Search Results
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Search for other papers by Henrik Falhammar in
Google Scholar
PubMed
Department of Breast and Endocrine Surgery, Karolinska University Hospital, Stockholm, Sweden
Search for other papers by Magnus Kjellman in
Google Scholar
PubMed
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Search for other papers by Jan Calissendorff in
Google Scholar
PubMed
Background
With the increasing access to imaging more pheochromocytomas are diagnosed in the workup of adrenal incidentalomas. This may have changed the occurrence of the classic presentation with hypertension and the classic triad (headaches, sweating and palpitation).
Methods
We reviewed 94 consecutive cases of pheochromocytomas. Two cases of ectopic ACTH-syndrome were subsequently excluded.
Results
Of the 92 cases included 64% had presented as an incidentaloma, 32% as a suspected pheochromocytoma and 4% had been screened because of previously diagnosed MEN2A. Those screened were youngest while those with incidentalomas were oldest. The females were more common in the incidentaloma and the screening groups, and males in the suspected pheochromocytoma group. Measurements of noradrenaline/normetanephrine levels were highest in the suspected pheocromocytoma group and lowest in the screening group. Hypertension was present in 63% of the incidentalomas, 79% of suspected pheochromocytomas and in none of the screening group. Paroxysmal symptoms were present in almost all with suspected pheochromocytoma while only in half of the other groups. The suspected pheocromocytoma group had most symptoms and the screening group least. The classic triad was present in 14% of the incidentalomas, in 28% of the suspected and in none of the screening group, while no symptoms at all was present in 12%, 0% and 25%, respectively. Pheochromocytoma crisis occurred in 5%. There was a positive correlation between tumor size vs hormone levels, and catecholamine levels vs blood pressure.
Conclusion
Clinicians need to be aware of the modern presentation of pheochromocytomas since early identification can be life-saving.
Endocrine Unit, Royal Victoria Infirmary, Newcastle upon Tyne, UK
Search for other papers by Earn H Gan in
Google Scholar
PubMed
Search for other papers by Wendy Robson in
Google Scholar
PubMed
Search for other papers by Peter Murphy in
Google Scholar
PubMed
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
Search for other papers by Robert Pickard in
Google Scholar
PubMed
Endocrine Unit, Royal Victoria Infirmary, Newcastle upon Tyne, UK
Search for other papers by Simon Pearce in
Google Scholar
PubMed
Search for other papers by Rachel Oldershaw in
Google Scholar
PubMed
Background
The highly plastic nature of adrenal cortex suggests the presence of adrenocortical stem cells (ACSC), but the exact in vivo identity of ACSC remains elusive. A few studies have demonstrated the differentiation of adipose or bone marrow-derived mesenchymal stem cells (MSC) into steroid-producing cells. We therefore investigated the isolation of multipotent MSC from human adrenal cortex.
Methods
Human adrenals were obtained as discarded surgical material. Single-cell suspensions from human adrenal cortex (n = 3) were cultured onto either complete growth medium (CM) or MSC growth promotion medium (MGPM) in hypoxic condition. Following ex vivo expansion, their multilineage differentiation capacity was evaluated. Phenotype markers were analysed by immunocytochemistry and flow cytometry for cell-surface antigens associated with bone marrow MSCs and adrenocortical-specific phenotype. Expression of mRNAs for pluripotency markers was assessed by q-PCR.
Results
The formation of colony-forming unit fibroblasts comprising adherent cells with fibroblast-like morphology were observed from the monolayer cell culture, in both CM and MGPM. Cells derived from MGPM revealed differentiation towards osteogenic and adipogenic cell lineages. These cells expressed cell-surface MSC markers (CD44, CD90, CD105 and CD166) but did not express the haematopoietic, lymphocytic or HLA-DR markers. Flow cytometry demonstrated significantly higher expression of GLI1 in cell population harvested from MGPM, which were highly proliferative. They also exhibited increased expression of the pluripotency markers.
Conclusion
Our study demonstrates that human adrenal cortex harbours a mesenchymal stem cell-like population. Understanding the cell biology of adrenal cortex- derived MSCs will inform regenerative medicine approaches in autoimmune Addison’s disease.
Department of Endocrinology, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
Search for other papers by Sophie Howarth in
Google Scholar
PubMed
Search for other papers by Luca Giovanelli in
Google Scholar
PubMed
Search for other papers by Catherine Napier in
Google Scholar
PubMed
Department of Endocrinology, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
Search for other papers by Simon H Pearce in
Google Scholar
PubMed
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.
