Clinical characteristics of aldosterone-producing microadenoma, macroadenoma, and idiopathic hyperaldosteronism in 93 patients with primary aldosteronism.

PubMed

Omura, Masao; Sasano, Hironobu; Saito, Jun; Yamaguchi, Kunio; Kakuta, Yukio; Nishikawa, Tetsuo

2006-11-01

Primary aldosteronism (PA) due to aldosterone-producing adenoma (APA) is a form of surgically curable secondary hypertension, and distinguishing APA from idiopathic hyperaldosteronism (IHA) is important for treatment. We made a differential diagnosis between APA and IHA using imaging tests such as adrenal CT and MRI as well as adrenal venous sampling (AVS) in all 93 cases of PA presenting at our institutions over the last decade. We identified 27 patients with aldosterone-producing microadenoma (APmicroA), all of whom could be diagnosed by AVS but not by the imaging tests. Then, we compared the clinical and roent-genological findings of these 27 patients with those of 42 patients with aldosterone-producing macroadenoma (APmacroA) and of 24 patients with IHA. Using surgically removed adrenal tissues, histopathological examinations and immunohistochemical analyses of steroidogenic enzymes were conducted. The findings for APmicroA were similar to those for APmacroA, except with respect to the diameter of the adrenal adenomas. Endocrinological and roentgenological findings for APmicroA were similar to those for IHA, but not to those for APmacroA. The rate of cure of hypertension was much greater in patients with APmicroA than in patients with APmacroA after the unilateral adrenalectomy (odds ratio, 4.0; p=0.028). In conclusion, it is important to accurately diagnose APmicroA, in which the laterality of the hyperproduction of aldosterone is only detectable by AVS, and to treat these patients by unilateral adrenalectomy in order to avoid long-term medical treatment and prevent hypertensive vascular complications.

Purkinje Cell Protein 4 Expression Is Associated With DNA Methylation Status in Aldosterone-Producing Adenoma.

PubMed

Kobuke, Kazuhiro; Oki, Kenji; Gomez-Sanchez, Celso E; Ohno, Haruya; Itcho, Kiyotaka; Yoshii, Yoko; Yoneda, Masayasu; Hattori, Noboru

2018-03-01

Aldosterone production is stimulated by activation of calcium signaling in aldosterone-producing adenomas (APAs), and epigenetic factors such as DNA methylation may be associated with the expression of genes involved in aldosterone regulation. Our aim was to investigate the DNA methylation of genes related to calcium signaling cascades in APAs and the association of mutations in genes linked to APAs with DNA methylation levels. Nonfunctioning adrenocortical adenoma (n = 12) and APA (n = 35) samples were analyzed. The KCNJ5 T158A mutation was introduced into human adrenocortical cell lines (HAC15 cells) using lentiviral delivery. DNA methylation array analysis was conducted using adrenal tumor samples and HAC15 cells. The Purkinje cell protein 4 (PCP4) gene was one of the most hypomethylated in APAs. DNA methylation levels in two sites of PCP4 showed a significant inverse correlation with messenger RNA expression in adrenal tumors. Bioinformatics and multiple regression analysis revealed that CCAAT/enhancer binding protein alpha (CEBPA) may bind to the methylation site of the PCP4 promoter. According to chromatin immunoprecipitation assay, CEBPA was bound to the PCP4 hypomethylated region by chromatin immunoprecipitation assay. There were no significant differences in PCP4 methylation levels among APA genotypes. Moreover, KCNJ5 T158A did not influence PCP4 methylation levels in HAC15 cells. We showed that the PCP4 promoter was one of the most hypomethylated in APAs and that PCP4 transcription may be associated with demethylation as well as with CEBPA in APAs. KCNJ5 mutations known to result in aldosterone overproduction were not related to PCP4 methylation in either clinical or in vitro studies.

Effect of KCNJ5 Mutations on Gene Expression in Aldosterone-Producing Adenomas and Adrenocortical Cells

PubMed Central

Monticone, Silvia; Hattangady, Namita G.; Nishimoto, Koshiro; Mantero, Franco; Rubin, Beatrice; Cicala, Maria Verena; Pezzani, Raffaele; Auchus, Richard J.; Ghayee, Hans K.; Shibata, Hirotaka; Kurihara, Isao; Williams, Tracy A.; Giri, Judith G.; Bollag, Roni J.; Edwards, Michael A.; Isales, Carlos M.

2012-01-01

Context: Primary aldosteronism is a heterogeneous disease that includes both sporadic and familial forms. A point mutation in the KCNJ5 gene is responsible for familial hyperaldosteronism type III. Somatic mutations in KCNJ5 also occur in sporadic aldosterone producing adenomas (APA). Objective: The objective of the study was to define the effect of the KCNJ5 mutations on gene expression and aldosterone production using APA tissue and human adrenocortical cells. Methods: A microarray analysis was used to compare the transcriptome profiles of female-derived APA samples with and without KCNJ5 mutations and HAC15 adrenal cells overexpressing either mutated or wild-type KCNJ5. Real-time PCR validated a set of differentially expressed genes. Immunohistochemical staining localized the KCNJ5 expression in normal adrenals and APA. Results: We report a 38% (18 of 47) prevalence of KCNJ5 mutations in APA. KCNJ5 immunostaining was highest in the zona glomerulosa of NA and heterogeneous in APA tissue, and KCNJ5 mRNA was 4-fold higher in APA compared with normal adrenals (P < 0.05). APA with and without KCNJ5 mutations displayed slightly different gene expression patterns, notably the aldosterone synthase gene (CYP11B2) was more highly expressed in APA with KCNJ5 mutations. Overexpression of KCNJ5 mutations in HAC15 increased aldosterone production and altered expression of 36 genes by greater than 2.5-fold (P < 0.05). Real-time PCR confirmed increases in CYP11B2 and its transcriptional regulator, NR4A2. Conclusions: KCNJ5 mutations are prevalent in APA, and our data suggest that these mutations increase expression of CYP11B2 and NR4A2, thus increasing aldosterone production. PMID:22628608

Vascular complications in patients with aldosterone producing adenoma in Japan: comparative study with essential hypertension. The Research Committee of Disorders of Adrenal Hormones in Japan.

PubMed

Takeda, R; Matsubara, T; Miyamori, I; Hatakeyama, H; Morise, T

1995-05-01

The incidence of vascular complications in 224 patients with aldosterone-producing adenoma (APA) which was proven on adrenal surgery, was compared to that in 224 sex- and age-matched patients with essential hypertension (EHT). The incidence of cerebral hemorrhage was significantly higher (p < 0.05) in the patients with APA when compared to the EHT group. On the other hand, the incidence of myocardial infarction and/or congestive heart failure in the APA group was lower, although this difference did not reach statistical significance. Diastolic blood pressure in the APA group was significantly higher (p < 0.001) in the EHT group. However, a significant difference in diastolic blood pressure was not detected between the APA groups with and without vascular complications, whereas in the EHT group diastolic blood pressure was significantly higher (p < 0.001) in cases with vascular complications as compared to those without complications. As a possible factor contributing to the higher incidence of cerebral hemorrhage in the APA group, proteinuria was suggested. It was recommended that patients with primary aldosteronism should undergo operation when localization of the APA is established.

Local Control of Aldosterone Production and Primary Aldosteronism.

PubMed

Lalli, Enzo; Barhanin, Jacques; Zennaro, Maria-Christina; Warth, Richard

2016-03-01

Primary aldosteronism (PA) is caused by excessive production of aldosterone by the adrenal cortex and is determined by a benign aldosterone-producing adenoma (APA) in a significant proportion of cases. Local mechanisms, as opposed to circulatory ones, that control aldosterone production in the adrenal cortex are particularly relevant in the physiopathological setting and in the pathogenesis of PA. A breakthrough in our understanding of the pathogenetic mechanisms in APA has been the identification of somatic mutations in genes controlling membrane potential and intracellular calcium concentrations. However, recent data show that the processes of nodule formation and aldosterone hypersecretion can be dissociated in pathological adrenals and suggest a model envisaging different molecular events for the pathogenesis of APA. Copyright © 2016 Elsevier Ltd. All rights reserved.

Use of plasma metanephrine to aid adrenal venous sampling in combined aldosterone and cortisol over-secretion.

PubMed

Goupil, Rémi; Wolley, Martin; Ungerer, Jacobus; McWhinney, Brett; Mukai, Kuniaki; Naruse, Mitsuhide; Gordon, Richard D; Stowasser, Michael

2015-01-01

In patients with primary aldosteronism (PA) undergoing adrenal venous sampling (AVS), cortisol levels are measured to assess lateralization of aldosterone overproduction. Concomitant adrenal autonomous cortisol and aldosterone secretion therefore have the potential to confound AVS results. We describe a case where metanephrine was measured during AVS to successfully circumvent this problem. A 55-year-old hypertensive male had raised plasma aldosterone/renin ratios and PA confirmed by fludrocortisone suppression testing. Failure of plasma cortisol to suppress overnight following dexamethasone and persistently suppressed corticotrophin were consistent with adrenal hypercortisolism. On AVS, comparison of adrenal and peripheral A/F ratios (left 5.7 vs peripheral 1.0; right 1.7 vs peripheral 1.1) suggested bilateral aldosterone production, with the left gland dominant but without contralateral suppression. However, using aldosterone/metanephrine ratios (left 9.7 vs peripheral 2.4; right 1.3 vs peripheral 2.5), aldosterone production lateralized to the left with good contralateral suppression. The patient underwent left laparoscopic adrenalectomy with peri-operative glucocorticoid supplementation to prevent adrenal insufficiency. Pathological examination revealed adrenal cortical adenomas producing both cortisol and aldosterone within a background of aldosterone-producing cell clusters. Hypertension improved and cured of PA and hypercortisolism were confirmed by negative post-operative fludrocortisone suppression and overnight 1 mg dexamethasone suppression testing. Routine dexamethasone suppression testing in patients with PA permits detection of concurrent hypercortisolism which can confound AVS results and cause unilateral PA to be misdiagnosed as bilateral with patients thereby denied potentially curative surgical treatment. In such patients, measurement of plasma metanephrine during AVS may overcome this issue. Simultaneous autonomous overproduction of cortisol

[Factors for postoperative persistent hypertension in patients with aldosterone-producing adenoma].

PubMed

Liu, D; Zheng, C; Chen, Q

1997-07-01

We determined the factors for postoperative persistent hypertension in the patients with aldosterone-producing adrenal adenoma (APA) in 53 patients with APA who were followed up for average 3.1 years. All had normal serum potassium concentration postoperatively. Blood pressure was normal in 37 patients (69.8%) but 18.7/12.7 kPa or more in 16 patients (30.2%) with persistent hypertension. Also compared were sex, age, history of hypertension, effect of reducing blood pressure to antisterone, preoperative blood pressure, time of persistent hypertension, serum potassium concentration, aldosterone concentration in 24 hour urine, amount of PRA, and the type of operation. The results showed that an APA patient aged 50 years or more appears to have a great chance of persistent hypertension than an APA patient under age of 40 years, and the odds ratio is 3:1. There was a significant difference between the mean age for persistent hypertension and for normal blood pressure, and varioas response of reducing blood pressure to antisterone (P < 0.05). It is suggested that for an older APA patient and the patient without of reducing blood pressure to antisterone, there are other factors for hypertension such as renal veinlet change or renal interstitial lesions except for hyperaldosteronism. We recommend renal biopsy (using kidney puncture) at the operating table for those patients in order to understand pathological change and guide treatment after operation.

Metoclopramide unmasks potentially misleading contralateral suppression in patients undergoing adrenal vein sampling for primary aldosteronism.

PubMed

Rossitto, Giacomo; Miotto, Diego; Battistel, Michele; Barbiero, Giulio; Maiolino, Giuseppe; Bisogni, Valeria; Sanga, Viola; Rossi, Gian Paolo

2016-11-01

As metoclopramide stimulates aldosterone secretion, we tested its usefulness in the assessment of lateralization of primary aldosteronism by adrenal vein sampling (AVS). Prospective within-patient study in consecutive patients undergoing AVS for primary aldosteronism subtyping. We compared the diagnostic accuracy of baseline and postmetoclopramide lateralization index and relative (to cortisol) aldosterone secretion indices (RASI) for each adrenal gland with aldosterone-producing adenoma (APA) determined by the four corners criteria as the reference diagnosis. We recruited 93 consecutive patients (mean age: 52 years; women 31%). Metoclopramide increased plasma aldosterone in the inferior vena cava and in both adrenal veins. The postmetoclopramide lateralization index was accurate in identifying APA, but did not increase diagnostic accuracy over baseline lateralization index, because the RASI increased similarly in both sides. Conversely, metoclopramide raised RASI to values more than 0.90 bilaterally in non-APA patients allowing accurate identification of factitious aldosterone suppression. In contrast, RASI was 0.90 or less in 48% contralateral to the tumor in APA patients. Regression analysis showed the APA patients with persistent suppression of RASI contralaterally showed a more florid primary aldosteronism phenotype. Metoclopramide does not enhance lateralization of aldosterone excess in APA, but consistently increased the value of RASI in non-APA cases, thus unmasking potentially misleading suppression of aldosterone. Postmetoclopramide RASI may therefore allow a more precise diagnosis when AVS can be achieved only unilaterally.

Calneuron 1 Increased Ca2+ in the Endoplasmic Reticulum and Aldosterone Production in Aldosterone-Producing Adenoma.

PubMed

Kobuke, Kazuhiro; Oki, Kenji; Gomez-Sanchez, Celso E; Gomez-Sanchez, Elise P; Ohno, Haruya; Itcho, Kiyotaka; Yoshii, Yoko; Yoneda, Masayasu; Hattori, Noboru

2018-01-01

Aldosterone production is initiated by angiotensin II stimulation and activation of intracellular Ca 2+ signaling. In aldosterone-producing adenoma (APA) cells, the activation of intracellular Ca 2+ signaling is independent of the renin-angiotensin-aldosterone systems. The purpose of our study was to clarify molecular mechanisms of aldosterone production related to Ca 2+ signaling. Transcriptome analysis revealed that the CALN1 gene encoding calneuron 1 had the strongest correlation with CYP11B2 (aldosterone synthase) among genes encoding Ca 2+ -binding proteins in APA. CALN1 modulation and synthetic or fluorescent compounds were used for functional studies in human adrenocortical carcinoma (HAC15) cells. CALN1 expression was 4.4-fold higher in APAs than nonfunctioning adrenocortical adenomas. CALN1 expression colocalized with CYP11B2 expression as investigated using immunohistochemistry in APA and zona glomerulosa of male rats fed by a low-salt diet. CALN1 expression was detected in the endoplasmic reticulum (ER) by using GFP-fused CALN1, CellLight ER-RFP, and the corresponding antibodies. CALN1 -overexpressing HAC15 cells showed increased Ca 2+ in the ER and cytosol fluorescence-based studies. Aldosterone production was potentiated in HAC15 cells by CALN1 expression, and dose-responsive inhibition with TMB-8 showed that CALN1-mediated Ca 2+ storage in ER involved sarcoendoplasmic reticulum calcium transport ATPase. The silencing of CALN1 decreased Ca 2+ in ER, and abrogated angiotensin II- or KCNJ5 T158A-mediated aldosterone production in HAC15 cells. Increased CALN1 expression in APA was associated with elevated Ca 2+ storage in ER and aldosterone overproduction. Suppression of CALN1 expression prevented angiotensin II- or KCNJ5 T158A-mediated aldosterone production in HAC15 cells, suggesting that CALN1 is a potential therapeutic target for excess aldosterone production. © 2017 American Heart Association, Inc.

Role of adrenal vein sampling in primary aldosteronism: the Monash Health experience.

PubMed

Teng, J; Hutchinson, M E; Doery, J C G; Choy, K W; Chong, W; Fuller, P J; Yang, J

2015-11-01

Adrenal vein sampling (AVS) is useful for distinguishing unilateral versus bilateral hypersecretion in primary aldosteronism (PA), but is technically challenging. Furthermore, the use of adrenocorticotropic hormone (ACTH)-stimulation in AVS is controversial. We implemented a Monash Health-specific AVS protocol in 2010. The audit aimed to: (i) examine the impact of a dedicated protocol on success rates of AVS at a tertiary referral centre; (ii) evaluate the impact of AVS on sub-typing of PA; and (iii) assess the utility of ACTH stimulation in AVS. AVS was performed on patients with PA confirmed by positive saline suppression testing (aldosterone level >140 pmol/L post-saline infusion), with sequential sampling of adrenal and peripheral veins, pre- and post-ACTH infusion. Patients with unilateral aldosterone-producing adenoma diagnosed on successful AVS were referred for adrenalectomy. Between 2010 and 2014 inclusive, a total of 28 AVS procedures was performed, with complete pre- and post-ACTH data for 19 procedures. Bilateral successful cannulation rates improved post-implementation of our protocol (61% vs 41%). Of the patients, 32% had discordant imaging and AVS results: four patients with unilateral adenomas did not lateralise on AVS and were managed medically; four patients with bilateral or no adenomas on imaging, lateralised on AVS and had surgery. Overall, use of ACTH did not increase successful cannulation and tended to mask lateralisation. AVS is crucial in subtype classification of PA and should be performed by a dedicated radiologist with a standardised protocol. AVS outcomes were not improved with the use of ACTH stimulation. © 2015 Royal Australasian College of Physicians.

Is there a role for segmental adrenal venous sampling and adrenal sparing surgery in patients with primary aldosteronism?

PubMed

Satoh, Fumitoshi; Morimoto, Ryo; Seiji, Kazumasa; Satani, Nozomi; Ota, Hideki; Iwakura, Yoshitsugu; Ono, Yoshikiyo; Kudo, Masataka; Nezu, Masahiro; Omata, Kei; Tezuka, Yuta; Kawasaki, Yoshihide; Ishidoya, Shigeto; Arai, Yoichi; Takase, Kei; Nakamura, Yasuhiro; McNamara, Keely; Sasano, Hironobu; Ito, Sadayoshi

2015-10-01

Adrenal venous sampling (AVS) is critical to determine the subtype of primary aldosteronism (PA). Central AVS (C-AVS)--that is, the collection of effluents from bilateral adrenal central veins (CV)--sometimes does not allow differentiation between bilateral aldosterone-producing adenomas (APA) and idiopathic hyperaldosteronism. To establish the best treatment course, we have developed segmental AVS (S-AVS); that is, we collect effluents from the tributaries of CV to determine the intra-adrenal sources of aldosterone overproduction. We then evaluated the clinical utility of this novel approach in the diagnosis and treatment of PA. We performed C-AVS and/or S-AVS in 297 PA patients and assessed the accuracy of diagnosis based on the results of C-AVS (n=138, 46.5%) and S-AVS (n=159, 53.5%) by comparison with those of clinicopathological evaluation of resected specimens. S-AVS demonstrated both elevated and attenuated secretion of aldosterone from APA and non-tumorous segments, respectively, in patients with bilateral APA and recurrent APA. These findings were completely confirmed by detailed histopathological examination after surgery. S-AVS, but not C-AVS, also served to identify APA located distal from the CV. Compared to C-AVS, S-AVS served to identify APA in some patients, and its use should expand the pool of patients eligible for adrenal sparing surgery through the identification of unaffected segments, despite the fact that S-AVS requires more expertise and time. Especially, this new technique could enormously benefit patients with bilateral or recurrent APA because of the preservation of non-tumorous glandular tissue. © 2015 European Society of Endocrinology.

[Role of adrenal vein sampling in differential diagnosis of primary aldosteronism subtypes].

PubMed

Li, H Y; Li, P; Shen, S M; Zhang, X B; Feng, W H; Huang, H; Chen, W; Zhu, D L

2017-11-14

Objective: To investigate the role of adrenal vein sampling (AVS) in identifying the subtype of primary aldosteronism (PA). Methods: AVS was performed in 50 patients who were confirmed as PA between September 2010 and September 2016 in Nanjing Drum Tower Hospital. Clinical, biochemical and follow-up data were reviewed retrospectively. Bilaterally simultaneous catheterization without cosyntropin stimulation and contemporaneous cortisol measurement during AVS were used. Selectivity index (SI)≥1.5 suggested that the sample was from the adrenal vein.Lateralization index (LI) ≥2 suggested unilateral disease.Clinical data was further compared and the AVS findings were analyzed. Results: AVS was successful performed in 41 cases of 50 patients, and the success rate was 82%. According to the results of AVS and postoperative pathology, 41 cases were divided into aldosterone-producing adenoma (APA)/unilateral adrenal hyperplasia (UAH) group (24 cases) and idiopathic hyperaldosteronism (IHA) group (17 cases). Compared with IHA group, patients with APA/UAH showed longer duration of hypertension[10.0 (5.0, 13.0) y vs 4.0 (2.0, 8.0) y, P =0.046], higher proportion of hypokalemia (95.8% vs 64.7%, P =0.009). Furthermore, patients with APA/UAH demonstrated lower plasma renin activity ( P =0.089), higher plasma aldosterone concentration and aldosterone to renin ratio (ARR) (both P <0.05). The diagnostic concordance between CT and adrenal vein sampling was only 48.8%(20/41). Conclusions: The application of bilaterally simultaneous catheterization and contemporaneous cortisol measurement improves success rate and diagnostic accuracy of AVS. AVS is useful in subtype diagnosis of PA with equivocal imaging findings.

LGR5 Activates Noncanonical Wnt Signaling and Inhibits Aldosterone Production in the Human Adrenal.

PubMed

Shaikh, Lalarukh Haris; Zhou, Junhua; Teo, Ada E D; Garg, Sumedha; Neogi, Sudeshna Guha; Figg, Nichola; Yeo, Giles S; Yu, Haixiang; Maguire, Janet J; Zhao, Wanfeng; Bennett, Martin R; Azizan, Elena A B; Davenport, Anthony P; McKenzie, Grahame; Brown, Morris J

2015-06-01

Aldosterone synthesis and cellularity in the human adrenal zona glomerulosa (ZG) is sparse and patchy, presumably due to salt excess. The frequency of somatic mutations causing aldosterone-producing adenomas (APAs) may be a consequence of protection from cell loss by constitutive aldosterone production. The objective of the study was to delineate a process in human ZG, which may regulate both aldosterone production and cell turnover. This study included a comparison of 20 pairs of ZG and zona fasciculata transcriptomes from adrenals adjacent to an APA (n = 13) or a pheochromocytoma (n = 7). Interventions included an overexpression of the top ZG gene (LGR5) or stimulation by its ligand (R-spondin-3). A transcriptome profile of ZG and zona fasciculata and aldosterone production, cell kinetic measurements, and Wnt signaling activity of LGR5 transfected or R-spondin-3-stimulated cells were measured. LGR5 was the top gene up-regulated in ZG (25-fold). The gene for its cognate ligand R-spondin-3, RSPO3, was 5-fold up-regulated. In total, 18 genes associated with the Wnt pathway were greater than 2-fold up-regulated. ZG selectivity of LGR5, and its absence in most APAs, were confirmed by quantitative PCR and immunohistochemistry. Both R-spondin-3 stimulation and LGR5 transfection of human adrenal cells suppressed aldosterone production. There was reduced proliferation and increased apoptosis of transfected cells, and the noncanonical activator protein-1/Jun pathway was stimulated more than the canonical Wnt pathway (3-fold vs 1.3-fold). ZG of adrenal sections stained positive for apoptosis markers. LGR5 is the most selectively expressed gene in human ZG and reduces aldosterone production and cell number. Such conditions may favor cells whose somatic mutation reverses aldosterone inhibition and cell loss.

Plasma adrenocorticotropic hormone but not aldosterone is correlated with blood pressure in patients with aldosterone-producing adenomas.

PubMed

Kobayashi, Hiroki; Haketa, Akira; Takahiro, Ueno; Otsuka, Hiromasa; Tanaka, Sho; Hatanaka, Yoshinari; Ikeda, Yukihiro; Abe, Masanori; Fukuda, Noboru; Soma, Masayoshi

2017-03-01

Although plasma aldosterone concentration (PAC) varies depending on primary aldosteronism (PA) subtypes, patients with different subtypes may have similar blood pressure (BP). The authors hypothesized that hormones other than aldosterone might influence BP in PA patients. A total of 73 PA cases, including 30 cases of aldosterone-producing adenomas (APAs), 29 cases of bilateral hyperaldosteronism, and 24 control cases of essential hypertension were enrolled retrospectively. The authors examined the levels of aldosterone, cortisol, renin, and adrenocorticotropic hormone (ACTH) measured at 12 am, 6 am, 12 pm, and 6 pm and BP in the early morning (6 am to 7 am), late morning (9 am to 11 am), and early evening (5 pm to 7 pm). Results showed no statistically significant correlation between PAC and BP in the patients with PA; however, early and late morning systolic BP strongly correlated with ACTH at 6 am in patients with APA. These results suggest that hormones other than aldosterone, such as ACTH, may affect BP in patients with APA. ©2016 Wiley Periodicals, Inc.

Update in diagnosis and management of primary aldosteronism.

PubMed

Dick, Sofia M; Queiroz, Marina; Bernardi, Bárbara L; Dall'Agnol, Angélica; Brondani, Letícia A; Silveiro, Sandra P

2018-02-23

Primary aldosteronism (PA) is a group of disorders in which aldosterone is excessively produced. These disorders can lead to hypertension, hypokalemia, hypervolemia and metabolic alkalosis. The prevalence of PA ranges from 5% to 12% around the globe, and the most common causes are adrenal adenoma and adrenal hyperplasia. The importance of PA recognition arises from the fact that it can have a remarkably adverse cardiovascular and renal impact, which can even result in death. The aldosterone-to-renin ratio (ARR) is the election test for screening PA, and one of the confirmatory tests, such as oral sodium loading (OSL) or saline infusion test (SIT), is in general necessary to confirm the diagnosis. The distinction between adrenal hyperplasia (AH) or aldosterone-producing adenoma (APA) is essential to select the appropriate treatment. Therefore, in order to identify the subtype of PA, imaging exams such as computed tomography or magnetic ressonance imaging, and/or invasive investigation such as adrenal catheterization must be performed. According to the subtype of PA, optimal treatment - surgical for APA or pharmacological for AH, with drugs like spironolactone and amiloride - must be offered.

Transcriptome Pathway Analysis of Pathological and Physiological Aldosterone-Producing Human Tissues.

PubMed

Zhou, Junhua; Lam, Brian; Neogi, Sudeshna G; Yeo, Giles S H; Azizan, Elena A B; Brown, Morris J

2016-12-01

Primary aldosteronism is present in ≈10% of hypertensives. We previously performed a microarray assay on aldosterone-producing adenomas and their paired zona glomerulosa and fasciculata. Confirmation of top genes validated the study design and functional experiments of zona glomerulosa selective genes established the role of the encoded proteins in aldosterone regulation. In this study, we further analyzed our microarray data using AmiGO 2 for gene ontology enrichment and Ingenuity Pathway Analysis to identify potential biological processes and canonical pathways involved in pathological and physiological aldosterone regulation. Genes differentially regulated in aldosterone-producing adenoma and zona glomerulosa were associated with steroid metabolic processes gene ontology terms. Terms related to the Wnt signaling pathway were enriched in zona glomerulosa only. Ingenuity Pathway Analysis showed "NRF2-mediated oxidative stress response pathway" and "LPS (lipopolysaccharide)/IL-1 (interleukin-1)-mediated inhibition of RXR (retinoid X receptor) function" were affected in both aldosterone-producing adenoma and zona glomerulosa with associated genes having up to 21- and 8-fold differences, respectively. Comparing KCNJ5-mutant aldosterone-producing adenoma, zona glomerulosa, and zona fasciculata samples with wild-type samples, 138, 56, and 59 genes were differentially expressed, respectively (fold-change >2; P<0.05). ACSS3, encoding the enzyme that synthesizes acetyl-CoA, was the top gene upregulated in KCNJ5-mutant aldosterone-producing adenoma compared with wild-type. NEFM, a gene highly upregulated in zona glomerulosa, was upregulated in KCNJ5 wild-type aldosterone-producing adenomas. NR4A2, the transcription factor for aldosterone synthase, was highly expressed in zona fasciculata adjacent to a KCNJ5-mutant aldosterone-producing adenoma. Further interrogation of these genes and pathways could potentially provide further insights into the pathology of primary

Case Report: Nodule Development From Subcapsular Aldosterone-Producing Cell Clusters Causes Hyperaldosteronism.

PubMed

Nishimoto, Koshiro; Seki, Tsugio; Kurihara, Isao; Yokota, Kenichi; Omura, Masao; Nishikawa, Tetsuo; Shibata, Hirotaka; Kosaka, Takeo; Oya, Mototsugu; Suematsu, Makoto; Mukai, Kuniaki

2016-01-01

We previously reported that the human adrenal cortex remodels to form subcapsular aldosterone-producing cell clusters (APCCs). Some APCCs were recently found to carry aldosterone-producing adenoma (APA)-associated somatic mutations in ion channel/pump genes, which implied that APCCs produce aldosterone autonomously and are an origin of APA. However, there has been no report describing an APCC-to-APA transitional lesion. A histological examination revealed unilateral multiple adrenocortical micronodules in the adrenals of two patients with primary aldosteronism (PA). Based on immunohistochemistry for aldosterone synthase, some of the micronodules were identified as possible APCC-to-APA transitional lesions (pAATLs; a tentative term used in this manuscript), which consisted of a subcapsular APCC-like portion and an inner micro-APA-like (mAPA-like) portion without an apparent histological border. Genomic DNA samples prepared from pAATL histological sections were analyzed by next-generation sequencing for the known APA-associated mutations. The mAPA-like portions from two of the three large pAATLs examined harbored mutations (KCNJ5 [p.G151R] in pAATL 3 and ATP1A1 [p.L337M] in pAATL 7), whereas their corresponding APCC-like portions did not, suggesting their role in the formation of mAPA. Another lesion carried novel mutations in ATP1A1 (p.Ile322_Ile325del and p.Ile327Ser) in both the mAPA-like and APCC-like portions, thereby supporting these portions having a clonal origin. A novel aldosterone-producing pathology, pAATL that causes unilateral PA, was detected in the adrenals of two patients. Next-generation sequencing analyses of the large pAATLs suggested that the introduction of APA-associated mutations in the ion channel/pump genes may be involved in the development of mAPA from existing APCCs.

