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Free access

Ravi Kumar Dutta, Peter Söderkvist, and Oliver Gimm

Hypertension is a common medical condition and affects approximately 20% of the population in developed countries. Primary aldosteronism is the most common form of secondary hypertension and affects 8–13% of patients with hypertension. The two most common causes of primary aldosteronism are aldosterone-producing adenoma and bilateral adrenal hyperplasia. Familial hyperaldosteronism types I, II and III are the known genetic syndromes, in which both adrenal glands produce excessive amounts of aldosterone. However, only a minority of patients with primary aldosteronism have one of these syndromes. Several novel susceptibility genes have been found to be mutated in aldosterone-producing adenomas: KCNJ5, ATP1A1, ATP2B3, CTNNB1, CACNA1D, CACNA1H and ARMC5. This review describes the genes currently known to be responsible for primary aldosteronism, discusses the origin of aldosterone-producing adenomas and considers the future clinical implications based on these novel insights.

Free access

Christina Wei and Elizabeth C Crowne

Endocrine abnormalities are common among childhood cancer survivors. Abnormalities of the hypothalamic–pituitary–adrenal axis (HPAA) are relatively less common, but the consequences are severe if missed. Patients with tumours located and/or had surgery performed near the hypothalamic–pituitary region and those treated with an accumulative cranial radiotherapy dose of over 30 Gy are most at risk of adrenocorticotrophic hormone (ACTH) deficiency. Primary adrenal insufficiency may occur in patients with tumours located in or involving one or both adrenals. The effects of adjunct therapies also need to be considered, particularly, new immunotherapies. High-dose and/or prolonged courses of glucocorticoid treatment can result in secondary adrenal insufficiency, which may take months to resolve and hence reassessment is important to ensure patients are not left on long-term replacement steroids inappropriately. The prevalence and cumulative incidences of HPAA dysfunction are difficult to quantify because of its non-specific presentation and lack of consensus regarding its investigations. The insulin tolerance test remains the gold standard for the diagnosis of central cortisol deficiency, but due to its risks, alternative methods with reduced diagnostic sensitivities are often used and must be interpreted with caution. ACTH deficiency may develop many years after the completion of oncological treatment alongside other pituitary hormone deficiencies. It is essential that health professionals involved in the long-term follow-up of childhood cancer survivors are aware of individuals at risk of developing HPAA dysfunction and implement appropriate monitoring and treatment.

Free access

Stephen J Marx

Five syndromes share predominantly hyperplastic glands with a primary excess of hormones: neonatal severe primary hyperparathyroidism, from homozygous mutated CASR, begins severely in utero; congenital non-autoimmune thyrotoxicosis, from mutated TSHR, varies from severe with fetal onset to mild with adult onset; familial male-limited precocious puberty, from mutated LHR, expresses testosterone oversecretion in young boys; hereditary ovarian hyperstimulation syndrome, from mutated FSHR, expresses symptomatic systemic vascular permeabilities during pregnancy; and familial hyperaldosteronism type IIIA, from mutated KCNJ5, presents in young children with hypertension and hypokalemia. The grouping of these five syndromes highlights predominant hyperplasia as a stable tissue endpoint and as their tissue stage for all of the hormone excess. Comparisons were made among this and two other groups of syndromes, forming a continuum of gland staging: predominant oversecretions express little or no hyperplasia; predominant hyperplasias express little or no neoplasia; and predominant neoplasias express nodules, adenomas, or cancers. Hyperplasias may progress (5 of 5) to neoplastic stages while predominant oversecretions rarely do (1 of 6; frequencies differ P<0.02). Hyperplasias do not show tumor multiplicity (0 of 5) unlike neoplasias that do (13 of 19; P<0.02). Hyperplasias express mutation of a plasma membrane-bound sensor (5 of 5), while neoplasias rarely do (3 of 14; P<0.002). In conclusion, the multiple distinguishing themes within the hyperplasias establish a robust pathophysiology. It has the shared and novel feature of mutant sensors in the plasma membrane, suggesting that these are major contributors to hyperplasia.