Search for other papers by Tatiana V Novoselova in
Google Scholar
PubMed
Search for other papers by Peter J King in
Google Scholar
PubMed
Search for other papers by Leonardo Guasti in
Google Scholar
PubMed
Search for other papers by Louise A Metherell in
Google Scholar
PubMed
Search for other papers by Adrian J L Clark in
Google Scholar
PubMed
Search for other papers by Li F Chan in
Google Scholar
PubMed
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.
Search for other papers by Gavin P Vinson in
Google Scholar
PubMed
Search for other papers by Caroline H Brennan in
Google Scholar
PubMed
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.
Search for other papers by Nilesh Lomte in
Google Scholar
PubMed
Search for other papers by Tushar Bandgar in
Google Scholar
PubMed
Search for other papers by Shruti Khare in
Google Scholar
PubMed
Search for other papers by Swati Jadhav in
Google Scholar
PubMed
Search for other papers by Anurag Lila in
Google Scholar
PubMed
Search for other papers by Manjunath Goroshi in
Google Scholar
PubMed
Search for other papers by Rajeev Kasaliwal in
Google Scholar
PubMed
Search for other papers by Kranti Khadilkar in
Google Scholar
PubMed
Search for other papers by Nalini S Shah in
Google Scholar
PubMed
Background
Bilateral adrenal masses may have aetiologies like hyperplasia and infiltrative lesions, besides tumours. Hyperplastic and infiltrative lesions may have coexisting hypocortisolism. Bilateral tumours are likely to have hereditary/syndromic associations. The data on clinical profile of bilateral adrenal masses are limited.
Aims
To analyse clinical, biochemical and radiological features, and management outcomes in patients with bilateral adrenal masses.
Methods
Retrospective analysis of 70 patients with bilateral adrenal masses presenting to a single tertiary care endocrine centre from western India (2002–2015).
Results
The most common aetiology was pheochromocytoma (40%), followed by tuberculosis (27.1%), primary adrenal lymphoma (PAL) (10%), metastases (5.7%), non-functioning adenomas (4.3%), primary bilateral macronodular adrenal hyperplasia (4.3%), and others (8.6%). Age at presentation was less in patients with pheochromocytoma (33 years) and tuberculosis (41 years) compared with PAL (48 years) and metastases (61 years) (P<0.001). The presenting symptoms for pheochromocytoma were hyperadrenergic spells (54%) and abdominal pain (29%), whereas tuberculosis presented with adrenal insufficiency (AI) (95%). The presenting symptoms for PAL were AI (57%) and abdominal pain (43%), whereas all cases of metastasis had abdominal pain. Mean size of adrenal masses was the largest in lymphoma (5.5cm) followed by pheochromocytoma (4.8cm), metastasis (4cm) and tuberculosis (2.1cm) (P<0.001). Biochemically, most patients with pheochromocytoma (92.8%) had catecholamine excess. Hypocortisolism was common in tuberculosis (100%) and PAL (71.4%) and absent with metastases (P<0.001).
Conclusion
In evaluation of bilateral adrenal masses, age at presentation, presenting symptoms, lesion size, and biochemical features are helpful in delineating varied underlying aetiologies.
Search for other papers by Magdalena Lech in
Google Scholar
PubMed
Search for other papers by Ruvini Ranasinghe in
Google Scholar
PubMed
Faculty of Life Sciences and Medicine, School of Life Course Sciences, King’s College London, London, UK
Search for other papers by Royce P Vincent in
Google Scholar
PubMed
Search for other papers by David R Taylor in
Google Scholar
PubMed
Search for other papers by Lea Ghataore in
Google Scholar
PubMed
Search for other papers by James Luxton in
Google Scholar
PubMed
Quebec Heart and Lung Institute, Laval University, Quebec, Canada
Search for other papers by Fannie Lajeunesse-Trempe in
Google Scholar
PubMed
Search for other papers by Pia Roser in
Google Scholar
PubMed
Search for other papers by Eftychia E Drakou in
Google Scholar
PubMed
Search for other papers by Ling Ling Chuah in
Google Scholar
PubMed
Barts and the London School of Medicine, Centre for Endocrinology, William Harvey Institute, London, UK
Neuroendocrine Tumour Unit, Royal Free Hospital, London, UK
Search for other papers by Ashley B Grossman in
Google Scholar
PubMed
Search for other papers by Simon J B Aylwin in
Google Scholar
PubMed
Obesity, Type 2 Diabetes and Immunometabolism Research Group, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Course Sciences, King’s College London, London, UK
Division of Reproductive Health, Warwick Medical School, University of Warwick, Coventry, UK
Search for other papers by Georgios K Dimitriadis in
Google Scholar
PubMed
Introduction
Adrenocortical carcinoma (ACC) is a rare malignancy of the adrenal cortex. Whilst surgery is the preferred treatment, adjunctive therapy with mitotane may be offered post-surgically to minimise the risk of recurrence or, in the absence of surgery, to attenuate progression.