What are the keys to successful adrenal venous sampling (AVS) in patients with primary aldosteronism?

PubMed

Young, William F; Stanson, Anthony W

2009-01-01

Adrenal venous sampling (AVS) is the criterion standard to distinguish between unilateral and bilateral adrenal disease in patients with primary aldosteronism. The keys to successful AVS include appropriate patient selection, careful patient preparation, focused technical expertise, defined protocol, and accurate data interpretation. The use of AVS should be based on patient preferences, patient age, clinical comorbidities, and the clinical probability of finding an aldosterone-producing adenoma. AVS is optimally performed in the fasting state in the morning. AVS is an intricate procedure because the right adrenal vein is small and may be difficult to locate - the success rate depends on the proficiency of the angiographer. The key factors that determine the successful catheterization of both adrenal veins are experience, dedication and repetition. With experience, and focusing the expertise to 1 or 2 radiologists at a referral centre, the AVS success rate can be as high as 96%. A centre-specific, written protocol is mandatory. The protocol should be developed by an interested group of endocrinologists, radiologists and laboratory personnel. Safeguards should be in place to prevent mislabelling of the blood tubes in the radiology suite and to prevent sample mix-up in the laboratory.

Gonadotropin-Releasing Hormone Stimulate Aldosterone Production in a Subset of Aldosterone-Producing Adenoma

PubMed Central

Kishimoto, Rui; Oki, Kenji; Yoneda, Masayasu; Gomez-Sanchez, Celso E.; Ohno, Haruya; Kobuke, Kazuhiro; Itcho, Kiyotaka; Kohno, Nobuoki

2016-01-01

Abstract We aimed to detect novel genes associated with G protein-coupled receptors (GPCRs) in aldosterone-producing adenoma (APA) and elucidate the mechanisms underlying aldosterone production. Microarray analysis targeting GPCR-associated genes was conducted using APA without known mutations (APA-WT) samples (n = 3) and APA with the KCNJ5 mutation (APA-KCNJ5; n = 3). Since gonadotropin-releasing hormone receptor (GNRHR) was the highest expression in APA-WT by microarray analysis, we investigated the effect of gonadotropin-releasing hormone (GnRH) stimulation on aldosterone production. The quantitative polymerase chain reaction assay results revealed higher GNRHR expression levels in APA-WT samples those in APA-KCNJ5 samples (P < 0.05). LHCGR levels were also significantly elevated in APA-WT samples, and there was a significant and positive correlation between GNRHR and LHCGR expression in all APA samples (r = 0.476, P < 0.05). Patients with APA-WT (n = 9), which showed higher GNRHR and LHCGR levels, had significantly higher GnRH-stimulated aldosterone response than those with APA-KCNJ5 (n = 13) (P < 0.05). Multiple regression analysis revealed that the presence of the KCNJ5 mutation was linked to GNRHR mRNA expression (β = 0.94 and P < 0.01). HAC15 cells with KCNJ5 gene carrying T158A mutation exhibited a significantly lower GNRHR expression than that in control cells (P < 0.05). We clarified increased expression of GNRHR and LHCGR in APA-WT, and the molecular analysis including the receptor expression associated with clinical findings of GnRH stimulation. PMID:27196470

Use of computed tomography in diagnosing the cause of primary aldosteronism

DOE Office of Scientific and Technical Information (OSTI.GOV)

White, E.A.; Schambelan, M.; Rost, C.R.

1980-12-25

Computed tomography (CT) was performed in 22 consecutive patients with primary aldosteronism to evaluate the usefulness of this technique in diagnosing and locating aldosterone-producing adenomas. Sixteen patients had severe hypokalemia, hyperaldosteronism, and elevated plasma levels of 18-hydroxycorticosterone suggestive of an adenoma. In 12 of these 16, a unilateral adrenal mass was demonstrated clearly, and in all 11 who had surgery an adenoma was confirmed. In the other four patients in this group, one adrenal gland was normal and the other was either not seen adequately or had minor abnormalities that could not be definitely classified; and adenoma was found inmore » the poorly visualized gland in each of the two patients who had surgery. The remaining six patients, who had milder biochemical abnormalities suggestive of idiopathic hyperaldosteronism, had bilateral adrenal enlargement or normal-appearing glands on scan and were not surgically explored.« less

The Many Faces of Primary Aldosteronism and Cushing Syndrome: A Reflection of Adrenocortical Tumor Heterogeneity.

PubMed

Mete, Ozgur; Duan, Kai

2018-01-01

Adrenal cortical tumors constitute a heterogeneous group of neoplasms with distinct clinical, morphological, and molecular features. Recent discoveries of specific genotype-phenotype correlations in adrenal cortical adenomas have transformed our understanding of their respective endocrine syndromes. Indeed, a proportion of patients with primary aldosteronism are now known to harbor adrenal cortical adenomas with heterogeneous molecular alterations ( KCNJ5, ATP1A1, ATP2B3 , and CACNA1D ) involving the calcium/calmodulin kinase signaling pathway. Several lines of evidence suggest that KCNJ5 -mutant aldosterone-producing adenomas have distinct clinicopathological phenotype compared to those harboring ATP1A1, ATP2B3 , and CACNA1D mutations. Benign adrenal cortical tumors presenting with Cushing syndrome often have diverse mutations ( PRKACA, PRKAR1A, GNAS, PDE11A , and PDE8B ) involving the cyclic AMP signaling pathway. In addition to cortisol-producing adenomas, bilateral micronodular adrenocortical disease and primary bilateral macronodular adrenal hyperplasia (PBMAH) have also expanded the spectrum of benign neoplasms causing adrenal Cushing disease. The recent discovery of inactivating ARMC5 germline mutations in PBMAH has challenged the old belief that this disorder is mainly a sporadic disease. Emerging evidence suggests that PBMAH harbors multiple distinct clonal proliferations, reflecting the heterogeneous genomic landscape of this disease. Although most solitary adrenal cortical tumors are sporadic, there is an increasing recognition that inherited susceptibility syndromes may also play a role in their pathogenesis. This review highlights the molecular and morphological heterogeneity of benign adrenal cortical neoplasms, reflected in the diverse presentations of primary aldosteronism and adrenal Cushing syndrome.

Contralateral suppression of aldosterone at adrenal venous sampling predicts hyperkalemia following adrenalectomy for primary aldosteronism.

PubMed

Shariq, Omair A; Bancos, Irina; Cronin, Patricia A; Farley, David R; Richards, Melanie L; Thompson, Geoffrey B; Young, William F; McKenzie, Travis J

2018-01-01

We aimed to determine whether a greater degree of contralateral suppression of aldosterone secretion at adrenal venous sampling predicted the development of postoperative hyperkalemia after unilateral adrenalectomy for primary aldosteronism. A retrospective analysis of patients undergoing unilateral adrenalectomy for primary aldosteronism between 2004-2015 was performed. Clinical and biochemical parameters of patients who developed hyperkalemia (≥5.2 mmol/L) after unilateral adreanlectomy were compared with those who remained normokalemic. The contralateral suppression index was defined as the aldosterone-to-cortisol ratio from the nondominant adrenal vein divided by the aldosterone-to-cortisol ratio from the external iliac vein. Of 192 patients who met criteria for inclusion, 12 (6.3%) developed hyperkalemia (median serum potassium 5.5 mmol/L, range 5.2-6.2 mmol/L), with a median time to onset of 13.5 days (range 7-55 days). Five patients had transiently increased serum potassium concentrations that normalized spontaneously. Four patients received mineralocorticoid replacement therapy with fludrocortisone. On univariate analysis, hyperkalemic patients had slightly greater preoperative serum creatinine levels (1.2 vs 1.0 mg/dL, P = .01), higher postoperative creatinine (1.3 vs 1.0 mg/dL, P = .02), lesser median contralateral suppression index (0.14 vs 0.27, P = .03), and larger adenomas (1.9 vs 1.4 cm, P = .02). On multivariable logistic regression, the contralateral suppression index remained the only significant predictor of postoperative hyperkalemia (P = .04) with an optimal cut-off of <0.47. Hyperkalemia after unilateral adrenalectomy for primary aldosteronism is uncommon and usually transient, but may require mineralocorticoid supplementation. Patients with a contralateral suppression index of <0.47 require meticulous follow-up and monitoring of serum potassium concentrations after unilateral adrenalectomy. Copyright © 2017

Adrenal venous sampling for stratifying patients for surgery of adrenal nodules detected using dynamic contrast enhanced CT

PubMed Central

Kim, Jin Young; Kim, See Hyung; Lee, Hee Jung; Kim, Young Hwan; Kim, Mi Jeong; Cho, Seung Hyun

2014-01-01

PURPOSE We aimed to assess the value of adrenal venous sampling (AVS) for diagnosing primary aldosteronism (PA) subtypes in patients with a unilateral nodule detected on adrenal computed tomography (CT) and scheduled for adrenalectomy. MATERIALS AND METHODS This retrospective study included 80 consecutive patients with PA undergoing CT and AVS. Different lateralization indices were assessed, and a cutoff established using receiver operating characteristic curve analysis. The value of CT alone versus CT with AVS for differentiating PA subtypes was compared. The adrenalectomy outcome was assessed, and predictors of cure were determined using univariate analysis. RESULTS AVS was successful in 68 patients. A cortisol-corrected aldosterone affected-to-unaffected ratio cutoff of 2.0 and affected-to-inferior vena cava ratio cutoff of 1.4 were the best lateralization indices, with accuracies of 82.5% and 80.4%, respectively. CT and AVS diagnosed 38 patients with aldosterone-producing adenomas, five patients with unilateral adrenal hyperplasia, and 25 patients with bilateral adrenal hyperplasia. Of the 52 patients with a nodule detected on CT, subsequent AVS diagnosed bilateral adrenal hyperplasia in 14 patients (27%). Compared to the results of combining CT with AVS, the accuracy of CT alone for diagnosing aldosterone-producing adenomas was 71.1% (P < 0.001). The cure rate for hypertension after adrenalectomy was 39.2%, with improvement in 53.5% of patients. On univariate analysis, predictors of persistent hypertension were male gender and preoperative systolic blood pressure. CONCLUSION To avoid inappropriate surgery, AVS is necessary for diagnosing unilateral nodules with aldosterone hypersecretion detected by CT. PMID:24047720

Regulation of aldosterone production by ion channels: From basal secretion to primary aldosteronism.

PubMed

Yang, Tingting; He, Min; Hu, Changlong

2018-03-01

Aldosterone is produced by zona glomerulosa (ZG) cells of the adrenal cortex and plays a key role in balancing water and electrolytes levels. Autonomous overproduction of aldosterone leads to primary aldosteronism (PA), which is the most common form of secondary endocrine hypertension. Recently, significant progress has been made towards understanding the genetic basis of PA, where increasing clinical evidence suggests that mutations in ion channels appear to be the major cause of aldosterone-producing adenomas. In this review, we focused on potassium and calcium channels that regulate aldosterone secretion, and their roles in the pathology of PA. Because potassium and calcium channels are differentially expressed in ZG cells in different species of mammals, the limitations of published studies are also discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

An occult aldosterone-producing adenoma initially presenting as hyperosmolar hyperglycaemic state.

PubMed

Kuo, Feng-Chih; Hung, Yi-Jen; Hsieh, Chang-Hsun; Hsiao, Fone-Ching

2012-09-01

Aldosterone-producing adenoma (APA), one of the most common causes of primary hyperaldosteronism, is clinically characterized by hypertension, increased sodium retention, increased potassium excretion and altered glucose metabolism. APA can also manifest in the form of hyperosmolar hyperglycaemic state (HHS), which is a life-threatening acute diabetic complication. Infection and inadequate fluid replacement are the common precipitating and predisposing factors for the occurrence of HHS. Here, we report a case of occult APA with the initial presentation of HHS, in which an unusually rapid correction of diabetes was observed after correct diagnosis and surgical resection of the APA. To our knowledge, this is the first case with such manifestations and outcome.

Inflammation and Fibrosis in Perirenal Adipose Tissue of Patients With Aldosterone-Producing Adenoma.

PubMed

Wu, Chunyan; Zhang, Huijian; Zhang, Jiajun; Xie, Cuihua; Fan, Cunxia; Zhang, Hongbin; Wu, Peng; Wei, Qiang; Tan, Wanlong; Xu, Lingling; Wang, Ling; Xue, Yaoming; Guan, Meiping

2018-01-01

The prevalence of primary aldosteronism is much higher than previously thought. Recent studies have shown that primary aldosteronism is related to a higher risk of cardiovascular events. However, the underlying mechanism is not yet clear. Here we investigate the characteristics, including inflammation, fibrosis, and adipokine expression, of adipose tissues from different deposits in patients with aldosterone-producing adenoma (APA). Inflammation and fibrosis changes were evaluated in perirenal and subcutaneous adipose tissues obtained from patients with APA (n = 16), normotension (NT; n = 10), and essential hypertension (EH; n = 5) undergoing laparoscopic surgery. We also evaluated the effect of aldosterone in isolated human perirenal adipose tissue stromal vascular fraction (SVF) cells and investigated the effect of aldosterone in mouse 3T3-L1 and brown preadipocytes. Compared with the EH group, significantly higher levels of interleukin-6 (IL-6) and tumor necrosis factor-α messenger RNA (mRNA) and protein were observed in perirenal adipose tissue of patients with APA. Expression of genes related to fibrosis and adipogenesis in perirenal adipose tissue was notably higher in patients with APA than in patients with NT and EH. Aldosterone significantly induced IL-6 and fibrosis gene mRNA expression in differentiated SVF cells. Aldosterone treatment enhanced mRNA expression of genes associated with inflammation and fibrosis and stimulated differentiation of 3T3-L1 and brown preadipocytes. In conclusion, these data indicate that high aldosterone in patients with APA may induce perirenal adipose tissue dysfunction and lead to inflammation and fibrosis, which may be involved in the high risk of cardiovascular events observed in patients with primary aldosteronism. Copyright © 2018 Endocrine Society.

8D.04: CLINICAL BENEFITS OF ADMINISTERING SUPER-SELECTIVE SEGMENTAL ADRENAL VENOUS SAMPLING AND PERFORMING ADRENAL SPARING SURGERY IN THE PATIENTS WITH PRIMARY ALDOSTERONISM.

PubMed

Satoh, F; Morimoto, R; Ono, Y; Iwakura, Y; Omata, K; Kudo, M; Satani, N; Ota, H; Seiji, K; Takase, K; Nakamura, Y; Sasano, H; Ito, S

2015-06-01

Adrenal venous sampling (AVS) has been well known to play pivotal roles in clinical differential diagnosis of unilateral aldosterone producing adenoma (APA) from bilateral idiopathic hyperaldosteronism (IHA). However, it is also true that a central vein AVS or c-AVS which collects the blood from right and left central adrenal veins can by no means discriminate bilateral APA from BHA. There have been no published studies reporting the reliable clinical differential diagnosis between bilateral APA and IHA, especially IHA cases with bilateral non-functioning adenomas (NFA), which has been considered practically impossible in clinical differential diagnosis. As an attempt to this clinical dilemma, segmental AVS (S-AVS), which could evaluate segmental effluents from adrenal tributary veins, has been recently developed. We have performed S-AVS in these patients above following C-AVS, via the insertion of a microcatheter in up to three intra-adrenal first-degree tributary veins on bilateral adrenals. S-AVS did enable us to evaluate the intra-adrenal localization of corticosteroidogenesis. These data did indicate that S-AVS should be performed in the PA patients who had increased aldosterone levels in bilateral central vein and demonstrated space occupying lesions in the bilateral adrenals in order to avoid bilateral adrenalectomy or long lasting medical treatment toward persistent PA. In addition to the situations above, we have administere S-AVS to the following patients; those who had clinically suspected APA but not sufficiently high lateralization indexes according to the results of C-AVS, very young ones with higher clinical probability of recurrence and those who could benefit from partial adrenalectomy by demonstrating the sites of specific steroidogenesis. However, it is also entirely true that S-AVS is more expensive, time-consuming and labor-intensive compared to C-AVS.(Figure is included in full-text article.)The angiography during S-AVS (A, B), the coronal CT

Adrenal venous sampling in primary aldosteronism: multinomial regression modeling to detect aldosterone secretion lateralization when right adrenal sampling is missing.

PubMed

Durivage, Camille; Blanchette, Rémi; Soulez, Gilles; Chagnon, Miguel; Gilbert, Patrick; Giroux, Marie-France; Bourdeau, Isabelle; Oliva, Vincent L; Lacroix, André; Therasse, Eric

2017-02-01

Difficulty to recognize or canulate the right adrenal vein is the most frequent cause of adrenal venous sampling (AVS) failure. We aimed to assess multinomial regression modeling (MRM) of peripheral and left adrenal vein samplings to detect lateralization of aldosterone secretion when the right AVS is missing. Simultaneous bilateral AVS samplings were performed before (basal) and after intravenous cosyntropin injection in 188 consecutive patients between December 1989 and September 2015. Different reference standards for lateralization of aldosterone secretion were defined for basal and for postcosyntropin AVS and according to lateralization index cutoffs at least 2 and at least 4. MRMs were built to detect lateralization of aldosterone secretion according to these reference standards using only peripheral and left adrenal veins samplings (without the right AVS). Detection accuracy was assessed by the area under the receiver operating characteristic (AUROC) curves and detection sensitivities were reported for specificity at least 95%. For basal AVS with lateralization index at least 2, AUROC were respectively 0.931 [95% confidence interval (CI) 0.894-0.968] and 0.922 (95% CI 0.882-0.962) for right and left lateralization of aldosterone secretion detection and MRM could detect respectively 65.5 and 62.7% of the right and left lateralization of aldosterone secretion. For AVS after cosyntropin with lateralization index at least 4, AUROC were respectively 0.964 (95% CI: 0.940-0.987) and 0.955 (95% CI: 0.927-0.983) for right and left lateralization of aldosterone secretion, and MRM could detect respectively 77.2 and 72.9% of the right and left lateralization of aldosterone secretion. MRM can detect lateralization of aldosterone secretion without the right AVS in most patients and could eliminate the need for repeat AVS when right adrenal vein canulation is nonselective or impossible.

Quantitative Value of Aldosterone-Renin Ratio for Detection of Aldosterone-Producing Adenoma: The Aldosterone-Renin Ratio for Primary Aldosteronism (AQUARR) Study.

PubMed

Maiolino, Giuseppe; Rossitto, Giacomo; Bisogni, Valeria; Cesari, Maurizio; Seccia, Teresa Maria; Plebani, Mario; Rossi, Gian Paolo

2017-05-21

Current guidelines recommend use of the aldosterone-renin ratio (ARR) for the case detection of primary aldosteronism followed by confirmatory tests to exclude false-positive results from further diagnostic workup. We investigated the hypothesis that this could be unnecessary in patients with a high ARR value if the quantitative information carried by the ARR is taken into due consideration. We interrogated 2 large data sets of prospectively collected patients studied with the same predefined protocol, which included the captopril challenge test. We used an unambiguous diagnosis of aldosterone-producing adenoma as reference index. We also assessed whether the post-captopril ARR and plasma aldosterone concentration fall furnished a diagnostic gain over baseline ARR values. We found that the false-positive rate fell exponentially, and, conversely, the specificity increased with rising ARR values. At receiver operating characteristics curves and diagnostic odds ratio analysis, the high baseline ARR values implied very high positive likelihood ratio and diagnostic odds ratio values. The baseline and post-captopril ARR showed similar diagnostic accuracy (area under the receiver operating characteristics curve) in both the exploratory and validation cohorts, indicating lack of diagnostic gain with this confirmatory test (between-area under the curve difference, 0.005; 95% CI, -0.031 to 0.040; P =0.7 for comparison, and 0.05; 95% CI, -0.061 to 0.064; P =0.051 for comparison, respectively). These results indicate that the ARR conveys key quantitative information that, if properly used, can simplify the diagnostic workup, resulting in saving of money and resources. This can offer the chance of diagnosis and ensuing adrenalectomy to a larger number of hypertensive patients, ultimately resulting in better control of blood pressure. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Dysregulation of Aldosterone Secretion in Mast Cell-Deficient Mice.

PubMed

Boyer, Hadrien-Gaël; Wils, Julien; Renouf, Sylvie; Arabo, Arnaud; Duparc, Céline; Boutelet, Isabelle; Lefebvre, Hervé; Louiset, Estelle

2017-12-01

Resident adrenal mast cells have been shown to activate aldosterone secretion in rat and man. Especially, mast cell proliferation has been observed in adrenal tissues from patients with aldosterone-producing adrenocortical adenoma. In the present study, we show that the activity of adrenal mast cells is stimulated by low-sodium diet and correlates with aldosterone synthesis in C57BL/6 and BALB/c mice. We have also investigated the regulation of aldosterone secretion in mast cell-deficient C57BL/6 Kit W-sh/W-sh mice in comparison with wild-type C57BL/6 mice. Kit W-sh/W-sh mice submitted to normal sodium diet had basal plasma aldosterone levels similar to those observed in wild-type animals. Conversely, low-sodium diet unexpectedly induced an exaggerated aldosterone response, which seemed to result from an increase in adrenal renin and angiotensin type 1 receptor expression. Severe hyperaldosteronism was associated with an increase in systolic blood pressure and marked hypokalemia, which favored polyuria. Adrenal renin and angiotensin type 1 receptor overexpression may represent a compensatory mechanism aimed at activating aldosterone production in the absence of mast cells. Finally, C57BL/6 Kit W-sh/W-sh mice represent an unexpected animal model of primary aldosteronism, which has the particularity to be triggered by sodium restriction. © 2017 American Heart Association, Inc.

Adrenal vein sampling versus CT scan to determine treatment in primary aldosteronism: an outcome-based randomised diagnostic trial.

PubMed

Dekkers, Tanja; Prejbisz, Aleksander; Kool, Leo J Schultze; Groenewoud, Hans J M M; Velema, Marieke; Spiering, Wilko; Kołodziejczyk-Kruk, Sylwia; Arntz, Mark; Kądziela, Jacek; Langenhuijsen, Johannes F; Kerstens, Michiel N; van den Meiracker, Anton H; van den Born, Bert-Jan; Sweep, Fred C G J; Hermus, Ad R M M; Januszewicz, Andrzej; Ligthart-Naber, Alike F; Makai, Peter; van der Wilt, Gert-Jan; Lenders, Jacques W M; Deinum, Jaap

2016-09-01

The distinction between unilateral aldosterone-producing adenoma or bilateral adrenal hyperplasia as causes of primary aldosteronism is usually made by adrenal CT or by adrenal vein sampling (AVS). Whether CT or AVS represents the best test for diagnosis remains unknown. We aimed to compare the outcome of CT-based management with AVS-based management for patients with primary aldosteronism. In a randomised controlled trial, we randomly assigned patients with aldosteronism to undergo either adrenal CT or AVS to determine the presence of aldosterone-producing adenoma (with subsequent treatment consisting of adrenalectomy) or bilateral adrenal hyperplasia (subsequent treatment with mineralocorticoid receptor antagonists). The primary endpoint was the intensity of drug treatment for obtaining target blood pressure after 1 year of follow-up, in the intention-to-diagnose population. Intensity of drug treatment was expressed as daily defined doses. Key secondary endpoints included biochemical outcome in patients who received adrenalectomy, health-related quality of life, cost-effectiveness, and adverse events. This trial is registered with ClinicalTrials.gov, number NCT01096654. We recruited 200 patients between July 6, 2010, and May 30, 2013. Of the 184 patients that completed follow-up, 92 received CT-based treatment (46 adrenalectomy and 46 mineralocorticoid receptor antagonist) and 92 received AVS-based treatment (46 adrenalectomy and 46 mineralocorticoid receptor antagonist). We found no differences in the intensity of antihypertensive medication required to control blood pressure between patients with CT-based treatment and those with AVS-based treatment (median daily defined doses 3·0 [IQR 1·0-5·0] vs 3·0 [1·1-5·9], p=0·52; median number of drugs 2 [IQR 1-3] vs 2 [1-3], p=0·87). Target blood pressure was reached in 39 (42%) patients and 41 (45%) patients, respectively (p=0·82). On secondary endpoints we found no differences in health-related quality of

SFE/SFHTA/AFCE consensus on primary aldosteronism, part 4: Subtype diagnosis.

PubMed

Bardet, Stéphane; Chamontin, Bernard; Douillard, Claire; Pagny, Jean-Yves; Hernigou, Anne; Joffre, Francis; Plouin, Pierre-François; Steichen, Olivier

2016-07-01

To establish the cause of primary aldosteronism (PA), it is essential to distinguish unilateral from bilateral adrenal aldosterone secretion, as adrenalectomy improves aldosterone secretion and controls hypertension and hypokalemia only in the former. Except in the rare cases of type 1 or 3 familial hyperaldosteronism, which can be diagnosed genetically and are not candidates for surgery, lateralized aldosterone secretion is diagnosed on adrenal CT or MRI and adrenal venous sampling. Postural stimulation tests and (131)I-norcholesterol scintigraphy have poor diagnostic value and (11)C-metomidate PET is not yet available. We recommend that adrenal CT or MRI be performed in all cases of PA. Imaging may exceptionally identify adrenocortical carcinoma, for which the surgical objectives are carcinologic, and otherwise shows either normal or hyperplastic adrenals or unilateral adenoma. Imaging alone carries a risk of false positives in patients over 35 years of age (non-aldosterone-secreting adenoma) and false negatives in all patients (unilateral hyperplasia). We suggest that all candidates for surgery over 35 years of age undergo adrenal venous sampling, simultaneously in both adrenal veins, without ACTH stimulation, to confirm the unilateral form of the hypersecretion. Sampling results should be confirmed on adrenal vein cortisol assay showing a concentration at least double that found in peripheral veins. Aldosterone secretion should be considered lateralized when aldosterone/cortisol ratio on the dominant side is at least 4-fold higher than contralaterally. Published by Elsevier Masson SAS.

The Occurrence of Apparent Bilateral Aldosterone Suppression in Adrenal Vein Sampling for Primary Aldosteronism

PubMed Central

Shibayama, Yui; Wada, Norio; Naruse, Mitsuhide; Kurihara, Isao; Ito, Hiroshi; Yoneda, Takashi; Takeda, Yoshiyu; Umakoshi, Hironobu; Tsuiki, Mika; Ichijo, Takamasa; Fukuda, Hisashi; Katabami, Takuyuki; Yoshimoto, Takanobu; Ogawa, Yoshihiro; Kawashima, Junji; Ohno, Yuichi; Sone, Masakatsu; Fujita, Megumi; Takahashi, Katsutoshi; Shibata, Hirotaka; Kamemura, Kohei; Fujii, Yuichi; Yamamoto, Koichi; Suzuki, Tomoko

2018-01-01

Abstract Context In adrenal venous sampling (AVS) for patients with primary aldosteronism (PA), apparent bilateral aldosterone suppression (ABAS), defined as lower aldosterone/cortisol ratios in the bilateral adrenal veins than that in the inferior vena cava, is occasionally experienced. ABAS is uninterpretable with respect to lateralization of excess aldosterone production. We previously reported that ABAS was not a rare phenomenon and was significantly reduced after adrenocorticotropic hormone (ACTH) administration. Objective To validate the effects of ACTH administration and adding sampling positions in the left adrenal vein on the prevalence of ABAS in the larger Japan Primary Aldosteronism Study. Patients The data from 1689 patients with PA who underwent AVS between January 2006 and October 2016 were studied. All patients in the previous study, the West Japan Adrenal Vein Sampling study, were excluded. Outcome Measurements The prevalence of ABAS was investigated at two sampling positions in the left adrenal vein, the central vein and the common trunk, without and with ACTH administration. Results The prevalence of ABAS with ACTH administration was significantly lower than that without ACTH administration [without ACTH vs with ACTH: 79/440 (18.0%) vs 45/591 (7.6%); P < 0.001]. With ACTH administration, the prevalence of ABAS was not different between the sampling position, at the central vein and at the common trunk [33/591 (5.6%) vs 32/591 (5.4%); P = 1.00]. Conclusions The effectiveness of ACTH administration for the reduction of ABAS in AVS regardless of the sampling position in the left adrenal vein was confirmed in the larger cohort. PMID:29687091

Overview of aldosterone-related genetic syndromes and recent advances.

PubMed

Zennaro, Maria-Christina; Fernandes-Rosa, Fabio L; Boulkroun, Sheerazed

2018-06-01

Primary aldosteronism is the most common form of secondary hypertension. Early diagnosis and treatment are key to cure of hypertension and prevention of cardiovascular complications. Recent genetic discoveries have improved our understanding on the pathophysiology of aldosterone production and triggered the development of new diagnostic procedures and targeted treatments for primary aldosteronism. Different inherited genetic abnormalities distinguish specific forms of familial hyperaldosteronism. Somatic mutations are found not only in aldosterone-producing adenoma (APA), leading to primary aldosteronism, but also in aldosterone producing cell clusters of normal and micronodules from image-negative adrenal glands. Genetic knowledge has allowed the discovery of surrogate biomarkers and specific pharmacological inhibitors. Ageing appears to be associated with dysregulated and relatively autonomous aldosterone production. New biochemical markers and pharmacological approaches may allow preoperative identification of somatic mutation carriers and use of targeted treatments.

