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Context
Bilateral inferior petrosal sinus sampling (BIPSS) using hCRH is currently considered the ‘gold standard’ test for the differential diagnosis of ACTH-dependent Cushing’s syndrome (CS). Vasopressin is more potent than CRH to stimulate ACTH secretion as shown in animal studies; however, no comparative data of its use are available during BIPSS.
Objective
To study the diagnostic accuracy and comparison of hCRH and lysine vasopressin (LVP) stimulation during BIPSS.
Patients and methods
29 patients (27-Cushing’s disease, 2-ectopic CS; confirmed on histopathology) underwent BIPSS and were included for the study. Patients were randomized to receive hCRH, 5 U LVP or 10 U LVP during BIPSS for ACTH stimulation. BIPSS and contrast-enhanced magnetic resonance imaging (CEMRI) were compared with intra-operative findings of trans-sphenoidal surgery (TSS) for localization and lateralization of the ACTH source.
Results
BIPSS correctly localized the source of ACTH excess in 29/29 of the patients with accuracy of 26/26 patients, using any of the agent, whereas sensitivity and PPV for lateralization with hCRH, 5 U LVP and 10 U LVP was seen in 10/10, 6/10; 10/10,8/10 and 7/7,6/7 patients respectively. Concordance of BIPSS with TSS was seen in 20/27, CEMRI with BIPSS in 16/24 and CEMRI with TSS in 18/24 of patients for lateralizing the adenoma. Most of the side effects were transient and were comparable in all the three groups.
Conclusion
BIPSS using either hCRH or LVP (5 U or 10 U) confirmed the source of ACTH excess in all the patients, while 10 U LVP correctly lateralized the pituitary adenoma in three fourth of the patients.
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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.
Department of Endocrinology, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
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Department of Endocrinology, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
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Autoimmune Addison’s disease (AAD) is defined as primary adrenal insufficiency due to immune-mediated destruction of the adrenal cortex. This destruction of steroid-producing cells has historically been thought of as an irreversible process, with linear progression from an ACTH-driven compensated phase to overt adrenal insufficiency requiring lifelong glucocorticoid replacement. However, a growing body of evidence suggests that this process may be more heterogeneous than previously thought, with potential for complete or partial recovery of glucocorticoid secretion. Although patients with persistent mineralocorticoid deficiency despite preserved or recovered glucocorticoid function are anecdotally mentioned, few well-documented cases have been reported to date. We present three patients in the United Kingdom who further challenge the long-standing hypothesis that AAD is a progressive, irreversible disease process. We describe one patient with a 4-year history of mineralocorticoid-only Addison’s disease, a patient with spontaneous recovery of adrenal function and one patient with clinical features of adrenal insufficiency despite significant residual cortisol function. All three patients show varying degrees of mineralocorticoid deficiency, suggesting that recovery of zona fasciculata function in the adrenal cortex may occur independently to that of the zona glomerulosa. We outline the current evidence for heterogeneity in the natural history of AAD and discuss possible mechanisms for the recovery of adrenal function.
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The melanocortin-2-receptor (MC2R), also known as the ACTH receptor, is a critical component of the hypothalamic–pituitary–adrenal axis. The importance of MC2R in adrenal physiology is exemplified by the condition familial glucocorticoid deficiency (FGD), a potentially fatal disease characterised by isolated cortisol deficiency. MC2R mutations cause ~25% of cases. The discovery of a MC2R accessory protein MRAP, mutations of which account for ~20% of FGD, has provided insight into MC2R trafficking and signalling. MRAP is a single transmembrane domain accessory protein highly expressed in the adrenal gland and essential for MC2R expression and function. Mouse models helped elucidate the action of ACTH. The Mc2r-knockout (Mc2r − / − ) mice was the first mouse model developed to have adrenal insufficiency with deficiencies in glucocorticoid, mineralocorticoid and catecholamines. We recently reported the generation of the Mrap − / − mice which better mimics the human FGD phenotype with isolated glucocorticoid deficiency alone. The adrenal glands of adult Mrap − / − mice were grossly dysmorphic with a thickened capsule, deranged zonation and deranged WNT4/beta-catenin and sonic hedgehog (SHH) pathway signalling. Collectively, these mouse models of FGD highlight the importance of ACTH and MRAP in adrenal progenitor cell regulation, cortex maintenance and zonation.