Free access

Sisi Liu, Emmanouil Saloustros, Annabel Berthon, Matthew F Starost, Isabelle Sahut-Barnola, Paraskevi Salpea, Eva Szarek, Fabio R Faucz, Antoine Martinez, and Constantine A Stratakis

Primary pigmented nodular adrenocortical disease (PPNAD), whether in the context of Carney complex (CNC) or isolated, leads to ACTH-independent Cushing's syndrome (CS). CNC and PPNAD are caused typically by inactivating mutations of PRKAR1A, a gene coding for the type 1a regulatory subunit (R1α) of cAMP-dependent protein kinase (PKA). Mice lacking Prkar1a, specifically in the adrenal cortex (AdKO) developed CS caused by bilateral adrenal hyperplasia (BAH), which is formed from the abnormal proliferation of fetal-like adrenocortical cells. Celecoxib is a cyclooxygenase 2 (COX2) inhibitor. In bone, Prkar1a inhibition is associated with COX2 activation and prostaglandin E2 (PGE2) production that, in turn, activates proliferation of bone stromal cells. We hypothesized that COX2 inhibition may have an effect in PPNAD. In vitro treatment of human cell lines, including one from a patient with PPNAD, with celecoxib resulted in decreased cell viability. We then treated AdKO and control mice with 1500 mg/kg celecoxib or vehicle. Celecoxib treatment led to decreased PGE2 and corticosterone levels, reduced proliferation and increased apoptosis of adrenocortical cells, and decreased steroidogenic gene expression. We conclude that, in vitro and in vivo, celecoxib led to decreased steroidogenesis. In a mouse model of PPNAD, celecoxib caused histological changes that, at least in part, reversed BAH and this was associated with a reduction of corticosterone levels.

Free access

Paraskevi Xekouki, Michael M Hatch, Lin Lin, De Alexandre Rodrigo, Monalisa Azevedo, Maria de la Luz Sierra, Isaac Levy, Emmanouil Saloustros, Andreas Moraitis, Anelia Horvath, E Kebebew, Dax A Hoffman, and Constantine A Stratakis

KCNJ5 mutations were recently described in primary hyperaldosteronism (PH or Conn's syndrome). The frequency of these mutations in PH and the way KCNJ5 defects cause disease remain unknown. A total of 53 patients with PH have been seen at the National Institutes of Health over the last 12 years. Their peripheral and tumor DNAs (the latter from 16 that were operated) were screened for KCNJ5 mutations; functional studies on the identified defects were performed after transient transfection. Only two mutations were identified, and both in the tumor DNA only. There were no germline sequencing defects in any of the patients except for known synonymous variants of the KCNJ5 gene. One mutation was the previously described c.G451C alteration; the other was a novel one in the same codon: c.G451A; both lead to the same amino acid substitution (G151R) in the KCNJ5 protein. Functional studies confirmed previous findings that both mutations caused loss of channel selectivity and a positive shift in the reversal potential. In conclusion, the KCNJ5 protein was strongly expressed in the zona glomerulosa of normal adrenal glands but showed variable expression in the aldosterone-producing adenomas with and without mutation. The rate of KCNJ5 mutations among patients with PH and/or their tumors is substantially lower than what was previously reported. The G151R amino acid substitution appears to be the most frequent one so far detected in PH, despite additional nucleotide changes. The mutation causes loss of this potassium channel's selectivity and may assist in the design of new therapies for PH.

Restricted access

Andrea Gutierrez Maria, Christina Tatsi, Annabel Berthon, Ludivine Drougat, Nikolaos Settas, Fady Hannah-Shmouni, Jerome Bertherat, Fabio R Faucz, and Constantine A Stratakis