Impact of aldosterone-producing cell clusters on diagnostic discrepancies in primary aldosteronism

PubMed Central

Kometani, Mitsuhiro; Yoneda, Takashi; Aono, Daisuke; Karashima, Shigehiro; Demura, Masashi; Nishimoto, Koshiro; Yamagishi, Masakazu; Takeda, Yoshiyu

2018-01-01

Adrenocorticotropic hormone (ACTH) stimulation is recommended in adrenal vein sampling (AVS) for primary aldosteronism (PA) to improve the AVS success rate. However, this method can confound the subtype diagnosis. Gene mutations or pathological characteristics may be related to lateralization by AVS. This study aimed to compare the rate of diagnostic discrepancy by AVS pre- versus post-ACTH stimulation and to investigate the relationship between this discrepancy and findings from immunohistochemical and genetic analyses of PA. We evaluated 195 cases of AVS performed in 2011–2017. All surgical specimens were analyzed genetically and immunohistochemically. Based on the criteria, AVS was successful in 158 patients both pre- and post-ACTH; of these patients, 75 showed diagnostic discrepancies between pre- and post-ACTH. Thus, 19 patients underwent unilateral adrenalectomy, of whom 16 had an aldosterone-producing adenoma (APA) that was positive for CYP11B2 immunostaining. Of them, 10 patients had discordant lateralization between pre- and post-ACTH. In the genetic analysis, the rate of somatic mutations was not significantly different between APA patients with versus without a diagnostic discrepancy. In the immunohistochemical analysis, CYP11B2 levels and the frequency of aldosterone-producing cell clusters (APCCs) in APAs were almost identical between patients with versus without a diagnostic discrepancy. However, both the number and summed area of APCCs in APAs were significantly smaller in patients with concordant results than in those whose diagnosis changed to bilateral PA post-ACTH stimulation. In conclusion, lateralization by AVS was affected by APCCs in the adjacent gland, but not by APA-related factors such as somatic gene mutations. PMID:29899838

Primary aldosteronism: diagnosis and treatment.

PubMed

Pimenta, Eduardo; Calhoun, David A

2006-12-01

Recent studies have indicated a higher prevalence of primary aldosteronism (PA) than reported historically. Aldosterone excess induces sodium and fluid retention with consequential increases in blood pressure. Patients with PA are at an increased risk of developing left ventricular hypertrophy, chronic kidney disease, and endothelial dysfunction. Measurement of the plasma aldosterone/plasma renin activity ratio is an effective screening test for PA. The majority of patients with PA do not have a discernable aldosterone-producing adenoma (APA), and the aldosterone excess is considered idiopathic in etiology and/or attributed to adrenal hyperplasia. Treatment of PA includes medical therapy with mineralocorticoid receptor antagonists and adrenalectomy for patients with a unilateral APA. A reasonable treatment strategy is to attempt medical therapy in all patients with a high plasma aldosterone/PRA ratio and reserve the extensive workup needed to identify an APA for those patients whose hypertension or hypokalemia cannot be controlled medically.

Renin knockout rat: control of adrenal aldosterone and corticosterone synthesis in vitro and adrenal gene expression

PubMed Central

Gehrand, Ashley; Bruder, Eric D.; Hoffman, Matthew J.; Engeland, William C.; Moreno, Carol

2014-01-01

The classic renin-angiotensin system is partly responsible for controlling aldosterone secretion from the adrenal cortex via the peptide angiotensin II (ANG II). In addition, there is a local adrenocortical renin-angiotensin system that may be involved in the control of aldosterone synthesis in the zona glomerulosa (ZG). To characterize the long-term control of adrenal steroidogenesis, we utilized adrenal glands from renin knockout (KO) rats and compared steroidogenesis in vitro and steroidogenic enzyme expression to wild-type (WT) controls (Dahl S rat). Adrenal capsules (ZG; aldosterone production) and subcapsules [zona reticularis/fasciculata (ZFR); corticosterone production] were separately dispersed and studied in vitro. Plasma renin activity and ANG II concentrations were extremely low in the KO rats. Basal and cAMP-stimulated aldosterone production was significantly reduced in renin KO ZG cells, whereas corticosterone production was not different between WT and KO ZFR cells. As expected, adrenal renin mRNA expression was lower in the renin KO compared with the WT rat. Real-time PCR and immunohistochemical analysis showed a significant decrease in P450aldo (Cyp11b2) mRNA and protein expression in the ZG from the renin KO rat. The reduction in aldosterone synthesis in the ZG of the renin KO adrenal seems to be accounted for by a specific decrease in P450aldo and may be due to the absence of chronic stimulation of the ZG by circulating ANG II or to a reduction in locally released ANG II within the adrenal gland. PMID:25394830

Adrenal Venous Sampling: Where Is the Aldosterone Disappearing to?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Solar, Miroslav; Ceral, Jiri, E-mail: ceral.jiri@fnhk.c; Krajina, Antonin

Adrenal venous sampling (AVS) is generally considered to be the gold standard in distinguishing unilateral and bilateral aldosterone hypersecretion in primary hyperaldosteronism. However, during AVS, we noticed a considerable variability in aldosterone concentrations among samples thought to have come from the right adrenal glands. Some aldosterone concentrations in these samples were even lower than in samples from the inferior vena cava. We hypothesized that the samples with low aldosterone levels were unintentionally taken not from the right adrenal gland, but from hepatic veins. Therefore, we sought to analyze the impact of unintentional cannulation of hepatic veins on AVS. Thirty consecutivemore » patients referred for AVS were enrolled. Hepatic vein sampling was implemented in our standardized AVS protocol. The data were collected and analyzed prospectively. AVS was successful in 27 patients (90%), and hepatic vein cannulation was successful in all procedures performed. Cortisol concentrations were not significantly different between the hepatic vein and inferior vena cava samples, but aldosterone concentrations from hepatic venous blood (median, 17 pmol/l; range, 40-860 pmol/l) were markedly lower than in samples from the inferior vena cava (median, 860 pmol/l; range, 460-4510 pmol/l). The observed difference was statistically significant (P < 0.001). Aldosterone concentrations in the hepatic veins are significantly lower than in venous blood taken from the inferior vena cava. This finding is important for AVS because hepatic veins can easily be mistaken for adrenal veins as a result of their close anatomic proximity.« less

Role of radiology in the management of primary aldosteronism.

PubMed

Patel, Shilpan M; Lingam, Ravi K; Beaconsfield, Tina I; Tran, Tan L; Brown, Beata

2007-01-01

The diagnosis of primary aldosteronism, the most common form of secondary hypertension, is based on clinical and biochemical features. Although radiology plays no role in the initial diagnosis, it has an important role in differentiating between the two main causes of primary aldosteronism: aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH). This distinction is important because APAs are generally managed surgically and BAH medically. Adrenal venous sampling is considered the standard of reference for determining the cause of primary aldosteronism but is technically demanding, operator dependent, costly, and time consuming, with a low but significant complication rate. Other imaging modalities, including computed tomography, magnetic resonance imaging, and adrenal scintigraphy, have also been used to determine the cause of primary aldosteronism. Cross-sectional imaging has traditionally focused on establishing the diagnosis of an APA, with that of BAH being one of exclusion. A high specificity for detecting an APA is desirable, since it will avert unnecessary surgery in patients with BAH. However, an overreliance on cross-sectional imaging can lead to the incorrect treatment of affected patients, mainly due to the wide variation in the reported diagnostic performance of these modalities. A combination of modalities is usually required to confidently determine the cause of primary aldosteronism. The quest for optimal radiologic management of primary aldosteronism continues just over a half century since this disease entity was first described. RSNA, 2007

Activity of [des-Aspartyl1]-Angiotensin II in Primary Aldosteronism

PubMed Central

Carey, Robert M.; Ayers, Carlos R.; Vaughan, E. Darracott; Peach, Michael J.; Herf, Steven M.

1979-01-01

This study describes the effects of [des-Aspartyl1]-angiotensin II ([des-Asp]-AII) on blood pressure and aldosterone production in patients with primary aldosteronism due to aldosterone-producing adrenal adenoma (APA) and idiopathic adrenal hyperplasia (IHA), and in normotensive control subjects. 10 patients with primary aldosteronism, 7 with APA and 3 with IHA, and 6 normotensive control subjects were placed on a constant 150-meq sodium diet for 4 days. [des-Asp]-AII was infused for 30 min at 6, 12, and 18 pmol/kg per min. Three groups of patients were identified on the basis of aldosterone response to [des-Asp]-AII. Group I, composed of normotensive control subjects, showed incremental increases in plasma aldosterone concentration from 6±1 to 14±3 ng/100 ml (P < 0.01) with [des-Asp]-AII infusion. Group II, composed of patients with primary aldosteronism, showed incremental increases in plasma aldosterone concentration from 33±8 to 65±13 ng/100 ml (P < 0.05) with 12 pmol/kg per min of [des-Asp]-AII. Group III, also composed of patients with primary aldosteronism, showed no increase of plasma aldosterone concentration with [des-Asp]-AII. Groups I and II showed similar percentage increases in plasma aldosterone concentration (P = NS). Group III showed significantly lower aldosterone responses than group I (P < 0.01). Group II included all patients with IHA and two patients with APA. Group III included only patients with APA. The blood pressure responses to [des-Asp]-AII of subjects in group I did not differ significantly from those of groups II or III. Thus, patients with IHA and a subgroup of patients with APA showed responsiveness to [des-Asp]-AII which was limited to adrenal cortical stimulation of aldosterone biosynthesis. This suggests that adrenal responsiveness to angiotensin is a major control mechanism in some forms of primary aldosteronism. The differential adrenal responsiveness to [des-Asp]-AII in patients with APA indicates either that there are two

Prevalence and Characterization of Somatic Mutations in Chinese Aldosterone-Producing Adenoma Patients

PubMed Central

Wang, Baojun; Li, Xintao; Zhang, Xu; Ma, Xin; Chen, Luyao; Zhang, Yu; Lyu, Xiangjun; Tang, Yuzhe; Huang, Qingbo; Gao, Yu; Fan, Yang; Ouyang, Jinzhi

2015-01-01

Abstract Recently somatic mutations of KCNJ5, ATP1A1, ATP2B3, and CACNA1D have been identified in patients with aldosterone-producing adenoma (APA). The present study sequenced the DNA in the tissues and blood samples from Chinese patients with APA for KCNJ5, ATP1A1, ATP2B3, and CACNA1D gene mutations. Among the 114 patients, 86 (75.4%) were identified with KCNJ5 somatic mutations, including 3 previously reported (G151R, L168R, T158A) and 2 other unreported mutations. One patient presented with both a point mutation (E147) and an insertion mutation, whereas another had a 36-base duplication, G153_G164dup. No mutation of ATP1A1 and ATP2B3 in the known hotspots was identified and only 1 male patient was detected with a novel CACNA1D mutation, V748I. Unlike other studies, male and female patients had similar KCNJ5 mutation rates (76.9% vs 74.2%). Mutation carriers were younger and had lower preoperative potassium level, whereas male (but not female) mutation carriers had higher preoperative plasma aldosterone concentration and preoperative blood pressures. Mutation carriers also had higher LV mass index (LVMI) than nonmutation carriers. After surgery, LVMI improved significantly in the KCNJ5 mutation group but not in the nonmutation group. The mRNA expression of KCNJ5, CYP11B2, and ATP2B3 was higher in the KCNJ5-mutated APA tissues. Functional characterization of the 2 novel KCNJ5 mutations showed that they were associated with decreased proliferation, membrane depolarization, elevated secretion of aldosterone, and increased expression of CYP11B1 and CYP11B2. In conclusion, Chinese APA patients appear to have a high frequency of somatic KCNJ5 mutation. Mutation prevalence rates are similar among men and women and 2 novel mutations are identified. KCNJ5-mutated patients benefit more from surgical resection of APA than nonmutated patients. PMID:25906099

Aldosterone hypersecretion in “non-salt-losing” congenital adrenal hyperplasia

PubMed Central

Bartter, Frederic C.; Henkin, Robert I.; Bryan, George T.

1968-01-01

Patients with the “non-salt-losing” form of the adrenogenital syndrome were studied before and after suppression of adrenal cortical activity with carbohydrate-active steroids. The response of aldosterone secretion to sodium deprivation was measured; in some patients response to adrenocorticotropic hormone (ACTH) was measured as well. The aldosterone secretion was normal and responded normally to sodium deprivation in all patients studied during suppression with carbohydrate-active steroids. This finding suggests that 21-hydroxylation of progesterone is normal in this syndrome. The sole abnormality in the production of aldosterone in these patients was found to be excessive secretion of aldosterone while they were not receiving suppressive doses of carbohydrate-active steroids. This finding strongly supports the view that the biogenetic pathways through which aldosterone is produced from progesterone are intact in this syndrome. No patient showed hypertension or hypokalemic alkalosis despite very high aldosterone secretion rates. This observation suggests that the hyper-aldosteronism is secondary to a tendency to sodium loss in the patient whose ACTH production is not suppressed. These studies provide additional evidence in support of the hypothesis that the salt-losing and “non-salt-losing” forms of adrenogenital syndrome are genetically and biochemically distinct. PMID:4299011

ADC histogram analysis for adrenal tumor histogram analysis of apparent diffusion coefficient in differentiating adrenal adenoma from pheochromocytoma.

PubMed

Umanodan, Tomokazu; Fukukura, Yoshihiko; Kumagae, Yuichi; Shindo, Toshikazu; Nakajo, Masatoyo; Takumi, Koji; Nakajo, Masanori; Hakamada, Hiroto; Umanodan, Aya; Yoshiura, Takashi

2017-04-01

To determine the diagnostic performance of apparent diffusion coefficient (ADC) histogram analysis in diffusion-weighted (DW) magnetic resonance imaging (MRI) for differentiating adrenal adenoma from pheochromocytoma. We retrospectively evaluated 52 adrenal tumors (39 adenomas and 13 pheochromocytomas) in 47 patients (21 men, 26 women; mean age, 59.3 years; range, 16-86 years) who underwent DW 3.0T MRI. Histogram parameters of ADC (b-values of 0 and 200 [ADC 200 ], 0 and 400 [ADC 400 ], and 0 and 800 s/mm 2 [ADC 800 ])-mean, variance, coefficient of variation (CV), kurtosis, skewness, and entropy-were compared between adrenal adenomas and pheochromocytomas, using the Mann-Whitney U-test. Receiver operating characteristic (ROC) curves for the histogram parameters were generated to differentiate adrenal adenomas from pheochromocytomas. Sensitivity and specificity were calculated by using a threshold criterion that would maximize the average of sensitivity and specificity. Variance and CV of ADC 800 were significantly higher in pheochromocytomas than in adrenal adenomas (P < 0.001 and P = 0.001, respectively). With all b-value combinations, the entropy of ADC was significantly higher in pheochromocytomas than in adrenal adenomas (all P ≤ 0.001), and showed the highest area under the ROC curve among the ADC histogram parameters for diagnosing adrenal adenomas (ADC 200 , 0.82; ADC 400 , 0.87; and ADC 800 , 0.92), with sensitivity of 84.6% and specificity of 84.6% (cutoff, ≤2.82) with ADC 200 ; sensitivity of 89.7% and specificity of 84.6% (cutoff, ≤2.77) with ADC 400 ; and sensitivity of 94.9% and specificity of 92.3% (cutoff, ≤2.67) with ADC 800 . ADC histogram analysis of DW MRI can help differentiate adrenal adenoma from pheochromocytoma. 3 J. Magn. Reson. Imaging 2017;45:1195-1203. © 2016 International Society for Magnetic Resonance in Medicine.

GENETICS IN ENDOCRINOLOGY: The expanding genetic horizon of primary aldosteronism.

PubMed

Monticone, Silvia; Buffolo, Fabrizio; Tetti, Martina; Veglio, Franco; Pasini, Barbara; Mulatero, Paolo

2018-03-01

Aldosterone is the main mineralocorticoid hormone in humans and plays a key role in maintaining water and electrolyte homeostasis. Primary aldosteronism (PA), characterized by autonomous aldosterone overproduction by the adrenal glands, affects 6% of the general hypertensive population and can be either sporadic or familial. Aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH) are the two most frequent subtypes of sporadic PA and 4 forms of familial hyperaldosteronism (FH-I to FH-IV) have been identified. Over the last six years, the introduction of next-generation sequencing has significantly improved our understanding of the molecular mechanisms responsible for autonomous aldosterone overproduction in both sporadic and familial PA. Somatic mutations in four genes ( KCNJ5, ATP1A1, ATP2B3 and CACNA1D ), differently implicated in intracellular ion homeostasis, have been identified in nearly 60% of the sporadic APAs. Germline mutations in KCNJ5 and CACNA1H cause FH-III and FH-IV, respectively, while germline mutations in CACNA1D cause the rare PASNA syndrome, featuring primary aldosteronism seizures and neurological abnormalities. Further studies are warranted to identify the molecular mechanisms underlying BAH and FH-II, the most common forms of sporadic and familial PA whose molecular basis is yet to be uncovered. © 2018 European Society of Endocrinology.

Adrenal GIPR expression and chromosome 19q13 microduplications in GIP-dependent Cushing's syndrome.

PubMed

Lecoq, Anne-Lise; Stratakis, Constantine A; Viengchareun, Say; Chaligné, Ronan; Tosca, Lucie; Deméocq, Vianney; Hage, Mirella; Berthon, Annabel; Faucz, Fabio R; Hanna, Patrick; Boyer, Hadrien-Gaël; Servant, Nicolas; Salenave, Sylvie; Tachdjian, Gérard; Adam, Clovis; Benhamo, Vanessa; Clauser, Eric; Guiochon-Mantel, Anne; Young, Jacques; Lombès, Marc; Bourdeau, Isabelle; Maiter, Dominique; Tabarin, Antoine; Bertherat, Jérôme; Lefebvre, Hervé; de Herder, Wouter; Louiset, Estelle; Lacroix, André; Chanson, Philippe; Bouligand, Jérôme; Kamenický, Peter

2017-09-21

GIP-dependent Cushing's syndrome is caused by ectopic expression of glucose-dependent insulinotropic polypeptide receptor (GIPR) in cortisol-producing adrenal adenomas or in bilateral macronodular adrenal hyperplasias. Molecular mechanisms leading to ectopic GIPR expression in adrenal tissue are not known. Here we performed molecular analyses on adrenocortical adenomas and bilateral macronodular adrenal hyperplasias obtained from 14 patients with GIP-dependent adrenal Cushing's syndrome and one patient with GIP-dependent aldosteronism. GIPR expression in all adenoma and hyperplasia samples occurred through transcriptional activation of a single allele of the GIPR gene. While no abnormality was detected in proximal GIPR promoter methylation, we identified somatic duplications in chromosome region 19q13.32 containing the GIPR locus in the adrenocortical lesions derived from 3 patients. In 2 adenoma samples, the duplicated 19q13.32 region was rearranged with other chromosome regions, whereas a single tissue sample with hyperplasia had a 19q duplication only. We demonstrated that juxtaposition with cis-acting regulatory sequences such as glucocorticoid response elements in the newly identified genomic environment drives abnormal expression of the translocated GIPR allele in adenoma cells. Altogether, our results provide insight into the molecular pathogenesis of GIP-dependent Cushing's syndrome, occurring through monoallelic transcriptional activation of GIPR driven in some adrenal lesions by structural variations.

Expression of inflammation-related genes in aldosterone-producing adenomas with KCNJ5 mutation.

PubMed

Murakami, Masanori; Yoshimoto, Takanobu; Nakano, Yujiro; Tsuchiya, Kyoichiro; Minami, Isao; Bouchi, Ryotaro; Fujii, Yasuhisa; Nakabayashi, Kazuhiko; Hashimoto, Koshi; Hata, Ken-Ichiro; Kihara, Kazunori; Ogawa, Yoshihiro

2016-08-05

The adrenocortical cells have been shown to produce various inflammatory cytokines such as TNFα and IL-6, which could modulate steroidogenesis. However, the role of inflammatory cytokines in aldosterone-producing adenomas (APAs) is not fully understood. In the present study, we examined the relationships between mRNA expression levels of the inflammation-related genes and somatic mutations in APA tissues. We evaluated mRNA expression levels of TNFA, IL6, and NFKB1 in APA tissues obtained from 44 Japanese APA patients. We revealed that mRNA expression patterns of the inflammation-related genes depended on a KCNJ5 somatic mutation. In addition, we showed that mRNA expression levels of the inflammation-related genes correlated with those of the steroidogenic enzyme CYP11B1 in the patients with APAs. The present study documented for the first time the expression of inflammation-related genes in APAs and the correlation of their expression levels with the KCNJ5 mutation status and mRNA expression levels of steroidogenic enzymes, indicating the pathophysiological relevance of inflammation-related genes in APAs. Copyright © 2016 Elsevier Inc. All rights reserved.

Persistent hypertension after adrenalectomy for an aldosterone-producing adenoma: weight as a critical prognostic factor for aldosterone’s lasting effect on the cardiac and vascular systems

PubMed Central

Carter, Yvette; Roy, Madhuchhanda; Sippel, Rebecca S.; Chen, Herbert

2012-01-01

Background Primary aldosteronism caused by an aldosterone producing adrenal tumor/aldosteronoma (APA), is a potentially curable form of hypertension, via unilateral adrenalectomy. Resolution of hypertension (HTN) is not as prevalent after tumor resection, as are the normalization of aldosterone secretion, hypokalemia, and other metabolic abnormalities. Here, we review the immediate and long term medical outcomes of laparoscopic adrenalectomy in patients with an APA, and attempt to identify any distinctive gender differences in the management of resistant hypertension. Materials and Methods We performed a retrospective review of the prospective Adrenal database at the University of Wisconsin between January 2001 and October 2010. Of the 165 adrenalectomies performed, thirty-two were for the resection of an aldosteronoma (APA). Patients were grouped according to their post-operative hypertension status. Those patients with normal blood pressure (<120/80 mmHg) and on no anti-hypertensive medication (CURE) were compared to those who continued to required medication for blood pressure control (HTN). We evaluated gender, age, body mass index (BMI), tumor size, duration of time with high blood pressure, and the differences in systolic and diastolic blood pressure following adrenalectomy. Statistical analysis was performed utilizing student’s t test. Statistical significance was defined as a p value < 0.05. Results We identified 32 patients with an APA based on biochemical and radiographic studies, two patients were excluded, due to missing data. There were 19 males (63%) and 11 (37%) females, with a mean age was 48.3 ± 2.1 years, and mean tumor size was 24 ± 3 mm. Post-operatively, patients required significantly fewer anti-hypertensive medications (1.5 ± 0.2 vs. 3.3 ± 0.3, p<0.001). Nine patients (31%) had complete resolution of their hypertension, requiring no post-operative anti-hypertensive medication. The only significant difference between the genders, was a

Of channels and pumps: different ways to boost the aldosterone?

PubMed

Bandulik, S

2017-07-01

The mineralocorticoid aldosterone is a major factor controlling the salt and water balance and thereby also the arterial blood pressure. Accordingly, primary aldosteronism (PA) characterized by an inappropriately high aldosterone secretion is the most common form of secondary hypertension. The physiological stimulation of aldosterone synthesis in adrenocortical glomerulosa cells by angiotensin II and an increased plasma K + concentration depends on a membrane depolarization and an increase in the cytosolic Ca 2+ activity. Recurrent gain-of-function mutations of ion channels and transporters have been identified in a majority of cases of aldosterone-producing adenomas and in familial forms of PA. In this review, the physiological role of these genes in the regulation of aldosterone synthesis and the altered function of the mutant proteins as well are described. The specific changes of the membrane potential and the cellular ion homoeostasis in adrenal cells expressing the different mutants are compared, and their impact on autonomous aldosterone production and proliferation is discussed. © 2016 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

Optimization of left adrenal vein sampling in primary aldosteronism: Coping with asymmetrical cortisol secretion.

PubMed

Kishino, Mitsuhiro; Yoshimoto, Takanobu; Nakadate, Masashi; Katada, Yoshiaki; Kanda, Eiichiro; Nakaminato, Shuichiro; Saida, Yukihisa; Ogawa, Yoshihiro; Tateishi, Ukihide

2017-03-31

We evaluated the influence of catheter sampling position and size on left adrenal venous sampling (AVS) in patients with primary aldosteronism (PA) and analyzed their relationship to cortisol secretion. This retrospective study included 111 patients with a diagnosis of primary aldosteronism who underwent tetracosactide-stimulated AVS. Left AVS was obtained from two catheter positions - the central adrenal vein (CAV) and the common trunk. For common trunk sampling, 5-French catheters were used in 51 patients, and microcatheters were used in 60 patients. Autonomous cortisol secretion was evaluated with a low-dose dexamethasone suppression test in 87 patients. The adrenal/inferior vena cava cortisol concentration ratio [selectivity index (SI)] was significantly lower in samples from the left common trunk than those of the left CAV and right adrenal veins, but this difference was reduced when a microcatheter was used for common trunk sampling. Sample dilution in the common trunk of the left adrenal vein can be decreased by limiting sampling speed with the use of a microcatheter. Meanwhile, there was no significant difference in SI between the left CAV and right adrenal veins. Laterality, determined according to aldosterone/cortisol ratio (A/C ratio) based criteria, showed good reproducibility regardless of sampling position, unlike the absolute aldosterone value based criteria. However, in 11 cases with autonomous cortisol co-secretion, the cortisol hypersecreting side tended to be underestimated when using A/C ratio based criteria. Left CAV sampling enables symmetrical sampling, and may be essential when using absolute aldosterone value based criteria in cases where symmetrical cortisol secretion is uncertain.

Favorable surgical outcomes of aldosterone-producing adenoma based on lateralization by CT imaging and hypokalemia: a non-AVS-based strategy.

PubMed

Li, Hai; Liu, Jianbin; Feng, Xiujuan; Liu, Liehua; Wei, Guohong; Cao, Xiaopei; Li, Yanbing

2017-12-01

To test the efficacy of a strategy based on CT imaging and clinical characteristics on lateralizing origin of excess aldosterone secretion in primary aldosteronism. Consecutive patients with diagnosed primary hyperaldosteronism from June 2006 to July 2012 in our center underwent adrenal surgeries without pre-operational adrenal venous sampling (AVS) if all the three criteria were met: (1) round- or oval-shaped occupational lesion of low density after contrast enhancement with diameter >1 cm on CT scan was located in one adrenal gland; (2) unequivocally normal contralateral adrenal gland; (3) serum potassium level lower than 3.5 mmol/L. Subjects who had received operation were taken into analysis and follow-ups. One hundred and twenty-five patients fulfilled the criteria and were recruited into our research. One hundred and twenty-two operated patients (97.6%) experienced complete resolution of hypokalemia as well as resolution or improvement in hypertension with reduction in antihypertensive medication, while 3 patients (2.4%) failed to obtain normal kalemia and continued on spironolactone therapy. At a median of 65-month (range 21-93) follow-up of these 122 subjects, 27 patients dropped out (22.1%). The 95 responding patients reported no episodes of paralysis or confirmed hypokalemia or any supplementation of potassium. Multivariate linear correlation analysis showed that plasma potassium level was correlated inversely with tumor diameter (r = -0.258, 95% CI -0.076, -0.514, p = 0.037) and basal plasma aldosterone level (r = -0.251, 95% CI -0.040, -0.464, p = 0.042). Most patients with typical unilateral adrenal macroadenomas, normal contralateral glands and hypokalemia could attain favorable surgical therapeutic outcomes without pre-operational AVS lateralization.

Adrenal GIPR expression and chromosome 19q13 microduplications in GIP-dependent Cushing’s syndrome

PubMed Central

Lecoq, Anne-Lise; Stratakis, Constantine A.; Viengchareun, Say; Chaligné, Ronan; Tosca, Lucie; Hage, Mirella; Berthon, Annabel; Faucz, Fabio R.; Hanna, Patrick; Boyer, Hadrien-Gaël; Servant, Nicolas; Salenave, Sylvie; Tachdjian, Gérard; Adam, Clovis; Benhamo, Vanessa; Clauser, Eric; Guiochon-Mantel, Anne; Young, Jacques; Lombès, Marc; Bourdeau, Isabelle; Maiter, Dominique; Tabarin, Antoine; Bertherat, Jérôme; Lefebvre, Hervé; Louiset, Estelle; Lacroix, André; Bouligand, Jérôme; Kamenický, Peter

2017-01-01

GIP-dependent Cushing’s syndrome is caused by ectopic expression of glucose-dependent insulinotropic polypeptide receptor (GIPR) in cortisol-producing adrenal adenomas or in bilateral macronodular adrenal hyperplasias. Molecular mechanisms leading to ectopic GIPR expression in adrenal tissue are not known. Here we performed molecular analyses on adrenocortical adenomas and bilateral macronodular adrenal hyperplasias obtained from 14 patients with GIP-dependent adrenal Cushing’s syndrome and one patient with GIP-dependent aldosteronism. GIPR expression in all adenoma and hyperplasia samples occurred through transcriptional activation of a single allele of the GIPR gene. While no abnormality was detected in proximal GIPR promoter methylation, we identified somatic duplications in chromosome region 19q13.32 containing the GIPR locus in the adrenocortical lesions derived from 3 patients. In 2 adenoma samples, the duplicated 19q13.32 region was rearranged with other chromosome regions, whereas a single tissue sample with hyperplasia had a 19q duplication only. We demonstrated that juxtaposition with cis-acting regulatory sequences such as glucocorticoid response elements in the newly identified genomic environment drives abnormal expression of the translocated GIPR allele in adenoma cells. Altogether, our results provide insight into the molecular pathogenesis of GIP-dependent Cushing’s syndrome, occurring through monoallelic transcriptional activation of GIPR driven in some adrenal lesions by structural variations. PMID:28931750

Antiaging Gene Klotho Regulates Adrenal CYP11B2 Expression and Aldosterone Synthesis

PubMed Central

Zhou, Xiaoli; Chen, Kai; Wang, Yongjun; Schuman, Mariano; Lei, Han

2016-01-01

Deficiency of the antiaging gene Klotho (KL) induces renal damage and hypertension through unknown mechanisms. In this study, we assessed whether KL regulates expression of CYP11B2, a key rate–limiting enzyme in aldosterone synthesis, in adrenal glands. We found that haplodeficiency of KL(+/−) in mice increased the plasma level of aldosterone by 16 weeks of age, which coincided with spontaneous and persistent elevation of BP. Blockade of aldosterone actions by eplerenone reversed KL deficiency–induced hypertension and attenuated the kidney damage. Protein expression of CYP11B2 was upregulated in adrenal cortex of KL(+/−) mice. KL and CYP11B2 proteins colocalized in adrenal zona glomerulosa cells. Silencing of KL upregulated and overexpression of KL downregulated CYP11B2 expression in human adrenocortical cells. Notably, silencing of KL decreased expression of SF-1, a negative transcription factor of CYP11B2, but increased phosphorylation of ATF2, a positive transcription factor of CYP11B2, which may contribute to upregulation of CYP11B2 expression. Therefore, these results show that KL regulates adrenal CYP11B2 expression. KL deficiency–induced spontaneous hypertension and kidney damage may be partially attributed to the upregulation of CYP11B2 expression and aldosterone synthesis. PMID:26471128

Characterization of Adrenal Adenoma by Gaussian Model-Based Algorithm.