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Simultaneous bilateral inferior petrosal sinus sampling (BIPSS) plays a crucial role in the diagnostic work-up of Cushing’s syndrome. It is the most accurate procedure in the differential diagnosis of hypercortisolism of pituitary or ectopic origin, as compared with clinical, biochemical and imaging analyses, with a sensitivity and specificity of 88–100% and 67–100%, respectively. In the setting of hypercortisolemia, ACTH levels obtained from venous drainage of the pituitary are expected to be higher than the levels of peripheral blood, thus suggesting pituitary ACTH excess as the cause of hypercortisolism. Direct stimulation of the pituitary corticotroph with corticotrophin-releasing hormone enhances the sensitivity of the procedure. The procedure must be undertaken in the presence of hypercortisolemia, which suppresses both the basal and stimulated secretory activity of normal corticotrophic cells: ACTH measured in the sinus is, therefore, the result of the secretory activity of the tumor tissue. The poor accuracy in lateralization of BIPSS (positive predictive value of 50–70%) makes interpetrosal ACTH gradient alone not sufficient for the localization of the tumor. An accurate exploration of the gland is recommended if a tumor is not found in the predicted area. Despite the fact that BIPSS is an invasive procedure, the occurrence of adverse events is extremely rare, particularly if it is performed by experienced operators in referral centres.
Department of Neurosurgery, Rui-Jin Lu-Wan Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Department of Neurosurgery, Rui-Jin Lu-Wan Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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College of Information Technology and Engineering, Chengdu University, Chengdu, China
College of Computer Science, Sichuan Normal University, Chengdu, Sichuan, China
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The adverse effects of hypercortisolism on the human brain have been highlighted in previous studies of Cushing’s disease (CD). However, the relative alterations in regional hypercortisolism in the brain remain unclear. Thus, we investigated regional volumetric alterations in CD patients. We also analyzed the associations between these volumetric changes and clinical characteristics. The study participants comprised of active CD (n = 60), short-term-remitted CD (n = 28), and long-term-remitted CD (n = 32) patients as well as healthy control subjects (n = 66). Gray matter volumes (GMVs) were measured via voxel-based morphometry. The GMVs of substructures were defined using the automated anatomical labeling (AAL) atlas. Trends toward normalization in GMV were found in most brain substructures of CD patients. Different trends, including enlarged, irreversible, and unaffected, were observed in the other subregions, such as the amygdala, thalamus, and caudate. Morphological changes in GMVs after the resolution of hypercortisolism are a complex phenomenon; the characteristics of these changes significantly differ within the brain substructures.
Department of Endocrinology, Department of Public Health, Department of Cancer Research and Molecular Medicine, Department of Medical Biochemistry, St Olavs Hospital, Trondheim University Hospital, P O Box 3250 Sluppen, N-7006 Trondheim, Norway
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Department of Endocrinology, Department of Public Health, Department of Cancer Research and Molecular Medicine, Department of Medical Biochemistry, St Olavs Hospital, Trondheim University Hospital, P O Box 3250 Sluppen, N-7006 Trondheim, Norway
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Department of Endocrinology, Department of Public Health, Department of Cancer Research and Molecular Medicine, Department of Medical Biochemistry, St Olavs Hospital, Trondheim University Hospital, P O Box 3250 Sluppen, N-7006 Trondheim, Norway
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It has been suggested that comparison of posttest dexamethasone and cortisol concentrations may improve the evaluation of the dexamethasone suppression test (DST) for Cushing's syndrome. In particular, this would be reasonable if posttest cortisol differs by dexamethasone levels within the range that is usually attained in the DST. Using fractional polynomial regression, we therefore studied the association between posttest 0800 h dexamethasone and cortisol levels in 53 subjects without Cushing's syndrome who were tested with the 1 mg overnight DST. Plasma dexamethasone was associated with plasma cortisol (P<0.001), and the regression line suggested a strong negative association related to dexamethasone levels <5 nmol/l. However, among the 94% of subjects with plasma dexamethasone >5.0 nmol/l, there was no association between dexamethasone and cortisol levels (P=0.55). In conclusion, subjects tested with the 1 mg overnight DST usually attain an 0800 h plasma dexamethasone >5 nmol/l, and plasma cortisol does not differ by plasma dexamethasone in these subjects. This suggests that routine comparison of dexamethasone and cortisol levels may not be a useful approach to improve the performance of the 1 mg DST. However, dexamethasone measurements may identify subjects with inadequately low plasma dexamethasone and may therefore be of value when retesting subjects with possibly false-positive DST results.
Neuroendocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Introduction
Machine learning methods in sellar region diseases present a particular challenge because of the complexity and the necessity for reproducibility. This systematic review aims to compile the current literature on sellar region diseases that utilized machine learning methods and to propose a quality assessment tool and reporting checklist for future studies.
Methods
PubMed and Web of Science were searched to identify relevant studies. The quality assessment included five categories: unmet needs, reproducibility, robustness, generalizability and clinical significance.
Results
Seventeen studies were included with the diagnosis of general pituitary neoplasms, acromegaly, Cushing’s disease, craniopharyngioma and growth hormone deficiency. 87.5% of the studies arbitrarily chose one or two machine learning models. One study chose ensemble models, and one study compared several models. 43.8% of studies did not provide the platform for model training, and roughly half did not offer parameters or hyperparameters. 62.5% of the studies provided a valid method to avoid over-fitting, but only five reported variations in the validation statistics. Only one study validated the algorithm in a different external database. Four studies reported how to interpret the predictors, and most studies (68.8%) suggested possible clinical applications of the developed algorithm. The workflow of a machine-learning study and the recommended reporting items were also provided based on the results.
Conclusions
Machine learning methods were used to predict diagnosis and posttreatment outcomes in sellar region diseases. Though most studies had substantial unmet need and proposed possible clinical application, replicability, robustness and generalizability were major limits in current studies.
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Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK
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Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK
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Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK
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Endogenous Cushing’s syndrome (CS) poses considerable diagnostic challenges. Although late-night salivary cortisol (LNSC) is recommended as a first-line screening investigation, it remains the least widely used test in many countries. The combined measurement of LNSC and late-night salivary cortisone (LNS cortisone) has shown to further improve diagnostic accuracy. We present a retrospective study in a tertiary referral centre comparing LNSC, LNS cortisone, overnight dexamethasone suppression test, low-dose dexamethasone suppression test and 24-h urinary free cortisol results of patients investigated for CS. Patients were categorised into those who had CS (21 patients) and those who did not (33 patients). LNSC had a sensitivity of 95% and a specificity of 91%. LNS cortisone had a specificity of 100% and a sensitivity of 86%. With an optimal cut-off for LNS cortisone of >14.5 nmol/L the sensitivity was 95.2%, and the specificity was 100% with an area under the curve of 0.997, for diagnosing CS. Saliva collection is non-invasive and can be carried out at home. We therefore advocate simultaneous measurement of LNSC and LNS cortisone as the first-line screening test to evaluate patients with suspected CS.
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Substantial evidence shows that the hypophyseal–pituitary–adrenal (HPA) axis and corticosteroids are involved in the process of addiction to a variety of agents, and the adrenal cortex has a key role. In general, plasma concentrations of cortisol (or corticosterone in rats or mice) increase on drug withdrawal in a manner that suggests correlation with the behavioural and symptomatic sequelae both in man and in experimental animals. Corticosteroid levels fall back to normal values in resumption of drug intake. The possible interactions between brain corticotrophin releasing hormone (CRH) and proopiomelanocortin (POMC) products and the systemic HPA, and additionally with the local CRH–POMC system in the adrenal gland itself, are complex. Nevertheless, the evidence increasingly suggests that all may be interlinked and that CRH in the brain and brain POMC products interact with the blood-borne HPA directly or indirectly. Corticosteroids themselves are known to affect mood profoundly and may themselves be addictive. Additionally, there is a heightened susceptibility for addicted subjects to relapse in conditions that are associated with change in HPA activity, such as in stress, or at different times of the day. Recent studies give compelling evidence that a significant part of the array of addictive symptoms is directly attributable to the secretory activity of the adrenal cortex and the actions of corticosteroids. Additionally, sex differences in addiction may also be attributable to adrenocortical function: in humans, males may be protected through higher secretion of DHEA (and DHEAS), and in rats, females may be more susceptible because of higher corticosterone secretion.