Aim
The objective was to evaluate the effects of mitotane treatment on serum protein concentrations in patients treated for ACC with mitotane therapy and compare this to patients with other adrenal neoplasms and a normal pregnant cohort.
Methods
Serum cortisol, thyroid function tests, adrenocorticotrophic hormone (ACTH), cortisol-binding globulin (CBG), thyroxine-binding globulin (TBG), gonadotrophins and androgens were measured on plasma and serum samples. Thirty-five patients with ACC were included, and mitotane levels were noted to be sub-/supra-therapeutic. Data were tested for normality, reported as mean ± s.d., and compared to other two cohorts using paired-sample t-test with a 5% P-value for significance and a 95% CI.
Results
Patients on mitotane therapy had a higher mean serum CBG concentration compared to the adrenal neoplasm group (sub-therapeutic: 79.5 (95% CI: 33.6, 125.4 nmol/L), therapeutic: 85.3 (95% CI: 37.1–133.6 nmol/L), supra-therapeutic: 75.7 (95% CI: −19.3, 170.6 nmol/L) and adrenal neoplasm: 25.5 (95% CI: 17.5, 33.5 nmol/L). Negative correlations between serum cortisol and CBG concentration were demonstrated within the supra-therapeutic plasma mitotane and adrenal neoplasm groups.
Conclusion
Patients with ACC and therapeutic plasma mitotane concentrations had higher serum CBG concentrations compared to those with adrenal neoplasms or pregnant women, and higher serum cortisol. Whilst there was no direct correlation with cortisol and mitotane level, the negative correlation of cortisol with CBG may suggest that the direct effect of mitotane in increasing cortisol may also reflect that mitotane has a direct adrenolytic effect.
Search for other papers by R Walia in
Google Scholar
PubMed
Search for other papers by M Singla in
Google Scholar
PubMed
Search for other papers by K Vaiphei in
Google Scholar
PubMed
Search for other papers by S Kumar in
Google Scholar
PubMed
Search for other papers by A Bhansali in
Google Scholar
PubMed
Objective
To study the clinical profile and the management of patients with disorders of sex development (DSD).
Design and setting
Retrospective study from a tertiary care hospital of North India.
Methods and patients
One hundred ninety-four patients of DSD registered in the Endocrine clinic of Postgraduate Institute of Medical Education and Research, Chandigarh between 1995 and 2014 were included.
Results
One hundred and two patients (52.5%) had 46,XY DSD and seventy-four patients (38.1%) had 46,XX DSD. Sex chromosome DSD was identified in seven (3.6%) patients. Of 102 patients with 46,XY DSD, 32 (31.4%) had androgen insensitivity syndrome and 26 (25.5%) had androgen biosynthetic defect. Of the 74 patients with 46,XX DSD, 52 (70.27%) had congenital adrenal hyperplasia (CAH) and eight (10.8%) had ovotesticular DSD. Five patients with sex chromosome DSD had mixed gonadal dysgenesis. Excluding CAH, majority of the patients (90%) presented in the post-pubertal period. One-fourth of the patients with simple virilising CAH were reared as males because of strong male gender identity and behaviour and firm insistence by the parents. Corrective surgeries were performed in twenty patients (20%) of 46,XY DSD without hormonal evaluation prior to the presentation.
Conclusion
Congenital adrenal hyperplasia is the most common DSD in the present series. Most common XY DSD is androgen insensitivity syndrome, while CAH is the most common XX DSD. Delayed diagnosis is a common feature, and corrective surgeries are performed without seeking a definite diagnosis.