PubMed

Hsu, Larson D; Wang, Carolyn L; Clark, Toshimasa J

2016-01-01

We confirmed that computed tomography (CT) attenuation values of pixels in an adrenal nodule approximate a Gaussian distribution. Building on this and the previously described histogram analysis method, we created an algorithm that uses mean and standard deviation to estimate the percentage of negative attenuation pixels in an adrenal nodule, thereby allowing differentiation of adenomas and nonadenomas. The institutional review board approved both components of this study in which we developed and then validated our criteria. In the first, we retrospectively assessed CT attenuation values of adrenal nodules for normality using a 2-sample Kolmogorov-Smirnov test. In the second, we evaluated a separate cohort of patients with adrenal nodules using both the conventional 10HU unit mean attenuation method and our Gaussian model-based algorithm. We compared the sensitivities of the 2 methods using McNemar's test. A total of 183 of 185 observations (98.9%) demonstrated a Gaussian distribution in adrenal nodule pixel attenuation values. The sensitivity and specificity of our Gaussian model-based algorithm for identifying adrenal adenoma were 86.1% and 83.3%, respectively. The sensitivity and specificity of the mean attenuation method were 53.2% and 94.4%, respectively. The sensitivities of the 2 methods were significantly different (P value < 0.001). In conclusion, the CT attenuation values within an adrenal nodule follow a Gaussian distribution. Our Gaussian model-based algorithm can characterize adrenal adenomas with higher sensitivity than the conventional mean attenuation method. The use of our algorithm, which does not require additional postprocessing, may increase workflow efficiency and reduce unnecessary workup of benign nodules. Copyright © 2016 Elsevier Inc. All rights reserved.

Diagnostic value of ACTH stimulation test in determining the subtypes of primary aldosteronism.

PubMed

Jiang, Yiran; Zhang, Cui; Wang, Weiqing; Su, Tingwei; Zhou, Weiwei; Jiang, Lei; Zhu, Wei; Xie, Jing; Ning, Guang

2015-05-01

Adrenal venous sampling is recommended as the golden standard for subtyping primary aldosteronism (PA). However, it is invasive and inconvenient, and seeking a better way to make differential diagnosis of PA is necessary. The objective of the study was to evaluate the diagnostic value of ACTH stimulation test under 1 mg dexamethasone suppression test (DST) in determining the subtypes of PA. Ninety-five patients with PA confirmed by saline infusion test were included in this study. According to adrenal venous sampling and histopathology, 39 patients were diagnosed as bilateral adrenal hyperplasia (BAH), 37 as aldosterone-producing adenoma (APA), and 19 as unilateral adrenal hyperplasia (UAH). An ACTH stimulation test under 1 mg DST was performed in all patients. Plasma aldosterone and cortisol levels were measured every 30 minutes until 120 minutes after the iv injection of 50 IU ACTH. During the ACTH stimulation test, aldosterone levels in APA and UAH were similar (P > .05) but higher than those in BAH (P < .001). Furthermore, stimulated aldosterone levels of unilateral PA (APA and UAH) were significantly higher than bilateral PA (BAH) (P < .001). Receiver-operated characteristics curve analyses showed the aldosterone after ACTH stimulation was effective for distinguishing between unilateral PA and bilateral PA. The diagnostic accuracy was highest at 120 minutes after ACTH stimulation, and the optimal cutoff value of the aldosterone was 77.90 ng/dL, with a sensitivity of 76.8%, a specificity of 87.2%, a positive predictive value of 89.6%, and a negative predictive value of 72.3%. The ACTH stimulation test under 1 mg DST is useful to determine the subtypes of PA, especially in unilateral and bilateral PA, and may guide further treatment in PA patients.

Primary aldosteronism among newly diagnosed and untreated hypertensive patients in a Swedish primary care area.

PubMed

Westerdahl, Christina; Bergenfelz, Anders; Isaksson, Anders; Nerbrand, Christina; Valdemarsson, Stig

2011-03-01

To evaluate the prevalence of primary aldosteronism (PA) in newly diagnosed and untreated hypertensive patients in primary care using the aldosterone/renin ratio (ARR), and to assess clinical and biochemical characteristics in patients with high and normal ARR. Patient survey study. A total of 200 consecutive patients with newly diagnosed and untreated hypertension from six primary health care centres in Sweden were included. ARR was calculated from serum aldosterone and plasma renin concentrations. The cut-off level for ARR was 65. Patients with an increased ARR were considered for confirmatory testing with the fludrocortisone suppression test (FST), followed by adrenal computed tomographic radiology (CT) and adrenal venous sampling (AVS). Of 200 patients, 36 patients had an ARR > 65. Of these 36 patients, 11 patients had an incomplete aldosterone inhibition during FST. Three patients were diagnosed with an aldosterone producing adenoma (APA) and eight with bilateral adrenal hyperplasia (BHA). Except for moderately lower level of P-K in patients with an ARR > 65 and in patients with PA, there were no biochemical or clinical differences found among hypertensive patients with PA compared with patients without PA. Eleven of 200 evaluated patients (5.5%) were considered to have PA. The diagnosis of PA should therefore be considered in newly diagnosed hypertensive subjects and screening for the diagnosis is warranted.

Primary aldosteronism among newly diagnosed and untreated hypertensive patients in a Swedish primary care area

PubMed Central

Westerdahl, Christina; Bergenfelz, Anders; Isaksson, Anders; Nerbrand, Christina; Valdemarsson, Stig

2011-01-01

Objective To evaluate the prevalence of primary aldosteronism (PA) in newly diagnosed and untreated hypertensive patients in primary care using the aldosterone/renin ratio (ARR), and to assess clinical and biochemical characteristics in patients with high and normal ARR. Design Patient survey study. Setting and subjects A total of 200 consecutive patients with newly diagnosed and untreated hypertension from six primary health care centres in Sweden were included. Main outcome measures ARR was calculated from serum aldosterone and plasma renin concentrations. The cut-off level for ARR was 65. Patients with an increased ARR were considered for confirmatory testing with the fludrocortisone suppression test (FST), followed by adrenal computed tomographic radiology (CT) and adrenal venous sampling (AVS). Results Of 200 patients, 36 patients had an ARR > 65. Of these 36 patients, 11 patients had an incomplete aldosterone inhibition during FST. Three patients were diagnosed with an aldosterone producing adenoma (APA) and eight with bilateral adrenal hyperplasia (BHA). Except for moderately lower level of P-K in patients with an ARR > 65 and in patients with PA, there were no biochemical or clinical differences found among hypertensive patients with PA compared with patients without PA. Conclusion Eleven of 200 evaluated patients (5.5%) were considered to have PA. The diagnosis of PA should therefore be considered in newly diagnosed hypertensive subjects and screening for the diagnosis is warranted. PMID:21323498

Antiaging Gene Klotho Regulates Adrenal CYP11B2 Expression and Aldosterone Synthesis.

PubMed

Zhou, Xiaoli; Chen, Kai; Wang, Yongjun; Schuman, Mariano; Lei, Han; Sun, Zhongjie

2016-06-01

Deficiency of the antiaging gene Klotho (KL) induces renal damage and hypertension through unknown mechanisms. In this study, we assessed whether KL regulates expression of CYP11B2, a key rate-limiting enzyme in aldosterone synthesis, in adrenal glands. We found that haplodeficiency of KL(+/-) in mice increased the plasma level of aldosterone by 16 weeks of age, which coincided with spontaneous and persistent elevation of BP. Blockade of aldosterone actions by eplerenone reversed KL deficiency-induced hypertension and attenuated the kidney damage. Protein expression of CYP11B2 was upregulated in adrenal cortex of KL(+/-) mice. KL and CYP11B2 proteins colocalized in adrenal zona glomerulosa cells. Silencing of KL upregulated and overexpression of KL downregulated CYP11B2 expression in human adrenocortical cells. Notably, silencing of KL decreased expression of SF-1, a negative transcription factor of CYP11B2, but increased phosphorylation of ATF2, a positive transcription factor of CYP11B2, which may contribute to upregulation of CYP11B2 expression. Therefore, these results show that KL regulates adrenal CYP11B2 expression. KL deficiency-induced spontaneous hypertension and kidney damage may be partially attributed to the upregulation of CYP11B2 expression and aldosterone synthesis. Copyright © 2016 by the American Society of Nephrology.

Unilateral adrenalectomy improves urinary protein excretion but does not abolish its relationship to sodium excretion in patients with aldosterone-producing adenoma.

PubMed

Pimenta, E; Gordon, R D; Ahmed, A H; Cowley, D; Robson, D; Kogovsek, C; Stowasser, M

2011-10-01

Experimental and human data suggest that adverse cardiovascular (CV) and renal effects of aldosterone excess are dependent on concomitant dietary salt intake. Increased urinary protein (Uprot) is an early sign of nephropathy independently associated with CV risk. We have previously reported a positive association between Uprot and urinary sodium (UNa) in patients with hyperaldosteronism, but not in patients with normal aldosterone levels. We aimed to determine whether Uprot is related to UNa in patients with aldosterone-producing adenoma (APA) and whether the degree of Uprot and strength of this relationship is reduced following correction of hyperaldosteronism. Subjects with APA (n=24) underwent measurement of 24 h Uprot and UNa before and after unilateral adrenalectomy (follow-up 15.0±11.9 months). Following surgery, mean clinic systolic blood pressure fell (150.4±18.2 vs 134.5±14.5 mm Hg, P=0.0008), despite a reduction in number of antihypertensive medications, and Uprot (211.2±101.6 vs 106.0±41.8 mg per day, P<0.0001) decreased. There was a positive correlation between Uprot and UNa both before (r=0.5477, P=0.0056) and after (r=0.5097, P=0.0109) adrenalectomy. Changes in UNa independently predicted Uprot reduction (P=0.0189). These findings suggest that both aldosterone levels and dietary salt contribute to renal damage, and that once glomerular damage occurs it is not completely resolved following correction of hyperaldosteronism. Our study suggests that treatment strategies based on reduction of aldosterone effects, by adrenalectomy or mineralocorticoid receptor blockade, in conjunction with low-salt diet would provide additional target-organ protection in patients with primary aldosteronism.

Regulators of G-protein signaling 4 in adrenal gland: localization, regulation, and role in aldosterone secretion.

PubMed

Romero, Damian G; Zhou, Ming Yi; Yanes, Licy L; Plonczynski, Maria W; Washington, Tanganika R; Gomez-Sanchez, Celso E; Gomez-Sanchez, Elise P

2007-08-01

Regulators of G-protein signaling (RGS proteins) interact with Galpha subunits of heterotrimeric G-proteins, accelerating the rate of GTP hydrolysis and finalizing the intracellular signaling triggered by the G-protein-coupled receptor (GPCR)-ligand interaction. Angiotensin II (Ang II) interacts with its GPCR in adrenal zona glomerulosa cells and triggers a cascade of intracellular signals that regulates steroidogenesis and proliferation. On screening for adrenal zona glomerulosa-specific genes, we found that RGS4 was exclusively localized in the zona glomerulosa of the rat adrenal cortex. We studied RGS4 expression and regulation in the rat adrenal gland, including the signaling pathways involved, as well as the role of RGS4 in steroidogenesis in human adrenocortical H295R cells. We reported that RGS4 mRNA expression in the rat adrenal gland was restricted to the adrenal zonal glomerulosa and upregulated by low-salt diet and Ang II infusion in rat adrenal glands in vivo. In H295R cells, Ang II caused a rapid and transient increase in RGS4 mRNA levels mediated by the calcium/calmodulin/calmodulin-dependent protein kinase and protein kinase C pathways. RGS4 overexpression by retroviral infection in H295R cells decreased Ang II-stimulated aldosterone secretion. In reporter assays, RGS4 decreased Ang II-mediated aldosterone synthase upregulation. In summary, RGS4 is an adrenal gland zona glomerulosa-specific gene that is upregulated by aldosterone secretagogues, in vivo and in vitro, and functions as a negative feedback of Ang II-triggered intracellular signaling. Alterations in RGS4 expression levels or functions may be involved in deregulations of Ang II signaling and abnormal aldosterone secretion.

Genetics Home Reference: aldosterone-producing adenoma

MedlinePlus

... genes. The most commonly mutated gene is KCNJ5 , accounting for an estimated 40 percent of the tumors, ... across cell membranes. These abnormalities overactivate a biochemical process that increases adrenal cell growth and division (proliferation), ...

Testosterone-secreting adrenal adenoma in a peripubertal girl

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kamilaris, T.C.; DeBold, C.R.; Manolas, K.J.

1987-11-13

A 15-year-old girl who presented with primary amenorrhea and virilization had an adrenocortical adenoma that secreted predominantly testosterone. To the authors' knowledge, she is the first peripubertal and second youngest patient with a testosterone-secreting adrenal tumor described. Serum dehydroepiandrosterone sulfate and urinary 17-ketosteroid an 17-hydroxycorticosteroid levels were normal. A tumor was located by a computed tomographic (CT) scan and by uptake of 6-..beta..-(/sup 75/Se) selenomethylnorcholesterol. Microscopic examination of the tumor showed typical features of an adrenocortical adenoma with no histologic features characteristic of Leydig cells. Postoperatively, her hirsutism regressed, she rapidly went through puberty, and regular monthly menstruation started fourmore » months later. Finding the source of testosterone in a virilized patient can be difficult. Eleven of the 14 previously described patients with testosterone-secreting adrenal tumors initially underwent misdirected surgery on the ovaries. Review of these cases revealed that results of hormone stimulation and suppression tests are unreliable and that these tumors are usually large. Therefore, CT scanning of the adrenal glands is recommended in all patients suspected of having a testosterone-secreting tumor.« less

Therapeutic results of primary aldosteronism with special reference to renal or renovascular lesions.

PubMed

Nakada, T; Koike, H; Akiya, T; Katayama, T; Takata, M; Iida, H; Mizumura, Y

1988-01-01

A study was made of 9 patients with primary aldosteronism due to aldosterone-producing adenoma (APA) and 8 subjects with idiopathic adrenal hyperplasia (IHA) to clarify the pathogenesis of sustained hypertension after surgical or non-surgical treatment. Following each treatment, a complete improvement of hypertension was obtained in 12 patients (6 APA, 6 IHA), while 5 (3 APA, 2 IHA) showed still hypertensive status. Renal or renovascular lesions were prominent only in the hypertension-unchanged group. Under regular sodium diet, the ratio of urinary excretion of sodium to creatinine of this hypertensive group was significantly lower than that of the hypertension-improved group. However, the results of other renal function tests were similar in both groups. After respective treatments, suppressed plasma renin activity and elevated plasma aldosterone concentration were improved in all patients. In addition, patients of both groups showed normal response of the renin-aldosterone system following diuretic and dietary induced sodium and volume depletion. Based on these findings, renal or renovascular lesions appear to play an important role in the pathogenesis of maintenance of hypertension in this disorder after respective treatments.

Coexistence of Cushing syndrome from functional adrenal adenoma and Addison disease from immune-mediated adrenalitis.

PubMed

Colucci, Randall; Jimenez, Rafael E; Farrar, William; Malgor, Ramiro; Kohn, Leonard; Schwartz, Frank L

2012-06-01

A 56-year-old woman presented with an incidental adrenal adenoma and physical examination findings that included moderate obesity, a slight cervicothoracic fat pad ("buffalo hump"), increased supraclavicular fat pads, and white abdominal striae. Biochemical workup revealed elevated levels of 24-hour urinary free cortisol but normal serum morning cortisol and suppressed levels of corticotropin, suggestive of adrenal-dependent Cushing syndrome. The resected adrenal gland revealed macronodular cortical hyperplasia with a dominant nodule. Other findings included an absent cortisol response to corticotropin stimulation, presence of serum anti-21-hydroxylase antibodies, and mononuclear cell infiltration--consistent with adrenalitis. The findings represent, to the authors' knowledge, the first known case of a patient with coexistent functional cortisol-secreting macronodular adrenal tumor resulting in Cushing syndrome and immune-mediated adrenalitis resulting in Addison disease.

Cytomegalovirus and BK-Virus co-infection of a clinically non-functioning adrenal adenoma: innocent bystanders or new pathogenetic agents?

PubMed

Pomara, G; Cappello, F; Barzon, L; Morelli, G; Rappa, F; Benvegna, L; Giannarini, G; Palù, G; Selli, C

2006-01-01

We report a case of a 64-year-old woman who underwent left adrenalectomy with removal of a 8,5 cm clinically non-functioning adrenocortical adenoma and a 4-cm myelolipoma. Molecular testing for viral infection demonstrated the presence of cytomegalovirus (CMV) DNA sequences in the adrenal adenoma, but not in the myelolipoma (confirmed by immunohistochemistry). Moreover, the adrenal adenoma was also positive for parvovirus B19, and both adrenal tumor samples were positive for polyomavirus BK (BKV) and adenovirus DNA sequences. This is the first report of co-infection of an adrenocortical adenoma by CMV and BKV. The role of these viruses in adrenal tumorigenesis was postulated.

Calpain-10 Activity Underlies Angiotensin II-Induced Aldosterone Production in an Adrenal Glomerulosa Cell Model

PubMed Central

Seremwe, Mutsa; Schnellmann, Rick G.

2015-01-01

Aldosterone is a steroid hormone important in the regulation of blood pressure. Aberrant production of aldosterone results in the development and progression of diseases including hypertension and congestive heart failure; therefore, a complete understanding of aldosterone production is important for developing more effective treatments. Angiotensin II (AngII) regulates steroidogenesis, in part through its ability to increase intracellular calcium levels. Calcium can activate calpains, proteases classified as typical or atypical based on the presence or absence of penta-EF-hands, which are involved in various cellular responses. We hypothesized that calpain, in particular calpain-10, is activated by AngII in adrenal glomerulosa cells and underlies aldosterone production. Our studies showed that pan-calpain inhibitors reduced AngII-induced aldosterone production in 2 adrenal glomerulosa cell models, primary bovine zona glomerulosa and human adrenocortical carcinoma (HAC15) cells, as well as CYP11B2 expression in the HAC15 cells. Although AngII induced calpain activation in these cells, typical calpain inhibitors had no effect on AngII-elicited aldosterone production, suggesting a lack of involvement of classical calpains in this process. However, an inhibitor of the atypical calpain, calpain-10, decreased AngII-induced aldosterone production. Consistent with this result, small interfering RNA (siRNA)-mediated knockdown of calpain-10 inhibited aldosterone production and CYP11B2 expression, whereas adenovirus-mediated overexpression of calpain-10 resulted in increased AngII-induced aldosterone production. Our results indicate that AngII-induced activation of calpain-10 in glomerulosa cells underlies aldosterone production and identify calpain-10 or its downstream pathways as potential targets for the development of drug therapies for the treatment of hypertension. PMID:25836666

Long-term cognitive impairments and attentional deficits in patients with Cushing's disease and cortisol-producing adrenal adenoma in remission.

PubMed

Ragnarsson, Oskar; Berglund, Peter; Eder, Derek N; Johannsson, Gudmundur

2012-09-01

Cognitive function is impaired in patients with active Cushing's syndrome (CS). The aim was to study cognitive function in patients with CS in long-term remission. We conducted a cross-sectional, case-controlled, single center study. Fifty-five patients previously treated for Cushing's disease (n = 43) and cortisol-producing adrenal adenoma (n = 12) and 55 controls matched for age, gender, and educational level participated in the study. Working memory, attention, information-processing speed, verbal fluency, and reading speed were studied using standardized neuropsychological testing and alerting, orienting, and executive control using the Attentional Network Test. Fatigue impact scale and the comprehensive psychopathological rating scale were used to evaluate fatigue and affective disorder. Median (interquartile range) duration of remission was 13 (5-19) yr and the mean ± SD age at follow-up was 54 ± 14 yr. Compared to controls, patients had a higher score on the fatigue impact scale, indicating greater burdens of fatigue, and a higher score on the comprehensive psychopathological rating scale subscales for depression and anxiety. In a multivariate analysis, attention, spatial orienting, alerting, working memory, verbal fluency, and reading speed were all diminished in comparison to controls, independent of scores for affective disorder and fatigue. No overall difference in outcome was seen between patients in long-term remission for Cushing's disease and cortisol-producing adrenal adenoma. Patients with CS in remission have impaired cognitive function that cannot be explained by the coexistence of affective disorder or chronic fatigue. The pattern of cognitive and attentional deficits suggests a more global involvement of the brain function than has previously been suggested.

The subtyping of primary aldosteronism by adrenal vein sampling: sequential blood sampling causes factitious lateralization.

PubMed

Rossitto, Giacomo; Battistel, Michele; Barbiero, Giulio; Bisogni, Valeria; Maiolino, Giuseppe; Diego, Miotto; Seccia, Teresa M; Rossi, Gian Paolo

2018-02-01

The pulsatile secretion of adrenocortical hormones and a stress reaction occurring when starting adrenal vein sampling (AVS) can affect the selectivity and also the assessment of lateralization when sequential blood sampling is used. We therefore tested the hypothesis that a simulated sequential blood sampling could decrease the diagnostic accuracy of lateralization index for identification of aldosterone-producing adenoma (APA), as compared with bilaterally simultaneous AVS. In 138 consecutive patients who underwent subtyping of primary aldosteronism, we compared the results obtained simultaneously bilaterally when starting AVS (t-15) and 15 min after (t0), with those gained with a simulated sequential right-to-left AVS technique (R ⇒ L) created by combining hormonal values obtained at t-15 and at t0. The concordance between simultaneously obtained values at t-15 and t0, and between simultaneously obtained values and values gained with a sequential R ⇒ L technique, was also assessed. We found a marked interindividual variability of lateralization index values in the patients with bilaterally selective AVS at both time point. However, overall the lateralization index simultaneously determined at t0 provided a more accurate identification of APA than the simulated sequential lateralization indexR ⇒ L (P = 0.001). Moreover, regardless of which side was sampled first, the sequential AVS technique induced a sequence-dependent overestimation of lateralization index. While in APA patients the concordance between simultaneous AVS at t0 and t-15 and between simultaneous t0 and sequential technique was moderate-to-good (K = 0.55 and 0.66, respectively), in non-APA patients, it was poor (K = 0.12 and 0.13, respectively). Sequential AVS generates factitious between-sides gradients, which lower its diagnostic accuracy, likely because of the stress reaction arising upon starting AVS.

Prolonged oral administration of potassium upon aldosterone biosynthesis by rat glomerulosa tissue in vitro.

PubMed

Regöly-Mérei, J; Sólyom, J

1975-01-01

Steroid production rate of adrenals derived from rats drinking a 0.3 M KC1 + 5% glucose solution for 7 days was compared to that of control rats drinking a 5% glucose solution in order to investigate the effect of potassium loading upon the early and late step of aldosterone biosynthesis. Following potassium loading the quartered adrenals produced more aldosterone but less corticosterone as compared to the control. Potassium loading resulted in an increased aldosterone production rate by capsular adrenals (z. glomerulosa) provided that the corticosterone concentration in the incubation medium was elevated either by incubating it together with the decapsulated adrenal or adding exogenous corticosterone (4--16 mug/ml) to the medium. The corticosterone to aldosterone converting capacity of capsular adrenals is markedly higher in the potassium-loaded rats than in the controls. In the first 15 minutes of incubation the corticosterone production rate of the two groups was equal, aldosterone production rate by capsular adrenals of potassium-loaded rats, being higher than that of control animals. Corticosterone output of capsular adrenals from potassium-loaded rats decreased more rapidly in course of the incubation than it did in control tissue. These results suggest that the increase in aldosterone secretion in vivo following potassium loading is due to the stimulation of conversion of corticosterone to aldosterone in the glomerulosa cells. However, the endogenous corticosterone production during the incubation of glomerulosa cells from pottasium-loaded rats decreases so rapidly that the cells are not capable of producing more aldosterone than the control ones in spite of activated 18-hydroxylase.

Functional TASK-3-Like Channels in Mitochondria of Aldosterone-Producing Zona Glomerulosa Cells.

PubMed

Yao, Junlan; McHedlishvili, David; McIntire, William E; Guagliardo, Nick A; Erisir, Alev; Coburn, Craig A; Santarelli, Vincent P; Bayliss, Douglas A; Barrett, Paula Q

2017-08-01

Ca 2+ drives aldosterone synthesis in the cytosolic and mitochondrial compartments of the adrenal zona glomerulosa cell. Membrane potential across each of these compartments regulates the amplitude of the Ca 2+ signal; yet, only plasma membrane ion channels and their role in regulating cell membrane potential have garnered investigative attention as pathological causes of human hyperaldosteronism. Previously, we reported that genetic deletion of TASK-3 channels (tandem pore domain acid-sensitive K + channels) from mice produces aldosterone excess in the absence of a change in the cell membrane potential of zona glomerulosa cells. Here, we report using yeast 2-hybrid, immunoprecipitation, and electron microscopic analyses that TASK-3 channels are resident in mitochondria, where they regulate mitochondrial morphology, mitochondrial membrane potential, and aldosterone production. This study provides proof of principle that mitochondrial K + channels, by modulating inner mitochondrial membrane morphology and mitochondrial membrane potential, have the ability to play a pathological role in aldosterone dysregulation in steroidogenic cells. © 2017 American Heart Association, Inc.

Eighteen-deoxyaldosterone and other less polar forms of 18-hydroxycorticosterone as aldosterone precursors in rat adrenals.

PubMed

Cozza, E N; Burton, G; Ceballos, N R; Lantos, C P; Harnik, M; Scott, A I

1985-05-01

Samples containing as precursors either 18-hydroxycorticosterone (18-OH-B) in its M form, or this converted to less polar forms at pH 2 (ACM), or M or ACM enclosed in liposomes from adrenal lipids were incubated at pH 7.4, 4.8 or 3.3 in the presence or absence of quartered rat adrenals for 1 and 2 h. Optimal (10%) yields of aldosterone were obtained when (a) ACM was incubated at pH 4.8 and (b) M enclosed in liposomes was suspended in buffer and shaken without enzyme at pH 3.3. When conditions (a) were supplemented with malate and NADP, 16% of ACM was converted to aldosterone. ACM contained 80% of a fraction which, according to 13C NMR spectroscopy, was identical to 18-deoxyaldosterone (18-DAL). Experiments in which radioactivity from corticosterone (B) or M was trapped by radioinert M or 18-DAL disclosed a pathway comprising sequentially B, 18-OH-B, 18-DAL and aldosterone, and the combined evidence of this work, an enzymatic hydroxylation of 18-DAL to aldosterone.

Macrolides Blunt Aldosterone Biosynthesis: A Proof-of-Concept Study in KCNJ5 Mutated Adenoma Cells Ex Vivo.

PubMed

Caroccia, Brasilina; Prisco, Selene; Seccia, Teresa Maria; Piazza, Maria; Maiolino, Giuseppe; Rossi, Gian Paolo

2017-12-01

Aldosterone-producing adenoma (APA), a major subtype of primary hyperaldosteronism, the main curable cause of human endocrine hypertension, involves somatic mutations in the potassium channel Kir3.4 ( KCNJ5 ) in 30% to 70% of cases, typically the more florid phenotypes. Because KCNJ5 mutated channels were reported to be specifically sensitive to inhibition by macrolide antibiotics, which concentration dependently blunts aldosterone production in HAC15 transfected with the G151R and L168R mutated channel, we herein tested the effect of clarithromycin on aldosterone synthesis and secretion in a pure population of aldosterone-secreting cells obtained by immunoseparation (CD56 + cells) from APA tissues with/without the 2 most common KCNJ5 mutations. From a large cohort of patients with an unambiguous APA diagnosis, we recruited those who were wild type (n=3) or had G151R (n=2) and L168R (n=2) mutations. We found that clarithromycin concentration dependently lowered CYP11B2 gene expression (by 60%) and aldosterone secretion (by 70%; P <0.001 for both) in CD56 + cells isolated ex vivo from KCNJ5 mutated APAs, although it was ineffective in CD56 + cells from wild-type APAs. By proving the principle that the oversecretion of aldosterone can be specifically blunted in APA cells ex vivo with G151R and L168R mutations, these results provide compelling evidence of the possibility of specifically correcting aldosterone excess in patients with APA carrying the 2 most common KCNJ5 somatic mutations. © 2017 American Heart Association, Inc.

Angiotensin II receptors in cortical and medullary adrenal tumors.

PubMed

Opocher, G; Rocco, S; Cimolato, M; Vianello, B; Arnaldi, G; Mantero, F

1997-03-01

Several pieces of evidences suggest that angiotensin II (Ang II) has mitogenic effects, and a link between Ang II receptors and adrenal tumors can be suggested. In various adrenal tumors, aldosterone-producing adenoma (APA), Cushing's adrenal adenomas (Cush), pheochromocytomas (Pheo), and adrenal carcinomas, we studied the density, affinity, and subtype of Ang II receptors. Ang II binding was tested in cell membrane homogenates. [125I]Ang II was used as ligand, and Losartan and CGP 42112 were used as selective Ang II type 1 and type 2 antagonists, respectively. In APA, Ang II receptor density was 178.5 +/- 82.7 fmol/mg: however, due to the high degree of variability, the receptor density was not significantly higher than that in nontumorous adrenal cortex (59.3 +/- 8.4 fmol/mg). In Cush, the receptor density (27.6 +/- 8.2 fmol/mg; P < 0.05) was significantly lower than that in controls, whereas in Pheo and cortical carcinoma, Ang II binding was very low and in several cases almost undetectable. There was no remarkable difference in the Ang II receptor affinity among all tissues tested. The ratio between type 1 and type 2 Ang II receptors showed a large prevalence of type 1 in controls, APA, and three cases of Cush; in two cases of Cush, this ratio was reversed. In conclusion, our data indicate that Ang II receptors are normally expressed in APA and can also be detected in Cush, whereas they have a very low density in Pheo and adrenal carcinoma. Therefore, Ang II receptors are not involved in the lack of response to Ang II that is characteristic of APA; additionally, a reduction of Ang II receptors can be associated with dedifferentiation or malignancy of adrenal tumors. Further investigation of the expression and functional characterization of Ang II receptors is required to better clarify their possible role in adrenal tumorigenesis.