Mutations in the protein kinase A (PKA) regulatory subunit type 1A (PRKAR1A) and armadillo repeat-containing 5 (ARMC5) genes cause Cushing‘s syndrome (CS) due to primary pigmented nodular adrenocortical disease (PPNAD) and primary bilateral macronodular adrenocortical hyperplasia (PBMAH), respectively. Between the two genes, ARMC5 is highly polymorphic with several variants in the population, whereas PRKAR1A has very little, if any, non-pathogenic variation in its coding sequence. We tested the hypothesis that ARMC5 variants may affect the clinical presentation of PPNAD and CS among patients with PRKAR1A mutations. In this study, 91 patients with PPNAD due to PRKAR1A mutations were tested for abnormal cortisol secretion or CS and for ARMC5 sequence variants. Abnormal cortisol secretion was present in 71 of 74 patients with ARMC5 variants, whereas 11 of 17 patients negative for ARMC5 variants did not have hypercortisolemia. The presence of ARMC5 variants was a statistically strong predictor of CS among patients with PRKAR1A mutations (P < 0.001). Among patients with CS due to PPNAD, ARMC5 variants were associated with lower cortisol levels at baseline (P = 0.04) and after high dose dexamethasone administration (P = 0.02). The ARMC5 p.I170V variant increased ARMC5 protein accumulation in vitro and decreased viability of NCI-H295 cells (but not HEK 293T cells). PPNAD tissues with ARMC5 variants showed stronger ARMC5 protein expression than those that carried a normal ARMC5 sequence. Taken together, our results suggest that ARMC5 variants among patients with PPNAD due to PRKAR1A defects may play the role of a genetic modifier for the presence and severity of hypercortisolemia.

Free access

Rossella Libè, Amato Fratticci, and Jérôme Bertherat

Adrenocortical cancer (ACC) is a rare tumor with a poor prognosis. By contrast, benign adrenocortical tumors are frequent, underlying the importance of a correct diagnosis of malignancy of such tumors. ACC can be diagnosed by the investigation of endocrine signs of steroid excess, symptoms due to tumor growth or an adrenal incidentaloma. Hormonal investigations demonstrate in most ACC steroid oversecretion, the dominant characteristics being a co-secretion of cortisol and androgens. Imaging by CT-scan or MRI shows a large heterogeneous tumor with a low fat content. Careful pathological investigation with the assessment of the Weiss score is important for the diagnosis of malignancy. Molecular markers can also be helpful and in the future might be important for prognosis. Tumors localized to the adrenal gland (McFarlane stages 1 and 2) have a better outcome than invasive and metastatic tumors (stages 3 and 4). Tumor removal by a specialized team is crucial for treatment and should always aim at complete removal. In patients with metastatic or progressive disease, medical treatment is started with mitotane that requires a close monitoring of its blood level. Surgery is indicated when possible for local recurrence but also in some cases of metastasis. Local treatment (radiofrequency, chemoembolization, and radiation therapy) can have some indications for metastatic disease. In patients with disease progression cytotoxic chemotherapy can be used. Despite the best care, the overall prognosis of ACC is poor with a 5-year survival rate below 30% in most series. Therefore, progress in the understanding of the pathophysiology of ACC is important. Despite the rarity of ACC, significant advances have been made in the understanding of its pathogenesis the last decade. These progresses came mainly from the study of the genetics of ACC, both at the germline level in rare familial diseases, and at the somatic level by the study of molecular alterations in sporadic tumors. These advances underline the importance of genetic alterations in ACC development and point-out to various chromosomal regions (2, 11p15, 11q, 17p13) and genes (IGF-II, p53, β-catenin, ACTH receptor). This review will summarize these advances as well as the current clinical management of ACC.

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Fady Hannah-Shmouni, Annabel Berthon, Fabio R Faucz, Juan Medina Briceno, Andrea Gutierrez Maria, Andrew Demidowich, Mirko Peitzsch, Jimmy Masjkur, Fidéline Bonnet-Serrano, Anna Vaczlavik, Jérôme Bertherat, Martin Reincke, Graeme Eisenhofer, and Constantine A Stratakis