Center for Primary Health Care Research, Lund University, Malmö, Sweden
GeneWerk GmbH, Heidelberg, Germany
Search for other papers by Hauke Thomsen in
Google Scholar
PubMed
Search for other papers by Xinjun Li in
Google Scholar
PubMed
Departments of Family Medicine and Community Health, Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Center for Community-based Healthcare Research and Education (CoHRE), Department of Functional Pathology, School of Medicine, Shimane University, Shimane, Japan
Search for other papers by Kristina Sundquist in
Google Scholar
PubMed
Departments of Family Medicine and Community Health, Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Center for Community-based Healthcare Research and Education (CoHRE), Department of Functional Pathology, School of Medicine, Shimane University, Shimane, Japan
Search for other papers by Jan Sundquist in
Google Scholar
PubMed
Center for Primary Health Care Research, Lund University, Malmö, Sweden
Hopp Children’s Cancer Center (KiTZ), Heidelberg, Germany
Division of Pediatric Neurooncology, German Cancer Research Centre (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany
Search for other papers by Asta Försti in
Google Scholar
PubMed
Center for Primary Health Care Research, Lund University, Malmö, Sweden
Division of Cancer Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
Faculty of Medicine and Biomedical Center in Pilsen, Charles University in Prague, Pilsen, Czech Republic
Search for other papers by Kari Hemminki in
Google Scholar
PubMed
Design
Addison’s disease (AD) is a rare autoimmune disease (AID) of the adrenal cortex, present as an isolated AD or part of autoimmune polyendocrine syndromes (APSs) 1 and 2. Although AD patients present with a number of AID co-morbidities, population-based family studies are scarce, and we aimed to carry out an unbiased study on AD and related AIDs.
Methods
We collected data on patients diagnosed with AIDs in Swedish hospitals and calculated standardized incidence ratios (SIRs) in families for concordant AD and for other AIDs, the latter as discordant relative risks.
Results
The number of AD patients was 2852, which accounted for 0.4% of all hospitalized AIDs. A total of 62 persons (3.6%) were diagnosed with familial AD. The SIR for siblings was remarkably high, reaching 909 for singleton siblings diagnosed before age 10 years. It was 32 in those diagnosed past age 29 years and the risk for twins was 323. SIR was 9.44 for offspring of affected parents. AD was associated with 11 other AIDs, including thyroid AIDs and type 1 diabetes and some rarer AIDs such as Guillain–Barre syndrome, myasthenia gravis, polymyalgia rheumatica and Sjögren’s syndrome.
Conclusions
The familial risk for AD was very high implicating genetic etiology, which for juvenile siblings may be ascribed to APS-1. The adult part of sibling risk was probably contributed by recessive polygenic inheritance. AD was associated with many common AIDs; some of these were known co-morbidities in AD patients while some other appeared to more specific for a familial setting.
Search for other papers by Robert I Menzies in
Google Scholar
PubMed
Search for other papers by Xin Zhao in
Google Scholar
PubMed
Search for other papers by Linda J Mullins in
Google Scholar
PubMed
Search for other papers by John J Mullins in
Google Scholar
PubMed
Search for other papers by Carolynn Cairns in
Google Scholar
PubMed
Search for other papers by Nicola Wrobel in
Google Scholar
PubMed
Search for other papers by Donald R Dunbar in
Google Scholar
PubMed
Search for other papers by Matthew A Bailey in
Google Scholar
PubMed
Search for other papers by Christopher J Kenyon in
Google Scholar
PubMed
Chronic ACTH exposure is associated with adrenal hypertrophy and steroidogenesis. The underlying molecular processes in mice have been analysed by microarray, histological and immunohistochemical techniques. Synacthen infused for 2 weeks markedly increased adrenal mass and plasma corticosterone levels. Microarray analysis found greater than 2-fold changes in expression of 928 genes (P < 0.001; 397 up, 531 down). These clustered in pathways involved in signalling, sterol/lipid metabolism, cell proliferation/hypertrophy and apoptosis. Signalling genes included some implicated in adrenal adenomas but also upregulated genes associated with cyclic AMP and downregulated genes associated with aldosterone synthesis. Sterol metabolism genes were those promoting cholesterol supply (Scarb1, Sqle, Apoa1) and disposal (Cyp27a1, Cyp7b1). Oil red O staining showed lipid depletion consistent with reduced expression of genes involved in lipid synthesis. Genes involved in steroidogenesis (Star, Cyp11a1, Cyp11b1) were modestly affected (P < 0.05; <1.3-fold). Increased Ki67, Ccna2, Ccnb2 and Tk1 expression complemented immunohistochemical evidence of a 3-fold change in cell proliferation. Growth arrest genes, Cdkn1a and Cdkn1c, which are known to be active in hypertrophied cells, were increased >4-fold and cross-sectional area of fasciculata cells was 2-fold greater. In contrast, genes associated with apoptosis (eg Casp12, Clu,) were downregulated and apoptotic cells (Tunel staining) were fewer (P < 0.001) and more widely distributed throughout the cortex. In summary, long-term steroidogenesis with ACTH excess is sustained by genes controlling cholesterol supply and adrenal mass. ACTH effects on adrenal morphology and genes controlling cell hypertrophy, proliferation and apoptosis suggest the involvement of different cell types and separate molecular pathways.