PCP4: a regulator of aldosterone synthesis in human adrenocortical tissues

PubMed Central

Felizola, Saulo J. A.; Nakamura, Yasuhiro; Ono, Yoshikiyo; Kitamura, Kanako; Kikuchi, Kumi; Onodera, Yoshiaki; Ise, Kazue; Takase, Kei; Sugawara, Akira; Hattangady, Namita; Rainey, William E.; Satoh, Fumitoshi; Sasano, Hironobu

2014-01-01

Purkinje cell protein 4 (PCP4) is a calmodulin (CaM) binding protein that accelerates calcium association and dissociation with CaM. It has been previously detected in aldosterone-producing adenomas (APA) but details on its expression and function in adrenocortical tissues have remained unknown. Therefore, we performed the immunohistochemical analysis of PCP4 in the following tissues: normal adrenal (NA; n=15), APA (n=15), cortisol producing adenomas (CPA; n=15) and idiopathic hyperaldosteronism cases (IHA; n=5). APA samples (n=45) were also submitted to quantitative RT-PCR (qPCR) of PCP4, CYP11B1, and CYP11B2, as well as DNA sequencing for KCNJ5 mutations. Transient transfection analysis using PCP4 siRNA was also performed in H295R adrenocortical carcinoma cells, following ELISA analysis, and CYP11B2 luciferase assays were also performed after PCP4 vector transfection in order to study the regulation of PCP4 protein expression. In our findings, PCP4 immunoreactivity was predominantly detected in APA and in the zona glomerulosa (ZG) of NA and IHA. In APA, the mRNA levels of PCP4 were significantly correlated with those of CYP11B2 (P<0.0001) and were significantly higher in cases with KCNJ5 mutation than wild-type (P=0.005). Following PCP4 vector transfection, CYP11B2 luciferase reporter activity was significantly higher than controls in the presence of angiotensin-II. Knockdown of PCP4 resulted in a significant decrease in CYP11B2 mRNA levels (P=0.012) and aldosterone production (P=0.011). Our results indicate that PCP4 is a regulator of aldosterone production in normal, hyperplastic and neoplastic human adrenocortical cells. PMID:24403568

Adrenal vein sampling: substantial need for technical improvement at regional referral centres.

PubMed

Elliott, Panda; Holmes, Daniel T

2013-10-01

Adrenal vein sampling (AVS) is the gold standard for localization of aldosterone producing adenoma. The anatomy of the right adrenal vein makes this procedure technically demanding and it may yield no clinical information if the adrenal veins are not adequately cannulated. Having frequently observed the technical failure of AVS, we undertook a review of 220 procedures in British Columbia, Canada. Subjects were retrospectively identified through the laboratory information system. The following were collected: demographics, screening aldosterone concentration and renin activity/mass, results of dynamic function tests, AVS aldosterone and cortisol results. Standard calculations were performed on AVS data and site-specific success rates were compared. The effect of adrenocorticotropin hormone (ACTH) stimulation on the selectivity index (SI) and lateralization index (LI) were explored. The overall technical success-rate of AVS procedures was only 44% in procedures where no ACTH-stimulation was used (n=200) but this rose significantly (p<0.01) to 82% for those employing ACTH (n=139). ACTH-stimulation significantly increased the median SI (left: 5.8 vs 36.7, p<0.01; right: 7.0 vs 51.2, p<0.01), and salvaged 36 procedures from yielding no information, 21 of which demonstrated lateralization of aldosterone production. In 64 cases showing lateralization both pre and post-stimulation, ACTH significantly decreased the median LI from 5.4 to 2.2, p<0.01, creating substantial risk for spurious loss of lateralization. The technical success of AVS is lower than reported elsewhere. Provided that effects on the LI are considered, the use of ACTH-stimulation during AVS assists in the identification of unilateral forms of PA. Copyright © 2013 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Aldosterone Induced Galectin-3 Secretion In Vitro and In Vivo: From Cells to Humans

PubMed Central

Lin, Yen-Hung; Chou, Chia-Hung; Wu, Xue-Ming; Chang, Yi-Yao; Hung, Chi-Sheng; Chen, Ying-Hsien; Tzeng, Yu-Lin; Wu, Vin-Cent; Ho, Yi-Lwun; Hsieh, Fon-Jou; Wu, Kwan-Dun

2014-01-01

Context Patients with primary aldosteronism are associated with increased myocardial fibrosis. Galectin-3 is one of the most important mediators between macrophage activation and myocardial fibrosis. Objective To investigate whether aldosterone induces galectin-3 secretion in vitro and in vivo. Methods and Results We investigated the possible molecular mechanism of aldosterone-induced galectin-3 secretion in macrophage cell lines (THP-1 and RAW 264.7 cells). Aldosterone induced galectin-3 secretion through mineralocorticoid receptors via the PI3K/Akt and NF-κB transcription signaling pathways. In addition, aldosterone-induced galectin-3 expression enhanced fibrosis-related factor expression in fibroblasts. We observed that galectin-3 mRNA from peripheral blood mononuclear cells and serum galectin-3 levels were both significantly increased in mice implanted with aldosterone pellets on days 7 and 14. We then conducted a prospective preliminary clinical study to investigate the association between aldosterone and galectin-3. Patients with aldosterone-producing adenoma had a significantly higher plasma galectin-3 level than patients with essential hypertension. One year after adrenalectomy, the plasma galectin-3 level had decreased significantly in the patients with aldosterone-producing adenoma. Conclusion This study demonstrated that aldosterone could induce galectin-3 secretion in vitro and in vivo. PMID:25180794

GPER-1 and estrogen receptor-β ligands modulate aldosterone synthesis.

PubMed

Caroccia, Brasilina; Seccia, Teresa M; Campos, Abril Gonzalez; Gioco, Francesca; Kuppusamy, Maniselvan; Ceolotto, Giulio; Guerzoni, Eugenia; Simonato, Francesca; Mareso, Sara; Lenzini, Livia; Fassina, Ambrogio; Rossi, Gian Paolo

2014-11-01

Fertile women have lower blood pressure and cardiovascular risk than age-matched men, which suggests that estrogens exert cardiovascular protective effects. However, whether 17 β-estradiol (E2) blunts aldosterone secretion, and thereby affects the gender dimorphism of blood pressure, is unknown. We therefore sought for the estrogen receptor (ER) subtypes in human adrenocortical tissues ex vivo by performing gene and protein expression studies. We also investigated the effect of E2 on aldosterone synthesis and the involved receptors through in vitro functional experiments in the adrenocortical cells HAC15. We found that in the human adrenal cortex and aldosterone-producing adenoma cells, the most expressed ERs were the ERβ and the G protein-coupled receptor-1 (GPER-1), respectively. After selective ERβ blockade, E2 (10 nmol/L) markedly increased both the expression of aldosterone synthase and the production of aldosterone (+5- to 7-fold vs baseline, P < .001). Under the same condition, the GPER-1 receptor agonist 1-[4-(6-bromo-benzo (1, 3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c] quinolin-8-yl]-ethanone (G-1) (10 nmol/L) mimicked this effect, which was abrogated by cotreatment with either the GPER-1 receptor antagonist (3aS*,4R*,9bR*)-4-(6-Bro-mo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta[c]quinoline (G-15), or a selective protein kinase A inhibitor 8-Bromo-2-monobutyryladenosine-3,5-cyclic mono-phosphorothioate, Rp-isomer. Silencing of the ERβ significantly raised aldosterone synthase expression and aldosterone production. Conversely, silencing of the GPER-1 lowered aldosterone synthase gene and protein expression. Moreover, it blunted the stimulatory effect of E2 on aldosterone synthase that was seen during ERβ blockade. These results support the conclusion that in humans, E2 inhibits aldosterone synthesis by acting via ERβ. Pharmacologic disinhibition of ERβ unmasks a potent secretagogue effect of E2 that involves GPER-1 and protein kinase A

A marked proportional rise in IVC aldosterone following cosyntropin administration during AVS is a signal to the presence of adrenal hyperplasia in primary aldosteronism.

PubMed

Kline, G A; Pasieka, J L; Harvey, A; So, B; Dias, V C

2014-05-01

We hypothesized aldosteronoma responsiveness to cosyntropin may be a characterizing feature that could be determined in addition to standard adrenal vein sampling (AVS) data. We reviewed an AVS database from June 2005 to October 2011 including 65 patients with confirmed primary aldosteronism (PA) who underwent AVS and, if applicable, unilateral adrenalectomy. Patients were divided into confirmed lateralized and non-lateralized groups and subgrouped by histology. Plasma aldosterone in inferior vena cava (IVC) pre- and post-cosyntropin infusion during AVS was measured. Peak aldosterone and proportional change was compared between groups. Baseline and peak IVC aldosterone was higher in lateralized patients but incremental aldosterone rise was much greater in subjects with bilateral hyperplasia. From receiver operator characteristics (ROC) analysis, the optimized diagnostic cut point of peak IVC aldosterone of >649 pmol l(-1) would have a sensitivity of 94% for surgical disease although specificity of just 59%. A 250% increase in IVC aldosterone following cosyntropin would be specific enough to exclude 87% of surgical/lateralized disease. These diagnostic capabilities are similar to other results with non-AVS tests performed for diagnosis of lateralization. Although not specific enough to replace standard AVS interpretation, a marked IVC aldosterone increase after cosyntropin during AVS is a useful additional test to diagnose non-lateralizing forms of PA. Such a calculation requires no additional expense or tests.

Adrenal responses of large whales: Integrating fecal aldosterone as a complementary biomarker to glucocorticoids.

PubMed

Burgess, Elizabeth A; Hunt, Kathleen E; Kraus, Scott D; Rolland, Rosalind M

2017-10-01

Until now, physiological stress assessment of large whales has predominantly focused on adrenal glucocorticoid (GC) measures. Elevated GC concentrations in feces (fGC) are known to reflect stressful disturbances, such as fishing gear entanglement and human-generated underwater noise, in North Atlantic right whales (Eubalaena glacialis). However, there can be considerable variation in GC production as a function of sex and life history stage, which may confound the interpretation of fGC levels. Additionally, GC antibodies used in immunoassays can cross-react with other fecal metabolites (i.e., non-target steroids), potentially influencing fGC data. Here, aldosterone concentrations (fALD; aldosterone and related metabolites) were measured in fecal samples from right whales (total n=315 samples), including samples from identified individuals of known life history (n=82 individual whales), to evaluate its utility as a complementary biomarker to fGC for identifying adrenal activation. Concentrations of fALD were positively correlated with fGCs in right whales (r=0.59, P<0.001), suggesting concurrent secretion of these hormones by the adrenal gland. However, fALD levels were less influenced by concentrations of reproductive steroids in feces, minimizing the potential confounder of assay cross-reactivity in samples with highly skewed hormone ratios. Across different life history states for right whales, fALD concentrations showed similar patterns to those reported for fGC, with higher levels in pregnant females (35.9±7.6ng/g) followed by reproductively mature males (9.5±0.9ng/g) (P<0.05), providing further evidence of elevated adrenal activation in these groups of whales. The addition of fALD measurement as a biomarker of adrenal activation may help distinguish between intrinsic and external causes of stress hormone elevations in large whales, as well as other free-living wildlife species, providing a more comprehensive approach for associating adrenal activation with

Decreased plasma prorenin levels in primary aldosteronism: potential diagnostic implications.

PubMed

Berge, Constance; Courand, Pierre-Yves; Harbaoui, Brahim; Paget, Vinciane; Khettab, Fouad; Bricca, Giampiero; Fauvel, Jean-Pierre; Lantelme, Pierre

2015-01-01

Primary aldosteronism could exert a negative feedback on prorenin secretion, of possibly different magnitude, whether it is related to an aldosterone-producing adenoma (APA) or an idiopathic hyperaldosteronism (IHA). The objectives of this study were to evaluate the level of prorenin in three subgroups: APA, IHA, and essential hypertension; and the performance of the aldosterone-to-prorenin ratio (APR) for the diagnosis of an APA. Seven hundred and forty-six hypertensive patients with a standardized work-up, including a prorenin measurement, were considered. Ninety-six patients without neutral treatment and 38 patients with other forms of secondary hypertension were excluded. APA and IHA were categorized according to computed tomography scan, adrenal venous sampling, pathological analysis and improvement of hypertension after surgery. Thirty-five patients had a diagnosis of APA, 57 of IHA and 504 of essential hypertension. Prorenin was lower in APA and IHA than in essential hypertension (32.9, 40.4 and 50.3  pg/ml, respectively; P < 0.001). APR was higher in patients with APA and IHA than in those with essential hypertension (24.0, 11.8, and 4.0  pmol/l per pg/ml, respectively; P < 0.001). The APR was more discriminant than the aldosterone-to-renin ratio to identify APA compared to IHA (area under the receiver operating curve at 0.750 and 0.639, respectively; P = 0.04). The optimal cut-off values were 22  pmol/l per pg/ml for APR (sensitivity 57.0%, specificity 93.0%) and 440  pmol/l per pg/ml for aldosterone-to-renin ratio (sensitivity 54.3%, specificity 82.5%). Primary aldosteronism and particularly its most caricatural form, that is APA, seems associated with a lower level of prorenin than essential hypertension. The APR could be included in the diagnostic strategy of APA.

Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism.

PubMed

Milliez, Paul; Girerd, Xavier; Plouin, Pierre-François; Blacher, Jacques; Safar, Michel E; Mourad, Jean-Jacques

2005-04-19

The aim of this report was to show that the rate of cardiovascular events is increased in patients with either subtype of primary aldosteronism (PA). Primary aldosteronism involves hypertension (HTN), hypokalemia, and low plasma renin. The two major PA subtypes are unilateral aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia. During a three-year period, the diagnosis of PA was made in 124 of 5,500 patients referred for comprehensive evaluation and management. Adenomas were diagnosed in 65 patients and idiopathic hyperaldosteronism in 59 patients. During the same period, clinical characteristics and cardiovascular events of this group were compared with those of 465 patients with essential hypertension (EHT) randomly matched for age, gender, and systolic and diastolic blood pressure. A history of stroke was found in 12.9% of patients with PA and 3.4% of patients with EHT (odds ratio [OR] = 4.2; 95% confidence interval [CI] 2.0 to 8.6]). Non-fatal myocardial infarction was diagnosed in 4.0% of patients with PA and in 0.6% of patients with EHT (OR = 6.5; 95% CI 1.5 to 27.4). A history of atrial fibrillation was diagnosed in 7.3% of patients with PA and 0.6% of patients with EHT (OR = 12.1; 95% CI 3.2 to 45.2). The occurrence of cardiovascular complications was comparable in both subtypes of PA. Patients presenting with PA experienced more cardiovascular events than did EHT patients independent of blood pressure. The presence of PA should be detected, not only to determine the cause of HTN, but also to prevent such complications.

Mixed cortical adenoma and composite pheochromocytoma-ganglioneuroma: an unusual corticomedullary tumor of the adrenal gland.

PubMed

Lau, Sean K; Chu, Peiguo G; Weiss, Lawrence M

2011-06-01

Adrenal neoplasms composed of more than one cell type and demonstrating a mixed histologic appearance are exceedingly rare. We report the clinical and pathologic features of a morphologically distinctive tumor of the adrenal gland composed of cortical, chromaffin, and neural cells. Histologically, the tumor consisted of intermixed areas of proliferating cortical cells resembling adrenal cortical adenoma, neoplastic chromaffin cells consistent with pheochromocytoma, and a ganglioneuromatous stroma. The presence of the cortical, medullary, and neural components within the tumor was confirmed by immunohistochemical studies. The present case serves to broaden the morphologic spectrum of mixed tumors that may be encountered in the adrenal gland. Copyright © 2011 Elsevier Inc. All rights reserved.

C-Arm Computed Tomography-Assisted Adrenal Venous Sampling Improved Right Adrenal Vein Cannulation and Sampling Quality in Primary Aldosteronism.

PubMed

Park, Chung Hyun; Hong, Namki; Han, Kichang; Kang, Sang Wook; Lee, Cho Rok; Park, Sungha; Rhee, Yumie

2018-05-04

Adrenal venous sampling (AVS) is a gold standard for subtype classification of primary aldosteronism (PA). However, this procedure has a high failure rate because of the anatomical difficulties in accessing the right adrenal vein. We investigated whether C-arm computed tomography-assisted AVS (C-AVS) could improve the success rate of adrenal sampling. A total of 156 patients, diagnosed with PA who underwent AVS from May 2004 through April 2017, were included. Based on the medical records, we retrospectively compared the overall, left, and right catheterization success rates of adrenal veins during the periods without C-AVS (2004 to 2010, n=32) and with C-AVS (2011 to 2016, n=134). The primary outcome was adequate bilateral sampling defined as a selectivity index (SI) >5. With C-AVS, the rates of adequate bilateral AVS increased from 40.6% to 88.7% (P<0.001), with substantial decreases in failure rates (43.7% to 0.8%, P<0.001). There were significant increases in adequate sampling rates from right (43.7% to 91.9%, P<0.001) and left adrenal veins (53.1% to 95.9%, P<0.001) as well as decreases in catheterization failure from right adrenal vein (9.3% to 0.0%, P<0.001). Net improvement of SI on right side remained significant after adjustment for left side (adjusted SI, 1.1 to 9.0; P=0.038). C-AVS was an independent predictor of adequate bilateral sampling in the multivariate model (odds ratio, 9.01; P<0.001). C-AVS improved the overall success rate of AVS, possibly as a result of better catheterization of right adrenal vein. Copyright © 2018 Korean Endocrine Society.

Endocrine and Hypertensive Disorders of Potassium Regulation: Primary Aldosteronism

PubMed Central

Weiner, I. David

2013-01-01

The identification that primary aldosteronism is a common cause of resistant hypertension is a significant advance in our ability to care for patients with hypertension. Primary aldosteronism is common, and when unrecognized is associated with increased incidence of adverse cardiovascular outcomes. Identification of primary aldosteronism is based upon use of the plasma aldosterone level, plasma renin activity and the aldosterone:renin ratio (ARR). Differentiation between unilateral and bilateral autonomous adrenal aldosterone production then guides further therapy, with use of mineralocorticoid receptor blockers for those with bilateral autonomous adrenal aldosterone production and laparoscopic adrenalectomy for those with unilateral autonomous aldosterone production. In this review, we discuss in detail the pathogenesis of primary aldosteronism-induced hypertension and potassium disorders, the evaluation of the patient with suspected primary aldosteronism and the management of primary aldosteronism, both through medications and through surgery. PMID:23953804

Adrenal Incidentaloma

MedlinePlus

... or subclinical hypercortisolism: conditions caused by too much cortisol Hyperaldosteronism : too much aldosterone A pheochromocytoma: a rare ... in which the adrenal glands make too little cortisol and aldosterone, and too much androgen Cancer of ...

The Aldosterone Renin Ratio (ARR) APP as Tool to Enhance the Detection Rate of Primary Aldosteronism.

PubMed

Rossi, Gian Paolo; Bisogni, Valeria

2016-06-01

Primary aldosteronism is one of the most common forms of secondary hypertension, but it is often under diagnosed, which leads to the development of cardiovascular damage, and excess costs for long-term drug treatment and management of complications. The aldosterone to renin ratio (ARR) is a key step for early detection of primary aldosteronism, but unfortunately is not easily estimated. This is because plasma aldosterone and renin are measured with different assays, which provide results in different units of measure, with ensuing difficulty of obtaining the calculation of the ARR in the proper units and impossibility of interpreting results with reference to established cut off values. Therefore, doctors are often unable to draw unambiguous conclusions to be used for the clinical decision-making. To the aim of making the diagnostic work-up easier, we have developed an Application that provide a swift calculation of the ARR regardless of the units of measure used for plasma aldosterone and renin values. If the concomitant serum potassium level is available the App also provides the patient's probability of having an aldosterone-producing adenoma based on a validated logistic discriminant analysis.

Psychological Symptoms and Well-Being After Treatment for Primary Aldosteronism.

PubMed

Velema, Marieke S; Terlouw, Jannie M; de Nooijer, Aline H; Nijkamp, Marjan D; Jacobs, Nele; Deinum, Jaap

2018-06-12

Primary aldosteronism (PA) is an increasingly identified cause of secondary hypertension. PA can be caused by an aldosterone-producing adenoma or by bilateral adrenal hyperplasia, generally treated by adrenalectomy or mineralocorticoid receptor antagonists, respectively. Recent studies suggest that PA is associated with more psychological symptoms and lower levels of well-being. The purpose of this study was to investigate the associations between subtype of PA and psychological symptoms and well-being after specific treatment. We analyzed the outcomes of the Mental Health Continuum-Short Form and the Symptom Checklist in 160 patients (mean age 57 years; 74.3% males) with PA, comparing the scores for psychological symptoms and well-being between both subtypes of PA. Additionally, we performed subgroup analyses based on gender, age, time since initiation of treatment, and co-morbidity. Moreover, we compared the results with published norm scores. Mean follow-up after adrenalectomy or start of medication was four years and two months. Depressive symptoms, anxiety and obsessive-compulsive thoughts and well-being did not differ between subtypes of PA. Subgroup analysis did not reveal any differences, except for women with bilateral adrenal hyperplasia who scored higher on the anxiety subscale than women after adrenalectomy. Compared to the general population, patients with treated PA reported more psychological symptoms. In contrast, well-being did not differ significantly from norm scores. Subtype and treatment of PA were no important determinants of psychological symptoms and well-being on the long-term. We suggest that physicians should be alert for psychological symptoms, as these were more frequently present in patients with PA. © Georg Thieme Verlag KG Stuttgart · New York.

Clinical Investigation of Adrenal Incidentalomas in Japanese Patients of the Fukuoka Region with Updated Diagnostic Criteria for Sub-clinical Cushing's Syndrome.

PubMed

Abe, Ichiro; Sugimoto, Kaoru; Miyajima, Tetsumasa; Ide, Tomoko; Minezaki, Midori; Takeshita, Kaori; Takahara, Saori; Nakagawa, Midori; Fujimura, Yuki; Kudo, Tadachika; Miyajima, Shigero; Taira, Hiroshi; Ohe, Kenji; Ishii, Tatsu; Yanase, Toshihiko; Kobayashi, Kunihisa

2018-04-27

Objectives We retrospectively investigated the clinical and endocrinological characteristics of adrenal incidentalomas. Methods We studied 61 patients who had been diagnosed with adrenal incidentalomas and had undergone detailed clinical and endocrinological evaluations while hospitalized. We used common criteria to diagnose the functional tumors, but for sub-clinical Cushing's syndrome, we used an updated set of diagnosis criteria: serum cortisol ≥1.8 μg/dL after a positive response to a 1-mg dexamethasone suppression test if the patient has a low morning ACTH level (<10 pg/mL) and a loss of the diurnal serum cortisol rhythm. Results Of the 61 patients, none (0%) had malignant tumors, 8 (13.1%) had pheochromocytoma, and 15 (24.6%) had primary aldosteronism; when diagnosed by our revised criteria, 13 (21.3%) had cortisol-secreting adenomas (Cushing's syndrome and sub-clinical Cushing's syndrome), and 25 (41.0%) had non-functional tumors. Compared with the non-functional tumor group, the primary aldosteronism group and the cortisol-secreting adenoma group were significantly younger and had significantly lower rates of hypokalemia, whereas the pheochromocytoma group had significantly larger tumors and a significantly lower body mass index. Conclusion Our study found a larger percentage of functional tumors among adrenal incidentalomas than past reports, partly because we used a lower serum cortisol level after a dexamethasone suppression test to diagnose sub-clinical Cushing's syndrome and because all of the patients were hospitalized and could therefore receive more detailed examinations. Young patients with hypokalemia or lean patients with large adrenal tumors warrant particularly careful investigation.

A Multi-institutional Comparison of Adrenal Venous Sampling in Patients with Primary Aldosteronism: Caution Advised if Successful Bilateral Adrenal Vein Sampling is Not Achieved.

PubMed

Wang, Tracy S; Kline, Greg; Yen, Tina W; Yin, Ziyan; Liu, Ying; Rilling, William; So, Benny; Findling, James W; Evans, Douglas B; Pasieka, Janice L

2018-02-01

In patients with primary aldosteronism (PA), adrenal venous sampling (AVS) is recommended to differentiate between unilateral (UNI) or bilateral (BIL) adrenal disease. A recent study suggested that lateralization could be predicted, based on the ratio of aldosterone/cortisol levels (A/C) between the left adrenal vein (LAV) and inferior vena cava (IVC), with a 100% positive predictive value (PPV). This study aimed to validate those findings utilizing a larger, multi-institutional cohort. A retrospective review was performed of patients with PA who underwent AVS from 2 tertiary-care institutions. Laterality was predicted by an A/C ratio of >3:1 between the dominant and non-dominant adrenal. AVS results were compared to LAV/IVC ratios utilizing the published criteria (Lt ≥ 5.5; Rt ≤ 0.5). Of 222 patients, 124 (57%) had UNI and 98 (43%) had BIL disease based on AVS. AVS and LAV/IVC findings were concordant for laterality in 141 (64%) patients (69 UNI, 72 BIL). Using only the LAV/IVC ratio, 54 (24%) patients with UNI disease on AVS who underwent successful surgery would have been assumed to have BAH unless AVS was repeated, and 24 (11%) patients with BIL disease on AVS may have been incorrectly offered surgery (PPV 70%). Based on median LAV/IVC ratios (left 5.26; right 0.31; BIL 2.84), no LAV/IVC ratio accurately predicted laterality. This multi-institutional study of patients with both UNI and BIL PA failed to validate the previously reported PPV of LAV/IVC ratio for lateralization. Caution should be used in interpreting incomplete AVS data to differentiate between UNI versus BIL disease and strong consideration given to repeat AVS prior to adrenalectomy.

[Aldosterone response to various stimuli in hyperthyroidism: in vivo and in vitro studies].

PubMed

Kigoshi, T; Kaneko, M; Nakano, S; Azukizawa, S; Uchida, K; Morimoto, S

1993-06-20

Responses of plasma aldosterone (PA) to alpha-ACTH-(1-24) (250 micrograms, im) injection and graded angiotensin II (AII) infusions (2, 4 and 8ng/kg/min for 30 min at each dose) on a constant sodium intake (170mEq daily) were assessed in 17 patients with Basedow's disease and 13 age-matched normal subjects. Aldosterone production in response to ACTH, AII and potassium in adrenal zona glomerulosa cells from L-thyroxine-induced hyperthyroid rats (H-rats) were also examined. Basal levels of plasma renin activity (PRA) and urinary aldosterone excretion were significantly higher (p < 0.01 and p < 0.05, respectively) in the patients with Basedow's disease than in the normal subjects, whereas basal PA level was similar in the two groups. The ACTH injection induced similar increases in plasma cortisol, plasma 18-hydroxycorticosterone (18-OHB) and PA in the two groups. The graded AII infusions also produced increases in plasma 18-OHB and PA in the two groups. Responses of these two corticosteroids to AII were, however, significantly lower (p < 0.05) in the patients with Basedow's disease than in the normal subjects. In the experimental animal study, basal PRA levels and the adrenal glomerulosa cell count/adrenal were significantly higher (p < 0.05) in the H-rats than in the control rats, whereas basal PA levels were similar in the two groups. Aldosterone production in response to AII, ACTH, and potassium increased in a dose-dependent manner in the two groups. Responses of aldosterone production to AII were, however, significantly lower (p < 0.05) in the H-rats than in the control rats. These results suggest that the impaired responsiveness of adrenal zona glomerulosa cells to AII, as well as an increased metabolic clearance rate of aldosterone, may be involved in the abnormal aldosterone metabolism in hyperthyroidism.

In Utero Exposure to the Antiandrogen Di-(2-Ethylhexyl) Phthalate Decreases Adrenal Aldosterone Production in the Adult Rat1

PubMed Central

Martinez-Arguelles, Daniel B.; Guichard, Theodore; Culty, Martine; Zirkin, Barry R.; Papadopoulos, Vassilios

2011-01-01

We previously reported that in utero exposure of the male fetus to the plasticizer di-(2-ethylhexyl) phthalate (DEHP) resulted in decreased circulating levels of testosterone in the adult without affecting Leydig cell numbers, luteinizing hormone levels, or steroidogenic enzyme expression. Fetal exposure to DEHP resulted in reduced mineralocorticoid receptor (MR; NR3C2) expression in adult Leydig cells. In the present studies, treatment of pregnant Sprague-Dawley dams from Gestational Day 14 until birth with 20, 50, 100, 300, or 750 mg kg−1 day−1 of DEHP resulted in significant sex-specific decreases in serum aldosterone but not corticosterone levels at Postnatal Day 60 (PND60) but not at PND21. There was no effect on circulating levels of potassium, angiotensin II or adrenocorticotropin hormone (ACTH). However, there was reduced expression of AT receptor Agtr1a, Agtr1b, and Agtr2 mRNAs. The mRNA levels of proteins and enzymes implicated in aldosterone biosynthesis were not affected by in utero DEHP treatment except for Cyp11b2, which was decreased at high (≥500 mg kg−1 day−1) doses. The data presented herein, together with our previous observation that aldosterone stimulates testosterone production via an MR-mediated mechanism, suggest that in utero exposure to DEHP causes reduction in both adrenal aldosterone synthesis and MR expression in Leydig cells, leading to reduced testosterone production in the adult. Moreover, these results suggest the existence of a DEHP-sensitive adrenal-testis axis regulating androgen formation. PMID:21389346

Non-stimulated adrenal venous sampling using Dyna computed tomography in patients with primary aldosteronism

PubMed Central

Chang, Chin-Chen; Lee, Bo-Ching; Liu, Kao-Lang; Chang, Yeun-Chung; Wu, Vin-Cent; Huang, Kuo-How

2016-01-01

In this retrospective study, we aimed to examine the effect of applying Dyna computed tomography (CT) on the success rate of adrenal venous sampling (AVS) without adrenocorticotropic hormone stimulation. A total of 100 consecutive patients with primary aldosteronism who underwent AVS between May 2012 and July 2015 were enrolled. In all the cases, Dyna CT was used in AVS to validate catheter position in the right adrenal vein. A selectivity index (cortisoladrenal vein /cortisolinferior vena cava) of ≥2.0 of both adrenal veins were required for successful AVS. Dyna CT indicated misplaced catheters in 16 patients; of these patients, 75% (12/16) eventually had successful right AVS after catheter repositioning. The success rate of initial sampling at the right adrenal vein was 76% (76/100), which increased to 88% (88/100) after Dyna CT was applied (p < 0.001). The most common inadvertently catheterised vessels detected using Dyna CT were the accessory hepatic veins (56.3%, 9/16), followed by the renal capsular veins (37.5%, 6/16). The overall success rate of non-stimulated AVS using Dyna CT was 87% (87/100). Thus, the application of Dyna CT further increased the success rate of non-stimulated AVS. PMID:27876824

Laser autofluorescent spectroscopy in adrenal tumor surgery

NASA Astrophysics Data System (ADS)

Vetshev, Petr S.; Ippolitov, Leonid I.; Loschenov, Victor B.; Kazaryan, Airazat M.; Minnibaev, Marat T.; Vetshev, Sergei P.

