the clinical presentation overlaps enormously with that of Cushing’s disease (CD). Cortisol and ACTH levels are slightly elevated, the clinical presentation is progressive (> 6 months) and the prognosis is usually good, and a curative treatment is possible in about 75% of the cases.
Conclusion
Although there is no absolute differentiation between the two extremes of ECS, a classification could be established in two groups, guided by its clinical and biochemical characteristics, and mainly by the type and stage of the ACTH-secreting tumor. However, a small percentage of tumors do not fit in this simple grouping, and may present both phenotypes or an intermediate one.
To evaluate the diagnostic accuracy of the different tests commonly used in the evaluation of adrenal incidentalomas (AIs) for the identification of autonomous cortisol secretion (ACS) and ...comorbidities potentially related to ACS. In a retrospective study of patients with AIs ≥ 1 cm, we evaluated the diagnostic reliability and validity of the dexamethasone suppression test (DST), urinary free cortisol (UFC), ACTH, late-night salivary cortisol (LNSC), and dehydroepiandrosterone-sulphate (DHEAS) for the diagnosis of comorbidities potentially related to ACS. Diagnostic indexes were also calculated for UFC, ACTH, LNSC, and DHEAS considering DST as the gold standard test for the diagnosis of ACS, using three different post-DST cortisol thresholds (138 nmol/L, 50 nmol/L and 83 nmol/L). We included 197 patients with AIs in whom the results of the five tests abovementioned were available. At diagnosis, 85.9% of patients with one or more AIs had any comorbidity potentially related to ACS, whereas 9.6% had ACS as defined by post-DST cortisol > 138 nmol/L. The reliability of UFC, ACTH, LNSC, and DHEAS for the diagnosis of ACS was low (kappa index < 0.30). Of them, LNSC reached the highest diagnosis accuracy for ACS identification (AUC = 0.696 95% CI 0.626-0.759). The diagnostic performances of these tests for comorbidities potentially related to ACS was poor; of them, the DST was the most accurate (AUC = 0.661 95% CI 0.546-0.778) and had the strongest association with these comorbidities (OR 2.6, P = 0.045). Patients presenting with increased values of both DST and LNSC had the strongest association with hypertension (OR 7.1, P = 0.002) and with cardiovascular events (OR 3.6, P = 0.041). In conclusion, LNSC was the test showing the highest diagnosis accuracy for the identification of ACS when a positive DST was used as the gold standard for its diagnosis. The DST test showed the strongest association with comorbidities potentially related to ACS. The definition of ACS based on the combination of elevated DST and LNSC levels improved the identification of patients with increased cardiometabolic risk.
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