Biochemical characterization of primary bilateral macronodular adrenocortical hyperplasia (PBMAH) by distinct plasma steroid profiles and its putative correlation to disease has not been previously studied. LC-MS/MS–based steroid profiling of 16 plasma steroids was applied to 36 subjects (22 females, 14 males) with PBMAH, 19 subjects (16 females, 3 males) with other forms of adrenal Cushing's syndrome (ACS), and an age and sex-matched control group. Germline ARMC5 sequencing was performed in all PBMAH cases. Compared to controls, PBMAH showed increased plasma 11-deoxycortisol, corticosterone, 11-deoxycorticosterone, 18-hydroxycortisol, and aldosterone, but lower progesterone, DHEA, and DHEA-S with distinct differences in subjects with and without pathogenic variants in ARMC5. Steroids that showed isolated differences included cortisol and 18-oxocortisol with higher (P < 0.05) concentrations in ACS than in controls and aldosterone with higher concentrations in PBMAH when compared to controls. Larger differences in PBMAH than with ACS were most clear for corticosterone, but there were also trends in this direction for 18-hydroxycortisol and aldosterone. Logistic regression analysis indicated four steroids – DHEA, 11-deoxycortisol, 18-oxocortisol, and corticosterone – with the most power for distinguishing the groups. Discriminant analyses with step-wise variable selection indicated correct classification of 95.2% of all subjects of the four groups using a panel of nine steroids; correct classification of subjects with and without germline variants in ARMC5 was achieved in 91.7% of subjects with PBMAH. Subjects with PBMAH show distinctive plasma steroid profiles that may offer a supplementary single-test alternative for screening purposes.

Restricted access

M J Reed, R W Cheng, P A Beranek, and V H T James

There is evidence that the free, biologically active fraction of sex steroids in the plasma, is increased in subjects with endocrine-dependent tumours. However, little is known about factors which influence the distribution of these hormones in plasma. In order to investigate this, cortisol (14 μM) was infused, or ACTH (Synacthen, 250 μg, i.v.) was injected into male subjects and this resulted in a significant decrease (up to 38% from basal values) in the fraction of testosterone not bound to sex-hormone binding globulin (non-SHBG bound testosterone). The decrease in the non-SHBG bound testosterone fraction was accompanied by an increase (up to 20% from basal values) in the non-SHBG bound oestradiol fraction after ACTH injection. No significant changes in the unbound concentrations of testosterone or oestradiol were detected. The addition of cortisol (250 nM) to a plasma pool obtained from male subjects resulted in a similar decrease in the non-SHBG bound testosterone
Open access

K E Lines, P Filippakopoulos, M Stevenson, S Müller, H E Lockstone, B Wright, S Knapp, D Buck, C Bountra, and R V Thakker

Medical treatments for corticotrophinomas are limited, and we therefore investigated the effects of epigenetic modulators, a new class of anti-tumour drugs, on the murine adrenocorticotropic hormone (ACTH)-secreting corticotrophinoma cell line AtT20. We found that AtT20 cells express members of the bromo and extra-terminal (BET) protein family, which bind acetylated histones, and therefore, studied the anti-proliferative and pro-apoptotic effects of two BET inhibitors, referred to as (+)-JQ1 (JQ1) and PFI-1, using CellTiter Blue and Caspase Glo assays, respectively. JQ1 and PFI-1 significantly decreased proliferation by 95% (P < 0.0005) and 43% (P < 0.0005), respectively, but only JQ1 significantly increased apoptosis by >50-fold (P < 0.0005), when compared to untreated control cells. The anti-proliferative effects of JQ1 and PFI-1 remained for 96 h after removal of the respective compound. JQ1, but not PFI-1, affected the cell cycle, as assessed by propidium iodide staining and flow cytometry, and resulted in a higher number of AtT20 cells in the sub G1 phase. RNA-sequence analysis, which was confirmed by qRT-PCR and Western blot analyses, revealed that JQ1 treatment significantly altered expression of genes involved in apoptosis, such as NFκB, and the somatostatin receptor 2 (SSTR2) anti-proliferative signalling pathway, including SSTR2. JQ1 treatment also significantly reduced transcription and protein expression of the ACTH precursor pro-opiomelanocortin (POMC) and ACTH secretion by AtT20 cells. Thus, JQ1 treatment has anti-proliferative and pro-apoptotic effects on AtT20 cells and reduces ACTH secretion, thereby indicating that BET inhibition may provide a novel approach for treatment of corticotrophinomas.