1999-12-01

Determination of a histological type of adrenal lesion at the preoperative or intraoperative stage allows to choose the optimal volume of surgery and in the short time effectively correct the postoperative hormonal therapy. 12 patients with different adrenal tumours (3 - lightcellular adenoma, 3 - mixedcellular adenoma, 1 - darkcellular adenoma, 1 - trabecular adenoma, 1 - malignant lymphoma, 3 - aldosteroma, 1 - pheochromocytoma, including the chance of combination of mixedcellular adenoma and aldosteroma of left adrenal) were operated on. The patients' aged varied from 33 to 62 years. For the first time we made intraoperative laser autofluorescent spectroscopy (IOLAS). The laser ve1ength was 632.8 nm. We defined a autofluorescent intensity. Portable equipment was used. The duration of the procedure did not exceed 2mm. The autofluorescent peak of adrenal tissue was 1.33+/-0.05 relativistic unit (RU) at 685 nm. The autofiurescent peaks of adrenal adenomas were 1 .07 RU, 0.9-1 .15 RU, 1.7-1 .9 RU, 3.4 RU accordingly for trabecular adenoma, lightcellular adenoma, mixedcellular adenoma, darkcellular adenoma Besides greater contribution of longwave component to auflurescence is characteristic for mixecellular adenoma and especially for darkcellular adenoma. The autofiurescent peaks of aldosteroma and pheochromocytoma were accordingly 1.2-1.4 RU and 2.2 RU. Spectral distribution of intensity was like mixedcellular adenoma's one. In the case of malignant lymphoma the autofiurescence peak was 2,3 RU and we also noted displacement of maximum of autoflurescence (-15 nm, from 685 nm to 670 nm).The results of IOLAS application as a adjuvant diagnosticmethod point to promise for intraoperative rapid diagnostics of adrenal tumours.

Thapsigargin-induced increase in cytoplasmic Ca2+ concentration and aldosterone production in rat adrenal glomerulosa cells: interaction with potassium and angiotensin-II.

PubMed

Hajnóczky, G; Várnai, P; Holló, Z; Christensen, S B; Balla, T; Enyedi, P; Spät, A

1991-05-01

Thapsigargin (Tg), a microsomal Ca2+ pump inhibitor, dose-dependently increases the cytoplasmic Ca2+ concentration and aldosterone production without having any striking effect on the formation of inositol phosphates in isolated rat adrenal glomerulosa cells. The interaction of Tg with the major Ca2(+)-mediated stimuli of glomerulosa cells on aldosterone production was also examined. The effects of Tg and the Ca2(+)-mobilizing angiotensin-II (AII) were additive. The aldosterone production stimulatory effect of potassium, which induces Ca2+ influx via voltage-operated Ca2+ channels, was potentiated by Tg. The positive interaction between Tg and potassium on aldosterone production raises the possibility that stimuli generating Ca2+ signal by depleting intracellular Ca2+ stores, such as Tg or AII, enhance the response of the cell to depolarization. Such an interaction between AII and potassium may have an important role in the physiological control of aldosterone production.

Evaluation of quantitative parameters for distinguishing pheochromocytoma from other adrenal tumors.

PubMed

Ohno, Youichi; Sone, Masakatsu; Taura, Daisuke; Yamasaki, Toshinari; Kojima, Katsutoshi; Honda-Kohmo, Kyoko; Fukuda, Yorihide; Matsuo, Koji; Fujii, Toshihito; Yasoda, Akihiro; Ogawa, Osamu; Inagaki, Nobuya

2018-03-01

Adrenal tumors are increasingly found incidentally during imaging examinations. It is important to distinguish pheochromocytomas from other adrenal tumors because of the risk of hypertensive crisis. Although catecholamines and their metabolites are generally used to diagnose pheochromocytoma, false-positive test results are common. An effective screening method to distinguish pheochromocytoma from adrenal incidentalomas is needed. We analyzed 297 consecutive patients with adrenal incidentalomas. Our findings included 162 non-functioning tumors, 47 aldosterone-producing adenomas, 26 metastases, 22 cases of subclinical Cushing's syndrome, 21 pheochromocytomas, 12 cases of Cushing's syndrome, and 7 adrenocortical cancers. We checked quantitative parameters such as age, blood, and urine catecholamines and their metabolites, neuron-specific enolase, size and computed tomography (CT) attenuation values. Among catecholamine-related parameters, the sum of urine metanephrine and normetanephrine (urineMNM) levels produced the highest area under the receiver operating characteristic curve regarding discrimination of pheochromocytoma from other lesions. Size and CT attenuation values also differed significantly. However, size was correlated with catecholamine levels. CT attenuation was not correlated with other factors. The optimal thresholds were 19 Hounsfield units (HU) for CT attenuation (sensitivity, 100%; specificity, 60%) and 0.43 mg/24 h for urineMNM (sensitivity, 89%; specificity, 96%). No pheochromocytomas were evident when CT attenuation values were under 19 HU. Even in adrenal tumors with CT attenuation values ≥ 19 HU, when urineMNM was < 0.43 mg/24 h, the frequency of pheochromocytoma was only 4.3%, when urineMNM was ≥ 0.43 mg/24 h, the frequency of pheochromocytoma was 93% and when urineMNM was > 0.77 mg/24 h the frequency of pheochromocytoma was 100%. CT attenuation value and urineMNM represented the most useful combination for

Small-Conductance Ca2+-Activated Potassium Channels Negatively Regulate Aldosterone Secretion in Human Adrenocortical Cells.

PubMed

Yang, Tingting; Zhang, Hai-Liang; Liang, Qingnan; Shi, Yingtang; Mei, Yan-Ai; Barrett, Paula Q; Hu, Changlong

2016-09-01

Aldosterone, which plays a key role in maintaining water and electrolyte balance, is produced by zona glomerulosa cells of the adrenal cortex. Autonomous overproduction of aldosterone from zona glomerulosa cells causes primary hyperaldosteronism. Recent clinical studies have highlighted the pathological role of the KCNJ5 potassium channel in primary hyperaldosteronism. Our objective was to determine whether small-conductance Ca(2+)-activated potassium (SK) channels may also regulate aldosterone secretion in human adrenocortical cells. We found that apamin, the prototypic inhibitor of SK channels, decreased membrane voltage, raised intracellular Ca(2+) and dose dependently increased aldosterone secretion from human adrenocortical H295R cells. By contrast, 1-Ethyl-2-benzimidazolinone, an agonist of SK channels, antagonized apamin's action and decreased aldosterone secretion. Commensurate with an increase in aldosterone production, apamin increased mRNA expression of steroidogenic acute regulatory protein and aldosterone synthase that control the early and late rate-limiting steps in aldosterone biosynthesis, respectively. In addition, apamin increased angiotensin II-stimulated aldosterone secretion, whereas 1-Ethyl-2-benzimidazolinone suppressed both angiotensin II- and high K(+)-stimulated production of aldosterone in H295R cells. These findings were supported by apamin-modulation of basal and angiotensin II-stimulated aldosterone secretion from acutely prepared slices of human adrenals. We conclude that SK channel activity negatively regulates aldosterone secretion in human adrenocortical cells. Genetic association studies are necessary to determine whether mutations in SK channel subtype 2 genes may also drive aldosterone excess in primary hyperaldosteronism. © 2016 American Heart Association, Inc.

Interactions of NADPH oxidase, renin-angiotensin-aldosterone system and reactive oxygen species in mequindox-mediated aldosterone secretion in Wistar rats.

PubMed

Huang, Xian-Ju; Wang, Xu; Ihsan, Awais; Liu, Qin; Xue, Xi-Juan; Su, Shi-Jia; Yang, Chun-Hui; Zhou, Wen; Yuan, Zong-Hui

2010-10-05

High doses of mequindox (MEQ) are associated with oxidative stress and pathological toxicity in the kidney. In this study, we demonstrated long term effects of MEQ on intra- or extra-adrenal renin-angiotensin-aldosterone system (RAAS) in vivo. RAAS plays a major role in aldosterone secretion. High doses of MEQ in the diet for 180 days in male rats led to inhibition of intra- and extra-adrenal RAAS, concident with down-regulation of Na(+)/K(+)-ATPase (NAKA) and mineralocorticoid receptor (MR), the downstream of aldosterone action. Significant changes of malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD) in kidney were also observed in the high doses (110, 275mg/kg) groups. The mRNA levels of most subunits of NADPH oxidase were significantly upregulated at low doses (25-110mg/kg) but the upregulation was diminished at higher doses in both kidney and adrenal gland, indicating a complicated and contradictory effect of MEQ on NADPH. These results highlight the complex interactions of drug metabolism, RAAS, NADPH oxidase and oxidative stress in response to MEQ-induced tissue toxicity and aldosterone secretion. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

A step by step approach in differential diagnosing of adrenal incidentaloma (epinephroma), (with comments on the new Clinical Practice Guidelines of the European Society of Endocrinology).

PubMed

Farrugia, Frederick-Anthony; Misiakos, Evangelos; Martikos, Georgios; Tzanetis, Panagiotis; Charalampopoulos, Anestis; Zavras, Nicolaos; Sotiropoulos, Dimitrios; Koliakos, Nikolaos

2017-12-01

To present a step by step approach for the diagnosis of adrenal incidentaloma (AI). An extensive review of the literature was conducted, searching the Pub-Med and Google Scholar using the Mesh terms; Adrenal; Incidentaloma; Adrenal tumours; Radiology; Diagnosis. We also did a cross-referencing search of the literature. Comments on the new European guidelines are presented. The majority of the tumours are non-functioning benign adenomas. The most important radiological characteristic of an adrenal incidentaloma is the radiation attenuation coefficient. Wash out percentage and the imaging characteristics of the tumour may help in diagnosis. Density less than 10 HU is in most cases characteristic of a lipid rich benign adenoma. More than 10 HU or/and history of malignancy raise the possibility for cancer. 1 mg dexamethasone test and plasma metanephrines should be done in all patients. If there is history of hypokalemia and/or resistant hypertension we test the plasma aldosterone to plasma renin ratio (ARR). Newer studies have shown that tumours even nonfunctioning and less than 4 cm may increase the metabolic risks so we may consider surgery at an earlier stage.

Case report: schwannoma arising from the unilateral adrenal area with bilateral hyperaldosteronism.

PubMed

Babaya, Naru; Makutani, Yukako; Noso, Shinsuke; Hiromine, Yoshihisa; Ito, Hiroyuki; Taketomo, Yasunori; Ueda, Kazuki; Ushijima, Hokuto; Komoike, Yoshifumi; Yamazaki, Yuto; Sasano, Hironobu; Kawabata, Yumiko; Ikegami, Hiroshi

2017-12-06

We report a rare case of a juxta-adrenal schwannoma that could not be discriminated from an adrenal tumor before surgical resection and was complicated by bilateral hyperaldosteronism. To the best of our knowledge, this is first case in which both a juxta-adrenal schwannoma and hyperaldosteronism co-existed. A 69-year-old male treated for hypertension was found to have a left supra-renal mass (5.8 × 5.2 cm) by abdominal computed tomography. His laboratory data showed that his plasma aldosterone concentration (PAC) was within the normal range, but his plasma renin activity (PRA) was reduced, resulting in an increased aldosterone/renin ratio (ARR). Load tests of captopril or furosemide in the standing position demonstrated autonomous aldosterone secretion and renin suppression. Adrenal venous sampling (AVS) with ACTH stimulation indicated bilateral hypersecretion of aldosterone. A left supra-renal tumor was resected because of the possibility of malignancy and was found to be a benign schwannoma arising from the juxta-adrenal region together with an adrenal gland. The dissected left adrenal gland was morphologically hyperplastic in the zona glomerulosa, but was immunohistochemically negative for CYP11B2 (aldosterone synthase). Multiple CYP11B2-positive adrenocortical micronodules were detected in the adrenal gland, indicating micronodular hyperplasia. Although bilateral aldosteronism was indicated by AVS before the operation, the PRA, PAC and ARR values were within their respective reference ranges after resection of the unilateral tumor, suggesting that the slight increase in hormone secretion from the remaining right-sided lesion could not be detected after resection. A clinical and morphologic diagnosis of juxta-adrenal schwannoma is difficult, particularly in a case of hyperaldosteronism, as shown in this case. These data suggest the complexity and difficulty diagnosing adrenal incidentaloma.

Transplantable, STH-producing and diabetogenic pituitary adenoma of the BD IX-strain of rats.

PubMed

Stekar, J

1976-03-19

A chromophobic pituitary adenoma induced on BD IX-rats has been grafted on animals of the same strain. The transplanted tumour takes in 90-100%; it grows at a slow rate (in 7 months after grafting a weight of 7-20 g is attained). Tumour-bearing animals display gigantism and hypertrophy of adrenals; moreover, in 33% of cases, diabetes is observed. With non-diabetic animals, splenomegaly and marked leukocytosis are observed; immature white and red cells are present in the peripheral blood. Spontaneous regression of the tumour never occurs. After surgical removal, tumour regrowth and the formation of metastases are observed. Diabetes is characterised by pronounced hyperglycaemia, glucosuria, polyphagia and polydipsia. Histochemically, insulin cannot be detected in pancreas. Splenomegaly is never observed in diabetic animals. Transplanted adenoma frequently tends to stop growing. No recurrence is observable after extirpation. Spontaneous regression of the tumour sometimes occurs. Gigantism, hypertrophy of adrenals and diabetes are considered as consequences of growth hormone- and ACTH-secretion of the transplanted adenoma. At present the tumour is running in the 8th passage. It did not change its characteristics over a period of 5 years.

Adrenalectomy amplifies aldosterone induced injury in cardiovascular tissue: an effect attenuated by adrenally derived steroids.

PubMed

Brem, Andrew S; Morris, David J; Li, Xiangpo; Ge, Yan; Shaw, Sunil; Gong, Rujun

2013-03-01

Aldosterone induces fibrotic changes in cardiovascular tissues but its effects have usually been demonstrated in models of pre-existing renal injury and/or hypertension. This study tests the hypothesis that aldosterone can directly induce vascular fibrotic changes in the absence of prior renal injury or hypertension. Experiments were conducted in intact or adrenalectomized (ADX) mice. Mice were divided into groups and treated for 1 week with vehicle or aldosterone (8 μg/kg/day)± inhibitor (800 μg/kg/day): CONTROLS, mice treated with aldosterone, ADX-CONTROLS, ADX+corticosterone (CORT 8 μg/kg/day), ADX with aldosterone, ADX with aldosterone plus the mineralocorticoid receptor (MR) antagonist RU-318, ADX with aldosterone+CORT (CORT inhibitor dose), and ADX with aldosterone+11-dehydro-CORT. Aortic smooth muscle to collagen ratio, aorta intimal thickness (μm), heart weight/body weight ratio (mg/gm), and left ventricular collagen (%) were measured. Prior to sacrifice, blood pressures were normal in all animals. Lower dose CORT alone had no effect on any of the variables examined. Aldosterone exposure was associated with extra-cellular matrix accumulation in cardiovascular tissues in intact mice and adrenalectomy exacerbated these effects. RU-318, CORT (inhibitor dose), and 11-deydro-CORT each attenuated the early fibrotic changes induced by aldosterone. In the heart, aldosterone exposure affected all the parameters measured and caused intimal hypercellularity with monocytes adhering to endothelial cells lining coronary vessels. Cultured endothelial cells exposed to aldosterone (10nM) released E-selectin, produced collagen, and promoted monocyte adhesion. These effects were inhibited by RU-318 and 11-deydro-CORT but not by CORT. Thus, adrenalectomy enhances aldosterone induced early fibrotic changes in heart and aorta. Aldosterone initially targets vascular endothelial cells. MR antagonists and 11-dehydro-CORT, an 11β-HSD dehydrogenase end-product, directly

Association Between Pituitary-Adrenal Axis Dominance Over the Renin-Angiotensin-Aldosterone System and Hypertension.

PubMed

Daimon, Makoto; Kamba, Aya; Murakami, Hiroshi; Takahashi, Kazuhisa; Otaka, Hideyuki; Makita, Koushi; Yanagimachi, Miyuki; Terui, Ken; Kageyama, Kazunori; Nigawara, Takeshi; Sawada, Kaori; Takahashi, Ippei; Nakaji, Shigeyuki

2016-03-01

The hypothalamus-pituitary-adrenal (HPA) axis and the renin-angiotensin aldosterone system (RAAS) are well known to be associated with hypertension. However, the extent of the effects is not yet well elucidated in general conditions. To separately determine the effect of the HPA axis and the RAAS on hypertension in a general population. A population-based study of 859 Japanese individuals enrolled in the 2014 Iwaki study and without hypertension or steroid treatment (age, 50.2 ± 14.7 years). Hypertension prevalence, plasma concentration of aldosterone, ACTH, cortisol, and plasma renin activity. Principal component (PC) analysis using these four hormones identified two PCs (PC1 and PC2), which represent levels of these hormones as a whole, and dominance between the HPA axis (ACTH and cortisol) and the RAAS (plasma renin activity and plasma concentration of aldosterone), respectively. Association between these PCs and hypertension was significant (PC1, high vs low, odds ratio [OR], 1.48; 95% confidence interval [CI], 1.09-2.02; and PC2, HPA axis vs RAAS dominancy, OR, 2.08; and 95% CI, 1.51-2.85). However, association between the hormone levels as a whole and hypertension became insignificant after adjustment for multiple factors including these PCs together. However, association between the HPA axis dominance and hypertension remained significant even after the adjustment (the HPA axis vs the RAAS, OR, 1.73; 95% CI, 1.20-2.48). The HPA axis dominance over the RAAS is significantly associated with hypertension in a Japanese population.

Clinical and Genetic Heterogeneity, Overlap with Other Tumor Syndromes, and Atypical Glucocorticoid Hormone Secretion in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia Compared with Other Adrenocortical Tumors

PubMed Central

Hsiao, Hui-Pin; Kirschner, Lawrence S.; Bourdeau, Isabelle; Keil, Margaret F.; Boikos, Sosipatros A.; Verma, Somya; Robinson-White, Audrey J.; Nesterova, Maria; Lacroix, André; Stratakis, Constantine A.

2009-01-01

Objective: ACTH-independent macronodular adrenal hyperplasia (AIMAH) is often associated with subclinical cortisol secretion or atypical Cushing’s syndrome (CS). We characterized a large series of patients of AIMAH and compared them with patients with other adrenocortical tumors. Design and Patients: We recruited 82 subjects with: 1) AIMAH (n = 16); 2) adrenocortical cortisol-producing adenoma with CS (n = 15); 3) aldosterone-producing adenoma (n = 19); and 4) single adenomas with clinically nonsignificant cortisol secretion (n = 32). Methods: Urinary free cortisol (UFC) and 17-hydroxycorticosteroid (17OHS) were collected at baseline and during dexamethasone testing; aberrant receptor responses was also sought by clinical testing and confirmed molecularly. Peripheral and/or tumor DNA was sequenced for candidate genes. Results: AIMAH patients had the highest 17OHS excretion, even when UFCs were within or close to the normal range. Aberrant receptor expression was highly prevalent. Histology showed at least two subtypes of AIMAH. For three patients with AIMAH, there was family history of CS; germline mutations were identified in three other patients in the genes for menin (one), fumarate hydratase (one), and adenomatosis polyposis coli (APC) (one); a PDE11A gene variant was found in another. One patient had a GNAS mutation in adrenal nodules only. There were no mutations in any of the tested genes in the patients of the other groups. Conclusions: AIMAH is a clinically and genetically heterogeneous disorder that can be associated with various genetic defects and aberrant hormone receptors. It is frequently associated with atypical CS and increased 17OHS; UFCs and other measures of adrenocortical activity can be misleadingly normal. PMID:19509103

High risk of adrenal toxicity of N1-desoxy quinoxaline 1,4-dioxide derivatives and the protection of oligomeric proanthocyanidins (OPC) in the inhibition of the expression of aldosterone synthetase in H295R cells.

PubMed

Wang, Xu; Yang, Chunhui; Ihsan, Awais; Luo, Xun; Guo, Pu; Cheng, Guyue; Dai, Menghong; Chen, Dongmei; Liu, Zhenli; Yuan, Zonghui

2016-02-03

Quinoxaline 1,4-dioxide derivatives (QdNOs) with a wide range of biological activities are used in animal husbandry worldwide. It was found that QdNOs significantly inhibited the gene expression of CYP11B1 and CYP11B2, the key aldosterone synthases, and thus reduced aldosterone levels. However, whether the metabolites of QdNOs have potential adrenal toxicity and the role of oxidative stress in the adrenal toxicity of QdNOs remains unclear. The relatively new QdNOs, cyadox (CYA), mequindox (MEQ), quinocetone (QCT) and their metabolites, were selected for elucidation of their toxic mechanisms in H295R cells. Interestingly, the results showed that the main toxic metabolites of QCT, MEQ, and CYA were their N1-desoxy metabolites, which were more harmful than other metabolites and evoked dose and time-dependent cell damage on adrenal cells and inhibited aldosterone production. Gene and protein expression of CYP11B1 and CYP11B2 and mRNA expression of transcription factors, such as NURR1, NGFIB, CREB, SF-1, and ATF-1, were down regulated by N1-desoxy QdNOs. The natural inhibitors of oxidant stress, oligomeric proanthocyanidins (OPC), could upregulate the expression of diverse transcription factors, including CYP11B1 and CYP11B2, and elevated aldosterone levels to reduce adrenal toxicity. This study demonstrated for the first time that N1-desoxy QdNOs have the potential to be the major toxic metabolites in adrenal toxicity, which may shed new light on the adrenal toxicity of these fascinating compounds and help to provide a basic foundation for the formulation of safety controls for animal products and the design of new QdNOs with less harmful effects. Copyright © 2016. Published by Elsevier Ireland Ltd.

Clock genes and salt-sensitive hypertension: a new type of aldosterone-synthesizing enzyme controlled by the circadian clock and angiotensin II.

PubMed

Okamura, Hitoshi; Doi, Masao; Goto, Kaoru; Kojima, Rika

2016-10-01

With the current societal norm of shiftwork and long working hours, maintaining a stable daily life is becoming very difficult. An irregular lifestyle disrupts circadian rhythms, resulting in the malfunction of body physiology and ultimately leading to lifestyle-related diseases, including hypertension. By analyzing completely arrhythmic Cry1/Cry2 double-knockout (Cry-null) mice, we found salt-sensitive hypertension accompanied by hyperaldosteronism. On the basis of a DNA microarray analysis of the adrenal gland and subsequent biochemical analyses, we discovered that Hsd3b6/HSD3B1, a subtype of 3β-HSD, is markedly overexpressed in aldosterone-producing cells in the Cry-null adrenal cortex. In addition, we found that Hsd3b6/HSD3B1, which converts pregnenolone to progesterone, is a clock-controlled gene and might also be a key enzyme for the regulation of aldosterone biosynthesis, in addition to the previously established CYP11B2, which synthesizes aldosterone from deoxycorticosterone. Importantly, angiotensin II induces HSD3B1 via the transcription factor NGFIB in human adrenocortical H295R cells, similarly to CYP11B2. As HSD3B1 levels are abnormally high in the adrenal aldosterone-producing cells of idiopathic hyperaldosteronism (IHA), the temporal component of this system in the pathophysiology of IHA is a promising area for future research.

Cushing's syndrome and the nodular adrenal gland.

PubMed

Samuels, M H; Loriaux, D L

1994-09-01

This article examines Cushing's syndrome in four main categories as associated with nodular adrenal glands: adrenal adenoma, adrenal carcinoma, primary pigmented nodular adrenal dysplasia, and macronodular adrenal hyperplasia. A summary of clinical features of these four categories is presented.

Adrenal vein sampling in primary aldosteronism: concordance of simultaneous vs sequential sampling.

PubMed

Almarzooqi, Mohamed-Karji; Chagnon, Miguel; Soulez, Gilles; Giroux, Marie-France; Gilbert, Patrick; Oliva, Vincent L; Perreault, Pierre; Bouchard, Louis; Bourdeau, Isabelle; Lacroix, André; Therasse, Eric

2017-02-01

Many investigators believe that basal adrenal venous sampling (AVS) should be done simultaneously, whereas others opt for sequential AVS for simplicity and reduced cost. This study aimed to evaluate the concordance of sequential and simultaneous AVS methods. Between 1989 and 2015, bilateral simultaneous sets of basal AVS were obtained twice within 5 min, in 188 consecutive patients (59 women and 129 men; mean age: 53.4 years). Selectivity was defined by adrenal-to-peripheral cortisol ratio ≥2, and lateralization was defined as an adrenal aldosterone-to-cortisol ratio ≥2, the contralateral side. Sequential AVS was simulated using right sampling at -5 min (t = -5) and left sampling at 0 min (t = 0). There was no significant difference in mean selectivity ratio (P = 0.12 and P = 0.42 for the right and left sides respectively) and in mean lateralization ratio (P = 0.93) between t = -5 and t = 0. Kappa for selectivity between 2 simultaneous AVS was 0.71 (95% CI: 0.60-0.82), whereas it was 0.84 (95% CI: 0.76-0.92) and 0.85 (95% CI: 0.77-0.93) between sequential and simultaneous AVS at respectively -5 min and at 0 min. Kappa for lateralization between 2 simultaneous AVS was 0.84 (95% CI: 0.75-0.93), whereas it was 0.86 (95% CI: 0.78-0.94) and 0.80 (95% CI: 0.71-0.90) between sequential AVS and simultaneous AVS at respectively -5 min at 0 min. Concordance between simultaneous and sequential AVS was not different than that between 2 repeated simultaneous AVS in the same patient. Therefore, a better diagnostic performance is not a good argument to select the AVS method. © 2017 European Society of Endocrinology.

A Novel Phenotype of Familial Hyperaldosteronism Type III: Concurrence of Aldosteronism and Cushing's Syndrome

PubMed Central

Liu, Guanghua; Wang, Fen; Jiang, Jun; Yan, Zhaoli; Zhang, Dianxi; Zhang, Yinsheng

2016-01-01

Context: To date, all the familial hyperaldosteronism type III (FH-III) patients reported presenting with typical primary aldosteronism (PA), without showing other adrenal hormone abnormalities. Objective: This study characterized a novel phenotype of FH-III and explored the possible pathogenesis. Patients and Methods: A male patient presented with severe hypertension and hypokalemia at the age of 2 years and developed Cushing's syndrome at 20 years. He was diagnosed with PA and Cushing's syndrome on the basis of typical biochemical findings. He had massive bilateral adrenal hyperplasia and underwent left adrenalectomy. KCNJ5 was sequenced, and secretion of aldosterone and cortisol were observed both in vivo and in vitro. Results: A heterozygous germline p.Glu145Gln mutation of KCNJ5 was identified. ARMC5, PRKAR1A, PDE8B, PDE11A, and PRKACA genes and β-catenin, P53 immunoactivity were normal in the adrenal. CYP11B2 was highly expressed, whereas mRNA expression of CYP11B1, CYP17A1, and STAR was relatively low in the hyperplastic adrenal, compared with normal adrenal cortex and other adrenal diseases. In the primary cell culture of the resected hyperplastic adrenal, verapamil and nifedipine, two calcium channel blockers, markedly inhibited the secretion of both aldosterone and cortisol and the mRNA expression of CYP11B1, CYP11B2, CYP17A1, and STAR. Conclusions: We presented the first FH-III patient who had both severe PA and Cushing's syndrome. Hypersecretion of cortisol might be ascribed to overly large size of the hyperplastic adrenal because CYP11B1 expression was relatively low in his adrenal. Like aldosterone, synthesis and secretion of cortisol in the mutant adrenal may be mediated by voltage-gated Ca2+ channels. PMID:27403928

The prevalence of CTNNB1 mutations in primary aldosteronism and consequences for clinical outcomes.

PubMed

Wu, Vin-Cent; Wang, Shuo-Meng; Chueh, Shih-Chieh Jeff; Yang, Shao-Yu; Huang, Kuo-How; Lin, Yen-Hung; Wang, Jian-Jhong; Connolly, Rory; Hu, Ya-Hui; Gomez-Sanchez, Celso E; Peng, Kang-Yung; Wu, Kwan-Dun

2017-01-19

Constitutive activation of the Wnt pathway/β-catenin signaling may be important in aldosterone-producing adenoma (APA). However, significant gaps remain in our understanding of the prevalence and clinical outcomes after adrenalectomy in APA patients harboring CTNNB1 mutations. The molecular expression of CYP11B2 and gonadal receptors in adenomas were also explored. Adenomas from 219 APA patients (95 men; 44.2%; aged 50.5 ± 11.9 years) showed a high rate of somatic mutations (n = 128, 58.4%). The majority of them harbored KCNJ5 mutations (n = 116, 52.9%); 8 patients (3.7%, 6 women) had CTNNB1 mutations. Patients with APAs harboring CTNNB1 mutations were older and had shorter duration of hypertension. After adrenalectomy, CTNNB1 mutation carriers had a higher possibility (87.5%) of residual hypertension than other APA patients. APAs harboring CTNNB1 mutations have heterogeneous staining of β-catenin and variable expression of gonadal receptors and both CYP11B1 and CYP11B2. This suggests that CTNNB1 mutations may be more related to tumorigenesis rather than excessive aldosterone production.

Clinicopathological correlates of adrenal Cushing's syndrome.

PubMed

Duan, Kai; Hernandez, Karen Gomez; Mete, Ozgur

2015-06-01

Endogenous Cushing's syndrome is a rare endocrine disorder that incurs significant cardiovascular morbidity and mortality, due to glucocorticoid excess. It comprises adrenal (20%) and non-adrenal (80%) aetiologies. While the majority of cases are attributed to pituitary or ectopic corticotropin (ACTH) overproduction, primary cortisol-producing adrenal cortical lesions are increasingly recognised in the pathophysiology of Cushing's syndrome. Our understanding of this disease has progressed substantially over the past decade. Recently, important mechanisms underlying the pathogenesis of adrenal hypercortisolism have been elucidated with the discovery of mutations in cyclic AMP signalling (PRKACA, PRKAR1A, GNAS, PDE11A, PDE8B), armadillo repeat containing 5 gene (ARMC5) a putative tumour suppressor gene, aberrant G-protein-coupled receptors, and intra-adrenal secretion of ACTH. Accurate subtyping of Cushing's syndrome is crucial for treatment decision-making and requires a complete integration of clinical, biochemical, imaging and pathology findings. Pathological correlates in the adrenal glands include hyperplasia, adenoma and carcinoma. While the most common presentation is diffuse adrenocortical hyperplasia secondary to excess ACTH production, this entity is usually treated with pituitary or ectopic tumour resection. Therefore, when confronted with adrenalectomy specimens in the setting of Cushing's syndrome, surgical pathologists are most commonly exposed to adrenocortical adenomas, carcinomas and primary macronodular or micronodular hyperplasia. This review provides an update on the rapidly evolving knowledge of adrenal Cushing's syndrome and discusses the clinicopathological correlations of this important disease. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Clinicopathological correlates of adrenal Cushing's syndrome.

PubMed

Duan, Kai; Gomez Hernandez, Karen; Mete, Ozgur

2015-03-01

Endogenous Cushing's syndrome is a rare endocrine disorder that incurs significant cardiovascular morbidity and mortality, due to glucocorticoid excess. It comprises adrenal (20%) and non-adrenal (80%) aetiologies. While the majority of cases are attributed to pituitary or ectopic corticotropin (ACTH) overproduction, primary cortisol-producing adrenal cortical lesions are increasingly recognised in the pathophysiology of Cushing's syndrome. Our understanding of this disease has progressed substantially over the past decade. Recently, important mechanisms underlying the pathogenesis of adrenal hypercortisolism have been elucidated with the discovery of mutations in cyclic AMP signalling (PRKACA, PRKAR1A, GNAS, PDE11A, PDE8B), armadillo repeat containing 5 gene (ARMC5) a putative tumour suppressor gene, aberrant G-protein-coupled receptors, and intra-adrenal secretion of ACTH. Accurate subtyping of Cushing's syndrome is crucial for treatment decision-making and requires a complete integration of clinical, biochemical, imaging and pathology findings. Pathological correlates in the adrenal glands include hyperplasia, adenoma and carcinoma. While the most common presentation is diffuse adrenocortical hyperplasia secondary to excess ACTH production, this entity is usually treated with pituitary or ectopic tumour resection. Therefore, when confronted with adrenalectomy specimens in the setting of Cushing's syndrome, surgical pathologists are most commonly exposed to adrenocortical adenomas, carcinomas and primary macronodular or micronodular hyperplasia. This review provides an update on the rapidly evolving knowledge of adrenal Cushing's syndrome and discusses the clinicopathological correlations of this important disease. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

NADPH Oxidase-Derived H2O2 Contributes to Angiotensin II-Induced Aldosterone Synthesis in Human and Rat Adrenal Cortical Cells

PubMed Central

Rajamohan, Senthilkumar B.; Raghuraman, Gayatri; Prabhakar, Nanduri R.

2012-01-01

Abstract Background The Renin-Angiotensin-Aldosterone-System plays a pivotal role in hypertension. Angiotensin II (Ang II) is a major regulator of aldosterone synthesis and secretion, and it is known to facilitate reactive oxygen species (ROS) generation in many cell types. Aims: Here, we assessed the role of ROS signaling in Ang II-induced aldosterone synthesis by focusing on the regulation of aldosterone synthase (CYP11B2), a cytochrome P450 oxidase that catalyzes the final step in aldosterone biosynthetic pathway. Results: Ang II increased CYP11B2 activity, mRNA and protein with a concomitant elevation of 6-Carboxy- 2′,7′-dichlorodihydrofluorescein diacetate fluorescence, malondialdehyde and protein carbonyl levels (indices of ROS), NADPH oxidase (Nox) activity, and H2O2 levels in human and rat adrenal cortical cells. The expression of nuclear receptor related 1 protein, a transcription factor known to regulate CYP11B2 expression, was also augmented by Ang II. These Ang II-evoked effects were either abolished or attenuated by pretreatment of cells with either Ang II type I receptor (AT1R) antagonist, or antioxidants or Nox inhibitor or siRNA silencing of Nox1, 2 and 4, or inhibitors of phospholipase C and protein kinase C. Exogenous H2O2 mimicked the facilitatory effects of Ang II on CYP11B2 activity, mRNA, and protein expression, and these changes were significantly reduced by PEG-catalase. Innovation: ROS, particularly H2O2, is identified as a key regulator of aldosterone production. Conclusion: Our results suggest that Ang II facilitates CYP11B2 activity and the ensuing aldosterone production via activation of AT1R-Nox-H2O2 signaling pathway. Antioxid. Redox Signal. 17, 445–459. PMID:22214405

Application of strict criteria in adrenal venous sampling increases the proportion of missed patients with unilateral disease who benefit from surgery for primary aldosteronism.

PubMed

Kline, Gregory; Leung, Alexander; So, Benny; Chin, Alex; Harvey, Adrian; Pasieka, Janice L

2018-06-01

Adrenal vein sampling (AVS) is intended to confirm unilateral forms of primary aldosteronism, which are amenable to surgical cure. Excessively strict AVS criteria to define lateralization may result in many patients incorrectly categorized as bilateral primary aldosteronism and opportunity for surgical cure missed. Retrospective review of an AVS-primary aldosteronism database in which surgical cases are verified by standardized outcomes. Having used 'less strict' AVS criteria for lateralization, we examined the distribution of AVS lateralization indices in our confirmed unilateral primary aldosteronism cases both with and without cosyntropin stimulation. The proportion of proven unilateral cases that would have been missed with stricter AVS interpretation criteria was calculated. Particular focus was given to the proportion of missed cases according to use of international guidelines. False-positive lateralization with 'less strict' interpretation was also calculated. Of 80 surgical primary aldosteronism cases, 10-23% would have been missed with AVS lateralization indices of 3 : 1 to 5 : 1, with or without cosyntropin. If strict selectivity indices (for confirmation of catheterization) were combined with strict lateralization indices, up to 70% of unilateral primary aldosteronism cases could have been missed. Use of Endocrine Society AVS guidelines would have missed 21-43% of proven unilateral cases. 'Less strict' AVS interpretation yielded one case (1.2%) of false lateralization. Excessively strict AVS interpretation criteria will result in a high rate of missed unilateral primary aldosteronism with subsequent loss of opportunity for intervention. Use of more lenient lateralization criteria will improve the detection rate of unilateral primary aldosteronism with very low false-positive rate.

A case of adrenal Cushing's syndrome with bilateral adrenal masses.

PubMed

Guo, Ya-Wun; Hwu, Chii-Min; Won, Justin Ging-Shing; Chu, Chia-Huei; Lin, Liang-Yu

2016-01-01

A functional lesion in corticotrophin (ACTH)-independent Cushing's syndrome is difficult to distinguish from lesions of bilateral adrenal masses. Methods for distinguishing these lesions include adrenal venous sampling and (131)I-6β-iodomethyl-19-norcholesterol ((131)I-NP-59) scintigraphy. We present a case of a 29-year-old Han Chinese female patient with a history of hypercholesterolaemia and polycystic ovary syndrome. She presented with a 6month history of an 8kg body weight gain and gradual rounding of the face. Serial examinations revealed loss of circadian rhythm of cortisol, elevated urinary free-cortisol level and undetectable ACTH level (<5pg/mL). No suppression was observed in both the low- and high-dose dexamethasone suppression tests. Adrenal computed tomography revealed bilateral adrenal masses. Adrenal venous sampling was performed, and the right-to-left lateralisation ratio was 14.29. The finding from adrenal scintigraphy with NP-59 was consistent with right adrenal adenoma. The patient underwent laparoscopic right adrenalectomy, and the pathology report showed adrenocortical adenoma. Her postoperative cortisol level was 3.2μg/dL, and her Cushingoid appearance improved. In sum, both adrenal venous sampling and (131)I-NP-59 scintigraphy are good diagnostic methods for Cushing's syndrome presenting with bilateral adrenal masses. The clinical presentation of Cushing' syndrome includes symptoms and signs of fat redistribution and protein-wasting features.The diagnosis of patients with ACTH-independent Cushing's syndrome with bilateral adrenal masses is challenging for localisation of the lesion.Both adrenal venous sampling and (131)I-NP-59 scintigraphy are good methods to use in these patients with Cushing's syndrome presenting with bilateral adrenal masses.

Molecular identity and gene expression of aldosterone synthase cytochrome P450

DOE Office of Scientific and Technical Information (OSTI.GOV)

Okamoto, Mitsuhiro; Nonaka, Yasuki; Takemori, Hiroshi

11{beta}-Hydroxylase (CYP11B1) of bovine adrenal cortex produced corticosterone as well as aldosterone from 11-deoxycorticosterone in the presence of the mitochondrial P450 electron transport system. CYP11B1s of pig, sheep, and bullfrog, when expressed in COS-7 cells, also performed corticosterone and aldosterone production. Since these CYP11B1s are present in the zonae fasciculata and reticularis as well as in the zona glomerulosa, the zonal differentiation of steroid production may occur by the action of still-unidentified factor(s) on the enzyme-catalyzed successive oxygenations at C11- and C18-positions of steroid. In contrast, two cDNAs, one encoding 11{beta}-hydroxylase and the other encoding aldosterone synthase (CYP11B2), were isolatedmore » from rat, mouse, hamster, guinea pig, and human adrenals. The expression of CYP11B1 gene was regulated by cyclic AMP (cAMP)-dependent signaling, whereas that of CYP11B2 gene by calcium ion-signaling as well as cAMP-signaling. Salt-inducible protein kinase, a cAMP-induced novel protein kinase, was one of the regulators of CYP11B2 gene expression.« less

Adrenal hormones before and after venography during adrenal venous sampling: a self-controlled study.

PubMed

Koike, Yuya; Matsui, Seishi; Omura, Masao; Makita, Kohzoh; Obara, Alfonso W D; Moriya, Nobukazu; Nishikawa, Tetsuo

2017-03-01

A stress reaction involving increased adrenal hormone release occurs when starting adrenal venous sampling (AVS). The purpose of the present study was to investigate the effect of single shot venography on adrenal hormone production during AVS. This was a prospective self-controlled study. We enrolled 54 consecutive patients (21 men, 33 women; mean age 52 ± 11 years) with primary aldosteronism who underwent AVS from May 2014 to February 2015. Under non-stimulated conditions, blood samples were obtained from a common trunk of the left adrenal vein before and after single shot venography. The initial plasma aldosterone and cortisol concentration (PAC and PCC) were compared with those measured after venography for each patient. PAC and PCC were slightly but significantly decreased between before and after venography (after log transformation 2.12 ± 0.73 vs 2.07 ± 0.72, P = 0.00066, 1.89 ± 0.52 vs 1.83 ± 0.53, P = 0.00031, respectively). During non-stimulated left AVS, adrenal hormone secretion was slightly but significantly decreased after venography, similar to the normal time-related stress reaction. Venography did not increase the adrenal hormone secretion.

VLDL-activated cell signaling pathways that stimulate adrenal cell aldosterone production

PubMed Central

Tsai, Ying-Ying; Rainey, William E.; Johnson, Maribeth H.; Bollag, Wendy B.

2016-01-01

Aldosterone plays an important role in regulating ion and fluid homeostasis and thus blood pressure, and hyperaldosteronism results in hypertension. Hypertension is also observed with obesity, which is associated with additional health risks, including cardiovascular disease. Obese individuals have high serum levels of very low-density lipoprotein (VLDL), which has been shown to stimulate aldosterone production; however, the mechanisms underlying VLDL-induced aldosterone production are still unclear. Here we demonstrate in human adrenocortical carcinoma (HAC15) cells that submaximal concentrations of angiotensin II and VLDL stimulate aldosterone production in an additive fashion, suggesting the possibility of common mechanisms of action. We show using inhibitors that VLDL-induced aldosterone production is mediated by the PLC/IP3/PKC signaling pathway. Our results suggest that PKC is upstream of the extracellular signal-regulated kinase (ERK) activation previously observed with VLDL. An understanding of the mechanisms mediating VLDL-induced aldosterone production may provide insights into therapies to treat obesity-associated hypertension. PMID:27222295

VLDL-activated cell signaling pathways that stimulate adrenal cell aldosterone production.

PubMed

Tsai, Ying-Ying; Rainey, William E; Johnson, Maribeth H; Bollag, Wendy B

2016-09-15

Aldosterone plays an important role in regulating ion and fluid homeostasis and thus blood pressure, and hyperaldosteronism results in hypertension. Hypertension is also observed with obesity, which is associated with additional health risks, including cardiovascular disease. Obese individuals have high serum levels of very low-density lipoprotein (VLDL), which has been shown to stimulate aldosterone production; however, the mechanisms underlying VLDL-induced aldosterone production are still unclear. Here we demonstrate in human adrenocortical carcinoma (HAC15) cells that submaximal concentrations of angiotensin II and VLDL stimulate aldosterone production in an additive fashion, suggesting the possibility of common mechanisms of action. We show using inhibitors that VLDL-induced aldosterone production is mediated by the PLC/IP3/PKC signaling pathway. Our results suggest that PKC is upstream of the extracellular signal-regulated kinase (ERK) activation previously observed with VLDL. An understanding of the mechanisms mediating VLDL-induced aldosterone production may provide insights into therapies to treat obesity-associated hypertension. Published by Elsevier Ireland Ltd.

Acute and Chronic Regulation of Aldosterone Production

PubMed Central

Hattangady, Namita; Olala, Lawrence; Bollag, Wendy B.; Rainey, William E.

2011-01-01

Aldosterone is the major mineralocorticoid synthesized by the adrenal. Secretion of aldosterone is regulated tightly by the adrenocortical glomerulosa cells due to the selective expression of CYP11B2 in the outermost zone, the zona glomerulosa. Aldosterone is largely responsible for regulation of systemic blood pressure through the absorption of electrolytes and water under the regulation of certain specific agonists. Angiotensin II (Ang II), potassium (K+) and adrenocorticotropin (ACTH) are the main physiological agonists which regulate aldosterone secretion. The mechanisms involved in this process may be regulated minutes after a stimulus (acutely) through increased expression and phosphorylation of the steroidogenic acute regulatory (StAR) protein, over hours to days (chronically) by increased expression of the enzymes involved in the synthesis of aldosterone, particularly aldosterone synthase (CYP11B2). Imbalance in any of these processes may lead to several aldosterone excess disorders. In this review we attempt to summarize the key molecular events involved in and specifically attributed to the acute and chronic phases of aldosterone secretion. PMID:21839803

Impact of hypercortisolism on skeletal muscle mass and adipose tissue mass in patients with adrenal adenomas.

PubMed

Delivanis, Danae A; Iñiguez-Ariza, Nicole M; Zeb, Muhammad H; Moynagh, Michael R; Takahashi, Naoki; McKenzie, Travis J; Thomas, Melinda A; Gogos, Charalambos; Young, William F; Bancos, Irina; Kyriazopoulou, Venetsana

2018-02-01

Abdominal visceral adiposity and central sarcopenia are markers of increased cardiovascular risk and mortality. To assess whether central sarcopenia and adiposity can serve as a marker of disease severity in patients with adrenal adenomas and glucocorticoid secretory autonomy. Retrospective cohort study. Twenty-five patients with overt Cushing's syndrome (CS), 48 patients with mild autonomous cortisol excess (MACE) and 32 patients with a nonfunctioning adrenal tumour (NFAT) were included. Medical records were reviewed, and body composition measurements (visceral fat [VAT], subcutaneous fat [SAT], visceral/total fat [V/T], visceral/subcutaneous [V/S] and total abdominal muscle mass) were calculated based on abdominal computed tomography (CT). In patients with overt CS, when compared to patients with NFAT, the V/T fat and the V/S ratio were increased by 0.08 (P < .001) and by 0.3 (P < .001); however, these measurements were decreased by 0.04 (P = .007) and 0.2 (P = .01), respectively, in patients with MACE. Total muscle mass was decreased by -10 cm 2 (P = .02) in patients with overt CS compared to patients with NFAT. Correlation with morning serum cortisol concentrations after dexamethasone suppression testing revealed that for every 28 nmol/L cortisol increase there was a 0.008 increase in V/T (P < .001), 0.02 increase in the V/S fat ratio (P < .001) and a 1.2 cm 2 decrease in mean total muscle mass (P = .002). The severity of hypercortisolism was correlated with lower muscle mass and higher visceral adiposity. These CT-based markers may allow for a more reliable and objective assessment of glucocorticoid-related disease severity in patients with adrenal adenomas. © 2017 John Wiley & Sons Ltd.

Hyperandrogenism due to a testosterone-secreting Sertoli-Leydig cell tumor associated with a dehydroepiandrosterone sulfate-secreting adrenal adenoma in a postmenopausal woman: case presentation and review of literature.

PubMed

Herrera, Jorge D; Davidson, Jaime A; Mestman, Jorge H

2009-03-01

To report a case of hyperandrogenism attributable to the presence of an adrenal adenoma secreting dehydroepiandrosterone sulfate (DHEA-S) and an ovarian Sertoli-Leydig cell tumor secreting testosterone in a postmenopausal woman. The laboratory, radiologic, and pathologic findings in our case are described. In addition, the pertinent literature is reviewed. A 56-year-old woman presented with a history of gradual increase in facial and body hair, scalp hair loss, male pattern baldness, and deepening of her voice, beginning a few years after spontaneous menopause at age 49 years. She had hypertension, obesity, and type 2 diabetes mellitus. Laboratory tests showed elevated levels of total testosterone (348 ng/dL) and DHEA-S (2,058 microg/dL), and a left adrenal tumor (3 by 4 cm) was detected on abdominal computed tomographic scan. Laparoscopic left adrenalectomy was performed, and the pathologic diagnosis was adrenal adenoma. The DHEA-S returned to normal levels, but the serum testosterone concentration remained elevated. Transvaginal ultrasonography disclosed an ovarian tumor. Bilateral oophorectomy was performed, and an ovarian Sertoli-Leydig cell tumor was diagnosed. The hormonal and clinical picture normalized after this surgical intervention. After extensive review of the literature, we believe that this is the first reported case of a coincidental DHEA-S-secreting adrenal adenoma and a testosterone- secreting ovarian Leydig cell tumor causing signs of virilization.

Reversible heart rhythm complexity impairment in patients with primary aldosteronism

NASA Astrophysics Data System (ADS)

Lin, Yen-Hung; Wu, Vin-Cent; Lo, Men-Tzung; Wu, Xue-Ming; Hung, Chi-Sheng; Wu, Kwan-Dun; Lin, Chen; Ho, Yi-Lwun; Stowasser, Michael; Peng, Chung-Kang

2015-08-01

Excess aldosterone secretion in patients with primary aldosteronism (PA) impairs their cardiovascular system. Heart rhythm complexity analysis, derived from heart rate variability (HRV), is a powerful tool to quantify the complex regulatory dynamics of human physiology. We prospectively analyzed 20 patients with aldosterone producing adenoma (APA) that underwent adrenalectomy and 25 patients with essential hypertension (EH). The heart rate data were analyzed by conventional HRV and heart rhythm complexity analysis including detrended fluctuation analysis (DFA) and multiscale entropy (MSE). We found APA patients had significantly decreased DFAα2 on DFA analysis and decreased area 1-5, area 6-15, and area 6-20 on MSE analysis (all p < 0.05). Area 1-5, area 6-15, area 6-20 in the MSE study correlated significantly with log-transformed renin activity and log-transformed aldosterone-renin ratio (all p < = 0.01). The conventional HRV parameters were comparable between PA and EH patients. After adrenalectomy, all the altered DFA and MSE parameters improved significantly (all p < 0.05). The conventional HRV parameters did not change. Our result suggested that heart rhythm complexity is impaired in APA patients and this is at least partially reversed by adrenalectomy.

Clinical Characteristics and Long-Term Outcome of Primary Aldosteronism in a Norwegian Population.

PubMed

Grytaas, Marianne Aardal; Strømsøy, Siri S; Rørvik, Jarle Tor; Arnes, Jarle Birger; Heie, Anette; Arnesen, Thomas; Jørstad, Melissa D; Nedrebø, Bjørn Gunnar; Jøssang, Dag Erik; Jensen, Dag Kjartan; Rørvik, Håvard D; Sagen, Jørn Vegard; Mellgren, Gunnar; Thordarson, Hrafnkell B; Husebye, Eystein Sverre; Løvås, Kristian

2017-11-01

Primary aldosteronism (PA) is the most common cause of secondary hypertension (HT). We describe here clinical characteristics, diagnostic procedures, and long-term outcomes in a Norwegian population. All suspected PA patients investigated at a tertiary centre from 1998–2012 were retrospectively evaluated. Inclusion criteria were verified PA after confirmatory testing or otherwise considered highly likely PA. Clinical, biochemical, radiological, and adrenal vein sampling (AVS) findings were analysed. Surgically removed adrenals were re-evaluated histopathologically and tested for somatic mutations. All patients still alive by August 2014 were invited to a follow-up visit. One-hundred and eight patients were included, of whom 85% had a history of hypokalaemia. PA was verified by confirmatory testing in 83 (77%), and AVS performed in 95 (88%) patients. The proportion with AVS-confirmed bilateral PA increased during the study period. Sixty-eight patients (63%) underwent adrenalectomy. KCNJ5 mutations were found in 30% of the surgical specimens and were associated with female sex and a florid PA phenotype. Follow-up visits were undertaken in 73/108 (68%), of whom 52 adrenalectomised. After adrenalectomy, 83% were biochemically cured of PA, but only 21% were cured for HT. Female sex, a verified adenoma, and KCNJ5 mutations were associated with cure of HT. In conclusion, the majority of our patients had unilateral PA and hypokalaemia, indicating that patients with bilateral and milder PA may still be underdiagnosed. Female sex, a histopathological adenoma, and the presence of KCNJ5 mutations predicted cure of HT after adrenalectomy, but the overall cure rate of HT was low.

Suppressive effects of RXR agonist PA024 on adrenal CYP11B2 expression, aldosterone secretion and blood pressure.

PubMed

Suzuki, Dai; Saito-Hakoda, Akiko; Ito, Ryo; Shimizu, Kyoko; Parvin, Rehana; Shimada, Hiroki; Noro, Erika; Suzuki, Susumu; Fujiwara, Ikuma; Kagechika, Hiroyuki; Rainey, William E; Kure, Shigeo; Ito, Sadayoshi; Yokoyama, Atsushi; Sugawara, Akira

2017-01-01

The effects of retinoids on adrenal aldosterone synthase gene (CYP11B2) expression and aldosterone secretion are still unknown. We therefore examined the effects of nuclear retinoid X receptor (RXR) pan-agonist PA024 on CYP11B2 expression, aldosterone secretion and blood pressure, to elucidate its potential as a novel anti-hypertensive drug. We demonstrated that PA024 significantly suppressed angiotensin II (Ang II)-induced CYP11B2 mRNA expression, promoter activity and aldosterone secretion in human adrenocortical H295R cells. Human CYP11B2 promoter functional analyses using its deletion and point mutants indicated that the suppression of CYP11B2 promoter activity by PA024 was in the region from -1521 (full length) to -106 including the NBRE-1 and the Ad5 elements, and the Ad5 element may be mainly involved in the PA024-mediated suppression. PA024 also significantly suppressed the Ang II-induced mRNA expression of transcription factors NURR1 and NGFIB that bind to and activate the Ad5 element. NURR1 overexpression demonstrated that the decrease of NURR1 expression may contribute to the PA024-mediated suppression of CYP11B2 transcription. PA024 also suppressed the Ang II-induced mRNA expression of StAR, HSD3β2 and CYP21A2, a steroidogenic enzyme group involved in aldosterone biosynthesis. Additionally, the PA024-mediated CYP11B2 transcription suppression was shown to be exerted via RXRα. Moreover, the combination of PPARγ agonist pioglitazone and PA024 caused synergistic suppressive effects on CYP11B2 mRNA expression. Finally, PA024 treatment significantly lowered both the systolic and diastolic blood pressure in Tsukuba hypertensive mice (hRN8-12 x hAG2-5). Thus, RXR pan-agonist PA024 may be a candidate anti-hypertensive drugs that acts via the suppression of aldosterone synthesis and secretion.

Comparison between adrenal venous sampling and computed tomography in the diagnosis of primary aldosteronism and in the guidance of adrenalectomy

PubMed Central

Zhu, Limin; Zhang, Ying; Zhang, Hua; Zhou, Wenlong; Shen, Zhoujun; Zheng, Fangfang; Tang, Xiaofeng; Tao, Bo; Zhang, Jin; Lu, Xiaohong; Xu, Jianzhong; Chu, Shaoli; Zhu, Dingliang; Gao, Pingjin; Wang, Ji-Guang

2016-01-01

Abstract In our series of patients with primary aldosteronism, we compared diagnostic concordance and clinical outcomes after adrenalectomy between adrenal venous sampling (AVS) and computed tomography (CT) imaging. Our retrospective analysis included 886 patients with primary aldosteronism diagnosed in our hospital between 2005 and 2014. Of them, 269 patients with CT unilateral adrenal disease were included in the analysis on the diagnostic concordance and 126 patients with follow-up data in the analysis on clinical outcomes after adrenalectomy. Hypertension was considered cured if systolic/diastolic blood pressure (BP) was controlled (<140/90 mm Hg) without medication and improved if BP was controlled with a reduced number of antihypertensive drugs. In 269 patients with CT unilateral adrenal disease, the overall concordance rate between AVS and CT was 50.5% for lateralization on the same side. The concordance rate decreased with increasing age, with highest rate of 61% in patients aged <30 years (n = 16). In 126 patients with follow-up data after adrenalectomy, the AVS- (n = 96) and CT-guided patients (n = 30) had similar characteristics before adrenalectomy. After andrenalectomy, the AVS-guided patients had a significantly higher serum potassium concentration (4.3 ± 0.3 vs 4.0 ± 0.5 mmol/L, P = 0.04) and rate of cured and improved hypertension (98% vs 87%, P = 0.03). The AVS-guided patients (n = 50) had slightly higher cured rate than the CT-guided patients (n = 11) in those older than 50 years (26.0% vs 18.2%, P = 0.72). The age below which the cured rate in the CT-guided patients was 100% was 30 years. AVS guidance had moderate concordance with CT and slightly improved clinical outcomes after adrenalectomy. The age below which CT unilateralization achieved 100% cured rate was approximately 30 years. PMID:27684853

Image-Guided Ablation of Adrenal Lesions

PubMed Central

Yamakado, Koichiro

2014-01-01

Although laparoscopic adrenalectomy has remained the standard of care for the treatment for adrenal tumors, percutaneous image-guided ablation therapy, such as chemical ablation, radiofrequency ablation, cryoablation, and microwave ablation, has been shown to be clinically useful in many nonsurgical candidates. Ablation therapy has been used to treat both functioning adenomas and malignant tumors, including primary adrenal carcinoma and metastasis. For patients with functioning adenomas, biochemical and symptomatic improvement is achieved in 96 to 100% after ablation; for patients with malignant adrenal neoplasms, however, the survival benefit from ablation therapy remains unclear, though good initial results have been reported. This article outlines the current role of ablation therapy for adrenal lesions, as well as identifying some of the technical considerations for this procedure. PMID:25049444

Relative value of computed tomography scanning and venous sampling in establishing the cause of primary hyperaldosteronism.

PubMed

Sheaves, R; Goldin, J; Reznek, R H; Chew, S L; Dacie, J E; Lowe, D G; Ross, R J; Wass, J A; Besser, G M; Grossman, A B

1996-03-01

The purpose of this study was to evaluate the relative merits of the postural stimulation test, adrenal computed tomography (CT) and venous sampling in the differential diagnosis of patients presenting with primary hyperaldosteronism. The records of 20 patients presenting with primary hyperaldosteronism were reviewed retrospectively. There were 15 patients with a unilateral aldosterone-producing adenoma (APA), four patients with idiopathic hyperaldosteronism (IHA) and one patient with primary adrenal hyperplasia (PAH). The postural stimulation test was based on measurements of plasma aldosterone and renin activity at 08.00 h and at noon after 4 h of ambulation. The CT scans of the adrenals were reviewed by a single radiologist. Bilateral venous sampling of adrenal veins was attempted in all patients and blood collected for aldosterone and cortisol assay. Plasma aldosterone concentration increased after 4 h of standing in all cases of hyperplasia but was also demonstrated in 10/15 patients with a surgically-proven APA. If one defines a significant postural rise as being greater than 30%, then 8/15 patients with APA can be considered as being posturally responsive. Computed tomography scanning correctly identified all 15 cases of APA and also classified correctly the remaining five cases of hyperplasia (four cases of IHA and one case of PAH). Venous sampling failed technically in 4/15 cases of APA and in one case of IHA: a total of 5/20 (25%,). A correct diagnosis of APA or IHA was established in all the remaining cases. However, the one case of PAH was treated successfully by adrenalectomy following venous sampling, which suggested a unilateral adrenal lesion: this one result was the only instance where venous sampling altered clinical decision-making. Computed tomography scanning may be used alone to confirm the cause of hyperaldosteronism where postural studies suggest an adrenal adenoma, and such patients may be considered for early surgery. Venous

NEFM (Neurofilament Medium) Polypeptide, a Marker for Zona Glomerulosa Cells in Human Adrenal, Inhibits D1R (Dopamine D1 Receptor)-Mediated Secretion of Aldosterone.

PubMed

Maniero, Carmela; Garg, Sumedha; Zhao, Wanfeng; Johnson, Timothy Isaac; Zhou, Junhua; Gurnell, Mark; Brown, Morris J

2017-08-01

Heterogeneity among aldosterone-producing adenomas (APAs) has been highlighted by the discovery of somatic mutations. KCNJ5 mutations predominate in large zona fasciculata (ZF)-like APAs; mutations in CACNA1D , ATP1A1, ATP2B3 , and CTNNB1 are more likely to be found in small zona glomerulosa (ZG)-like APAs. Microarray comparison of KCNJ5 mutant versus wild-type APAs revealed significant differences in transcriptomes. NEFM , encoding a neurofilament subunit which is a D1R (dopamine D1 receptor)-interacting protein, was 4-fold upregulated in ZG-like versus ZF-like APAs and 14-fold more highly expressed in normal ZG versus ZF. Immunohistochemistry confirmed selective expression of NEFM (neurofilament medium) polypeptide in ZG and in ZG-like APAs. Silencing NEFM in adrenocortical H295R cells increased basal aldosterone secretion and cell proliferation; silencing also amplified aldosterone stimulation by the D1R agonist, fenoldopam, and inhibition by the D1R antagonist, SCH23390. NEFM coimmunoprecipitated with D1R, and its expression was stimulated by fenoldopam. Immunohistochemistry for D1R was mainly intracellular in ZG-like APAs but membranous in ZF-like APAs. Aldosterone secretion in response to fenoldopam in primary cells from ZF-like APAs was higher than in cells from ZG-like APAs. Transfection of mutant KCNJ5 caused a large reduction in NEFM expression in H295R cells. We conclude that NEFM is a negative regulator of aldosterone production and cell proliferation, in part by facilitating D1R internalization from the plasma membrane. Downregulation of NEFM in ZF-like APAs may contribute to a D1R/D2R imbalance underlying variable pharmacological responses to dopaminergic drugs among patients with APAs. Finally, taken together, our data point to the possibility that ZF-like APAs are in fact ZG in origin. © 2017 American Heart Association, Inc.

Regulation of aldosterone secretion by mineralocorticoid receptor-mediated signaling.

PubMed

Chong, Cherish; Hamid, Anis; Yao, Tham; Garza, Amanda E; Pojoga, Luminita H; Adler, Gail K; Romero, Jose R; Williams, Gordon H

2017-03-01

We posit the existence of a paracrine/autocrine negative feedback loop, mediated by the mineralocorticoid receptor (MR), regulating aldosterone secretion. To assess this hypothesis, we asked whether altering MR activity in zona glomerulosa (ZG) cells affects aldosterone production. To this end, we studied ex vivo ZG cells isolated from male Wistar rats fed chow containing either high (1.6% Na + (HS)) or low (0.03% Na + (LS)) amount of sodium. Western blot analyses demonstrated that MR was present in both the ZG and zona fasciculata/zona reticularis (ZF/ZR/ZR). In ZG cells isolated from rats on LS chow, MR activation by fludrocortisone produced a 20% and 60% reduction in aldosterone secretion basally and in response to angiotensin II (ANGII) stimulation, respectively. Corticosterone secretion was increased in these cells suggesting that aldosterone synthase activity was being reduced by fludrocortisone. In contrast, canrenoic acid, an MR antagonist, enhanced aldosterone production by up to 30% both basally and in response to ANGII. Similar responses were observed in ZG cells from rats fed HS. Modulating glucocorticoid receptor (GR) activity did not alter aldosterone production by ZG cells; however, altering GR activity did modify corticosterone production from ZF/ZR/ZR cells both basally and in response to adrenocorticotropic hormone (ACTH). Additionally, activating the MR in ZF/ZR/ZR cells strikingly reduced corticosterone secretion. In summary, these data support the hypothesis that negative ultra-short feedback loops regulate adrenal steroidogenesis. In the ZG, aldosterone secretion is regulated by the MR, but not the GR, an effect that appears to be secondary to a change in aldosterone synthase activity. © 2017 Society for Endocrinology.

Abnormal aldosterone physiology and cardiometabolic risk factors.

PubMed

Vaidya, Anand; Underwood, Patricia C; Hopkins, Paul N; Jeunemaitre, Xavier; Ferri, Claudio; Williams, Gordon H; Adler, Gail K

2013-04-01

Abnormal aldosterone physiology has been implicated in the pathogenesis of cardiometabolic diseases. Single aldosterone measurements capture only a limited range of aldosterone physiology. New methods of characterizing aldosterone physiology may provide a more comprehensive understanding of its relationship with cardiometabolic disease. We evaluated whether novel indices of aldosterone responses to dietary sodium modulation, the sodium-modulated aldosterone suppression-stimulation index (SASSI for serum and SAUSSI for urine), could predict cardiometabolic risk factors. We performed cross-sectional analyses on 539 subjects studied on liberal and restricted sodium diets with serum and urinary aldosterone measurements. SASSI and SAUSSI were calculated as the ratio of aldosterone on liberal (maximally suppressed aldosterone) to the aldosterone on restricted (stimulated aldosterone) diets and associated with risk factors using adjusted regression models. Cardiometabolic risk factors associated with either impaired suppression of aldosterone on liberal diet, or impaired stimulation on restricted diet, or both; in all of these individual cases, these risk factors associated with higher SASSI or SAUSSI. In the context of abnormalities that constitute the metabolic syndrome, there was a strong positive association between the number of metabolic syndrome components (0-4) and both SASSI and SAUSSI (P<0.0001) that was independent of known aldosterone secretagogues (angiotensin II, corticotropin, potassium). SASSI and SAUSSI exhibited a high sensitivity in detecting normal individuals with zero metabolic syndrome components (86% for SASSI and 83% for SAUSSI). Assessing the physiological range of aldosterone responses may provide greater insights into adrenal pathophysiology. Dysregulated aldosterone physiology may contribute to, or result from, early cardiometabolic abnormalities.

Adipocyte-Derived Hormone Leptin Is a Direct Regulator of Aldosterone Secretion, Which Promotes Endothelial Dysfunction and Cardiac Fibrosis.

PubMed

Huby, Anne-Cécile; Antonova, Galina; Groenendyk, Jake; Gomez-Sanchez, Celso E; Bollag, Wendy B; Filosa, Jessica A; Belin de Chantemèle, Eric J

2015-12-01

In obesity, the excessive synthesis of aldosterone contributes to the development and progression of metabolic and cardiovascular dysfunctions. Obesity-induced hyperaldosteronism is independent of the known regulators of aldosterone secretion, but reliant on unidentified adipocyte-derived factors. We hypothesized that the adipokine leptin is a direct regulator of aldosterone synthase (CYP11B2) expression and aldosterone release and promotes cardiovascular dysfunction via aldosterone-dependent mechanisms. Immunostaining of human adrenal cross-sections and adrenocortical cells revealed that adrenocortical cells coexpress CYP11B2 and leptin receptors. Measurements of adrenal CYP11B2 expression and plasma aldosterone levels showed that increases in endogenous (obesity) or exogenous (infusion) leptin dose-dependently raised CYP11B2 expression and aldosterone without elevating plasma angiotensin II, potassium or corticosterone. Neither angiotensin II receptors blockade nor α and β adrenergic receptors inhibition blunted leptin-induced aldosterone secretion. Identical results were obtained in cultured adrenocortical cells. Enhanced leptin signaling elevated CYP11B2 expression and plasma aldosterone, whereas deficiency in leptin or leptin receptors blunted obesity-induced increases in CYP11B2 and aldosterone, ruling out a role for obesity per se. Leptin increased intracellular calcium, elevated calmodulin and calmodulin-kinase II expression, whereas calcium chelation blunted leptin-mediated increases in CYP11B2, in adrenocortical cells. Mineralocorticoid receptor blockade blunted leptin-induced endothelial dysfunction and increases in cardiac fibrotic markers. Leptin is a newly described regulator of aldosterone synthesis that acts directly on adrenal glomerulosa cells to increase CYP11B2 expression and enhance aldosterone production via calcium-dependent mechanisms. Furthermore, leptin-mediated aldosterone secretion contributes to cardiovascular disease by promoting

Discordance between imaging and immunohistochemistry in unilateral primary aldosteronism.

PubMed

Nanba, Aya T; Nanba, Kazutaka; Byrd, James B; Shields, James J; Giordano, Thomas J; Miller, Barbara S; Rainey, William E; Auchus, Richard J; Turcu, Adina F

2017-12-01

Correct subtyping of primary aldosteronism (PA) is essential for good surgical outcomes. Adrenal vein sampling (AVS) and/or computed tomography (CT) are used for PA subclassification. Clinical and/or biochemical improvement after surgery, however, is not always achieved in patients with presumed unilateral PA. We aimed to identify the pitfalls in PA subclassification leading to surgical treatment failures. We retrospectively studied 208 patients who underwent adrenal vein sampling (AVS) for PA subclassification in a tertiary referral centre, between January 2009 and August 2016. Simultaneous bilateral AVS was performed before and after cosyntropin administration. We implemented immunohistochemistry for aldosterone synthase (CYP11B2) and 17α-hydroxylase/17,20 lyase (CYP17A1) in adrenal glands resected from patients without improvement of PA after surgical treatment and from those with limitations in AVS interpretation. Of 55 patients who underwent adrenalectomy, three (5.5%) had no improvement of PA. All three patients underwent partial adrenalectomy to remove a CT-detected nodule present on the same side with AVS lateralization. Immunohistochemistry revealed a CYP11B2-negative nodule in both cases available. All patients who underwent total adrenalectomy based on AVS lateralization benefitted from surgery, including three patients with unilateral unsuccessful AVS and aldosterone suppression in the catheterized side vs inferior vena cava. Radiographically identified adrenal nodules are not always a source of PA, even when ipsilateral with AVS lateralization. These data caution against reliance on imaging findings, either alone or in conjunction with AVS, to guide surgery for PA. © 2017 John Wiley & Sons Ltd.

Gallium-67 uptake by a benign adrenocortical adenoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jackson, J.A.; Naul, L.G.; Montgomery, J.L.

1988-08-01

A 55-yr-old man presented with an atypical relapsing meningitis and was found to have intense unilateral adrenal uptake by /sup 67/Ga imaging. Computed tomography showed a 4-cm right adrenal mass which was hypointense on the T1-weighted images and mildly hyperintense on the T2-weighted images of a magnetic resonance (MR) scan. At surgery, a coincidental benign adrenocortical adenoma was found. Because /sup 67/Ga uptake is usually associated with inflammatory or malignant lesions and malignant adrenal lesions are hyperintense on T2-weighted MR images, these findings contributed to diagnostic uncertainty in this patient. Thus, a nonhyperfunctional adrenocortical adenoma may be associated with abnormalmore » /sup 67/Ga uptake and atypical MR findings.« less

[Adrenal incidentaloma and nuclear medicine examination].

PubMed

Tenenbaum, F

2009-03-01

In the setting of adrenal incidentaloma, nuclear medicine evaluation is only indicated after biological and imaging work-up has been completed. MIBG scintigraphy is helpful to characterize pheochromocytomas. In lesions without MIBG uptake, 18F FDG or 18F DOPA PET can be considered to characterize chromaffin cell tumours. To characterize lesions of the adrenal cortex, iodocholesterol scintigraphy is performed to confirm the origin of the adenoma and the benign or malignant nature of the lesion since benign adenomas show tracer uptake and malignant lesions show no tracer uptake. 18F FDG PET only characterizes the lesion as benign or malignant.

Excessively low salt diet damages the heart through activation of cardiac (pro) renin receptor, renin-angiotensin-aldosterone, and sympatho-adrenal systems in spontaneously hypertensive rats.

PubMed

Okamoto, Chihiro; Hayakawa, Yuka; Aoyama, Takuma; Komaki, Hisaaki; Minatoguchi, Shingo; Iwasa, Masamitsu; Yamada, Yoshihisa; Kanamori, Hiromitsu; Kawasaki, Masanori; Nishigaki, Kazuhiko; Mikami, Atsushi; Minatoguchi, Shinya

2017-01-01

A high salt intake causes hypertension and leads to cardiovascular disease. Therefore, a low salt diet is now recommended to prevent hypertension and cardiovascular disease. However, it is still unknown whether an excessively low salt diet is beneficial or harmful for the heart. Wistar Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) received normal salt chow (0.9% salt diet) and excessively low salt chow (0.01% salt diet referred to as saltless diet) for 8 weeks from 8 to 16 weeks of age. The effects of the excessively low salt diet on the cardiac (pro) renin receptor, renin-angiotensin-aldosterone, and sympatho-adrenal systems were investigated. The excessively low salt diet did not affect the systolic blood pressure but significantly increased the heart rate both in WKYs and SHRs. The excessively low salt diet significantly elevated plasma renin activity, plasma angiotensin I, II and aldosterone concentrations, and plasma noradrenaline and adrenaline concentrations both in WKYs and SHRs. Cardiac expressions of renin, prorenin, (P)RR, angiotensinogen, and angiotensin II AT1 receptor and phosphorylated (p)-ERK1/2, p-HSP27, p-38MAPK, and TGF-ß1 were significantly enhanced by the excessively low salt diet in both WKYs and SHRs. The excessively low salt diet accelerated cardiac interstitial and perivascular fibrosis and increased the cardiomyocyte size and interventricular septum thickness in WKYs and SHRs but the extent was greater in SHRs. An excessively low salt diet damages the heart through activation of plasma renin-angiotensin-aldosterone and sympatho-adrenal systems and activation of cardiac (P)RR and angiotensin II AT1 receptor and their downstream signals both in WKYs and SHRs.

Nationwide review of hormonally active adrenal tumors highlights high morbidity in pheochromocytoma.

PubMed

Parikh, Punam P; Rubio, Gustavo A; Farra, Josefina C; Lew, John I

2017-07-01

Adrenal adenomas are benign tumors often discovered incidentally, and >70% are hormonally inactive. The remaining subset may produce excess aldosterone, cortisol, or catecholamine. Perioperative outcomes after adrenalectomy for such "hormonally active" tumors remain unclear. This study examines in-hospital outcomes after unilateral adrenalectomy for hormonally active tumors. A retrospective review was performed using the Nationwide Inpatient Sample (2006-2011) to identify patients undergoing unilateral adrenalectomy for hormonally active or inactive tumors. Malignant adrenal tumors were excluded. Demographics, comorbidities, and postoperative complications were evaluated by univariate analysis, using two-tailed Chi-square and t-tests and multivariate logistic regression. Of 27,312 patients who underwent adrenalectomy, 78% (n = 21,279) had hormonally inactive and 22% (n = 6033) had hormonally active adrenal tumors. Among the latter, 65% (n = 4000) had primary hyperaldosteronism (Conn's syndrome), 33% (n = 1996) had hypercortisolism (Cushing's syndrome), and 1.4% (n = 85) had pheochromocytoma. Patients with pheochromocytoma had higher rate of comorbidities including congestive heart failure, chronic lung disease, and malignant hypertension compared with remaining hormonally active tumors (12% versus 4%, 18% versus 11%, 6% versus 2%; P < 0.01). For patients with pheochromocytoma versus other hormonally active tumors, mean length of stay was 5 versus 3 d and total in-hospital cost was $50,000 versus $41,000 (P < 0.01). On multivariate analysis, pheochromocytoma had an independently higher risk for intraoperative blood transfusion (4.2, 95% confidence interval [CI] 2.4-7.2), postoperative cardiac (7.6, 95% CI 2.8-20.2), and respiratory (1.9, 95% CI 1.0-3.3) complications. Patients with pheochromocytoma have high rates of preoperative comorbidities, postoperative cardiopulmonary complications, and longer and more costly hospitalizations. Such high

ABNORMAL ALDOSTERONE PHYSIOLOGY AND CARDIO-METABOLIC RISK FACTORS

PubMed Central

Vaidya, Anand; Underwood, Patricia C.; Hopkins, Paul N.; Jeunemaitre, Xavier; Ferri, Claudio; Williams, Gordon H.; Adler, Gail K.

2013-01-01

Abnormal aldosterone physiology has been implicated in the pathogenesis of cardio-metabolic diseases. Single aldosterone measurements capture only a limited range of aldosterone physiology. New methods of characterizing aldosterone physiology may provide a more comprehensive understanding of its relationship with cardio-metabolic disease. We evaluated whether novel indices of aldosterone responses to dietary sodium modulation, the Sodium-modulated Aldosterone Suppression-Stimulation Index (SASSI for serum and SAUSSI for urine), could predict cardio-metabolic risk factors. We performed cross-sectional analyses on 539 subjects studied on liberal (LIB) and restricted (RES) sodium diets with serum and urinary aldosterone measurements. SASSI and SAUSSI were calculated as the ratio of aldosterone on LIB (maximally suppressed aldosterone) to aldosterone on RES (stimulated aldosterone) diets, and associated with risk factors using adjusted regression models. Cardio-metabolic risk factors associated with either impaired suppression of aldosterone on LIB diet, or impaired stimulation on RES diet, or both; in all of these individual cases, these risk factors associated with higher SASSI or SAUSSI. In the context of abnormalities that comprise the metabolic syndrome (MetS), there was a strong positive association between the number of MetS components (0–4) and both SASSI and SAUSSI (P<0.0001) that was independent of known aldosterone secretagogues (angiotensin II, corticotropin, potassium). SASSI and SAUSSI exhibited a high sensitivity in detecting normal individuals with zero MetS components (86% for SASSI and 83% for SAUSSI). Assessing the physiologic range of aldosterone responses may provide greater insights into adrenal pathophysiology. Dysregulated aldosterone physiology may contribute to, and/or result from, early cardio-metabolic abnormalities. PMID:23399714

Thyrotropin-producing pituitary adenoma simultaneously existing with Graves' disease: a case report.

PubMed

Arai, Nobuhiko; Inaba, Makoto; Ichijyo, Takamasa; Kagami, Hiroshi; Mine, Yutaka

2017-01-06

Thyrotropin-producing pituitary tumor is relatively rare. In particular, concurrent cases associated with Graves' disease are extremely rare and only nine cases have been reported so far. We describe a case of a thyrotropin-producing pituitary adenoma concomitant with Graves' disease, which was successfully treated. A 40-year-old Japanese woman presented with mild signs of hyperthyroidism. She had positive anti-thyroid-stimulating hormone receptor antibody, anti-thyroglobulin antibody, and anti-thyroid peroxidase antibody. Her levels of serum thyroid-stimulating hormone, which ranged from low to normal in the presence of high levels of serum free thyroid hormones, were considered to be close to a state of syndrome of inappropriate secretion of thyroid-stimulating hormone. Magnetic resonance imaging showed a macropituitary tumor. The coexistence of thyrotropin-producing pituitary adenoma and Graves' disease was suspected. Initial therapy included anti-thyroid medication, which was immediately discontinued due to worsening symptoms. Subsequently, surgical therapy for the pituitary tumor was conducted, and her levels of free thyroid hormones, including the thyroid-stimulating hormone, became normal. On postoperative examination, her anti-thyroid-stimulating hormone receptor antibody levels decreased, and the anti-thyroglobulin antibody became negative. The coexistence of thyrotropin-producing pituitary adenoma and Graves' disease is rarely reported. The diagnosis of this condition is complicated, and the appropriate treatment strategy has not been clearly established. This case suggests that physicians should consider the coexistence of thyrotropin-producing pituitary adenoma with Graves' disease in cases in which thyroid-stimulating hormone values range from low to normal in the presence of thyrotoxicosis, and the surgical treatment of thyrotropin-producing pituitary adenoma could be the first-line therapy in patients with both thyrotropin-producing pituitary adenoma

Aldosterone and Mineralocorticoid Receptors-Physiology and Pathophysiology.

PubMed

Funder, John W

2017-05-11

Aldosterone is a uniquely terrestrial hormone, first appearing in lungfish, which have both gills and lungs. Mineralocorticoid receptors (MRs), on the other hand, evolved much earlier, and are found in cartilaginous and bony fish, presumptive ligand cortisol. MRs have equivalent high affinity for aldosterone, progesterone, and cortisol; in epithelia, despite much higher cortisol circulating levels, aldosterone selectively activates MRs by co-expression of the enzyme 11β-hydroxysteroid dehydrogenase, Type 11. In tissues in which the enzyme is not expressed, MRs are overwhelmingly occupied but not activated by cortisol, which normally thus acts as an MR antagonist; in tissue damage, however, cortisol mimics aldosterone and acts as an MR agonist. The risk profile for primary aldosteronism (PA) is much higher than that in age-, sex-, and blood pressure-matched essential hypertensives. High levels of aldosterone per se are not the problem: in chronic sodium deficiency, as seen in the monsoon season in the highlands of New Guinea, plasma aldosterone levels are extraordinarily high, but cause neither hypertension nor cardiovascular damage. Such damage occurs when aldosterone levels are out of the normal feedback control, and are inappropriately elevated for the salt status of the individual (or experimental animal). The question thus remains of how excess salt can synergize with elevated aldosterone levels to produce deleterious cardiovascular effects. One possible mechanism is through the agency of the elusive ouabain-like factors (OLFs). Such factors are secreted from the adrenal in response to ACTH (adrenalocortical tropic hormone), to angiotensin via AT2R, and-the polar opposite of aldosterone-to sodium loading. They act on blood vessels to cause vasoconstriction and thus elevate blood pressure to dump excess sodium through pressure natriuresis. Their levels are chronically elevated in PA in response to the continually elevated sodium status, and they thus act to

Dietary sodium restriction restores nocturnal reduction of blood pressure in patients with primary aldosteronism.

PubMed

Takakuwa, Hiroshi; Shimizu, Kazuaki; Izumiya, Yoshiaki; Kato, Tamayo; Nakaya, Izaya; Yokoyama, Hitoshi; Kobayashi, Ken-ichi; Ise, Takuyuki

2002-09-01

The purpose of this study was to elucidate the effects of dietary sodium restriction on diurnal blood pressure (BP) variation in primary aldosteronism. We studied the diurnal variation in the systemic hemodynamic indices and in baroreflex sensitivity (BRS). In 13 subjects with aldosterone-producing adenomas (2 males; mean age, 39+/-2 years), intra-arterial pressure was monitored telemetrically on a normal salt diet (NaCl 10-12 g/day). Non-dippers were defined as those with a nocturnal reduction in systolic BP (SBP) of less than 10% of daytime SBP. Ten subjects showed a non-dipper pattern. Six of these "non-dippers" underwent repetitive hemodynamic studies on the last day of a 1-week low salt diet regimen (NaCl 2-4 g/day). Stroke volume was determined using Wesseling's pulse contour method, calibrated with indocyanine green dilution. BRS was calculated every 30 min as delta pulse interval/delta SBP on spontaneous variations. Nocturnal reduction of SBP was 4.1% on the normal salt diet. With sodium restriction, urinary sodium excretion decreased from 187+/-8 to 46+/-8 mmol/day, and body weight decreased from 57.9+/-2.1 to 56.6+/-1.9 kg. Night-time BP significantly decreased with dietary modification from 154+/-7/88+/-4 to 140+/-6/78+/-4 mmHg, whereas daytime BP was unaltered. With sodium restriction, cardiac index and stroke index decreased throughout the day. No significant difference was seen in either daytime or nighttime BRS between the two diets. We conclude that the non-dipper pattern is common in patients with an aldosterone-producing adenoma on a normal salt intake, and under such conditions, volume expansion appears to play a major role in the impairment of nocturnal BP reduction.

Prevalence of and risk factors for primary aldosteronism among patients with resistant hypertension in China.

PubMed

Sang, Xiaojing; Jiang, Yiran; Wang, Weiqing; Yan, Li; Zhao, Jiasheng; Peng, Yongde; Gu, Wei; Chen, Gang; Liu, Wei; Ning, Guang

2013-07-01

It is estimated that there are more than 16 million adults with drug-resistant hypertension in China. Nevertheless, the prevalence of and risk factors for primary aldosteronism, a highly curable condition among adults with drug-resistant hypertension, has not been fully investigated. Between January 2010 and October 2011, a multicenter epidemiologic study was conducted among 1656 patients with resistant hypertension in 11 provinces of China. Serum aldosterone and plasma renin activity were measured in every participant and aldosterone-to-renin ratio (ARR) was calculated. Patients with ARR more than 20 underwent an intravenous (i.v.) sodium infusion test, and diagnosis of primary aldosteronism was established by the presence of unsuppressed postinfusion aldosterone (>8 ng/dl). Patients with biochemically proved primary aldosteronism then underwent adrenal computed tomography (CT) scanning and adrenal vein sampling (AVS) for subtype classification. Among the 1656 patients, 494 (29.8%) had ARR greater than 20 and underwent i.v. sodium infusion. Of these 494, 118 were diagnosed as primary aldosteronism, yielding a prevalence of 7.1% (95% confidential interval 5.9-8.3%). Seventy of the 118 patients were categorized into unilateral (39) and bilateral (31) by AVS. Generalized additive regression analysis revealed that among all the factors investigated (age of hypertension onset, BMI, family history of hypertension, cigarette smoking, alcohol consumption, diabetes, serum potassium, hyperlipidemia, and creatinine), only age of hypertension onset and serum potassium were independently associated with the presence of primary aldosteronism. The prevalence of primary aldosteronism among Chinese patients with resistant hypertension is relatively lower than that reported previously for other ethnic populations. The screening for primary aldosteronism should be focused on those with early onset hypertension and/or hypokalemia.

Obesity-stimulated aldosterone release is not related to an S1P-dependent mechanism.

PubMed

Werth, Stephan; Müller-Fielitz, Helge; Raasch, Walter

2017-12-01

Aldosterone has been identified as an important factor in obesity-associated hypertension. Here, we investigated whether sphingosine-1-phosphate (S1P), which has previously been linked to obesity, increases aldosterone release. S1P-induced aldosterone release was determined in NCI H295R cells in the presence of S1P receptor (S1PR) antagonists. In vivo release of S1P (100-300 µg/kg bw ) was investigated in pithed, lean Sprague Dawley (SD) rats, diet-obese spontaneous hypertensive rats (SHRs), as well as in lean or obese Zucker rats. Aldosterone secretion was increased in NCI H295R cells by S1P, the selective S1PR1 agonist SEW2871 and the selective S1PR2 antagonist JTE013. Treatment with the S1PR1 antagonist W146 or fingolimod and the S1PR1/3 antagonist VPbib2319 decreased baseline and/or S1P-stimulated aldosterone release. Compared to saline-treated SD rats, plasma aldosterone increased by ~50 pg/mL after infusing S1P. Baseline levels of S1P and aldosterone were higher in obese than in lean SHRs. Adrenal S1PR expression did not differ between chow- or CD-fed rats that had the highest S1PR1 and lowest S1PR4 levels. S1P induced a short-lasting increase in plasma aldosterone in obese, but not in lean SHRs. However, 2-ANOVA did not demonstrate any difference between lean and obese rats. S1P-induced aldosterone release was also similar between obese and lean Zucker rats. We conclude that S1P is a local regulator of aldosterone production. S1PR1 agonism induces an increase in aldosterone secretion, while stimulating adrenal S1PR2 receptor suppresses aldosterone production. A significant role of S1P in influencing aldosterone secretion in states of obesity seems unlikely. © 2017 Society for Endocrinology.

A short review of primary aldosteronism in a question and answer fashion.

PubMed

Farrugia, Frederick-Anthony; Zavras, Nicolaos; Martikos, Georgios; Tzanetis, Panagiotis; Charalampopoulos, Anestis; Misiakos, Evangelos P; Sotiropoulos, Dimitrios; Koliakos, Nikolaos

2018-01-01

The aim of this study was to present up to date information concerning the diagnosis and treatment of primary aldosteronism (PA). PA is the most common cause of endocrine hypertension. It has been reported up to 24% of selective referred hypertensive patients. We did a search in Pub-Med and Google Scholar using the terms: PA, hyperaldosteronism, idiopathic adrenal hyperplasia, diagnosis of PA, mineralocorticoid receptor antagonists, adrenalectomy, and surgery. We also did cross-referencing search with the above terms. We had divided our study into five sections: Introduction, Diagnosis, Genetics, Treatment, and Conclusions. We present our results in a question and answer fashion in order to make reading more interesting. PA should be searched in all high-risk populations. The gold standard for diagnosis PA is the plasma aldosterone/plasma renin ratio (ARR). If this test is positive, then we proceed with one of the four confirmatory tests. If positive, then we proceed with a localizing technique like adrenal vein sampling (AVS) and CT scan. If the lesion is unilateral, after proper preoperative preparation, we proceed, in adrenalectomy. If the lesion is bilateral or the patient refuses or is not fit for surgery, we treat them with mineralocorticoid receptor antagonists, usually spironolactone. Primary aldosteronism is the most common and a treatable case of secondary hypertension. Only patients with unilateral adrenal diseases are eligible for surgery, while patients with bilateral and non-surgically correctable PA are usually treated by mineralocorticoid receptor antagonist (MRA). Thus, the distinction between unilateral and bilateral aldosterone hypersecretion is crucial.

AME position statement on adrenal incidentaloma.

PubMed

Terzolo, M; Stigliano, A; Chiodini, I; Loli, P; Furlani, L; Arnaldi, G; Reimondo, G; Pia, A; Toscano, V; Zini, M; Borretta, G; Papini, E; Garofalo, P; Allolio, B; Dupas, B; Mantero, F; Tabarin, A

2011-06-01

To assess currently available evidence on adrenal incidentaloma and provide recommendations for clinical practice. A panel of experts (appointed by the Italian Association of Clinical Endocrinologists (AME)) appraised the methodological quality of the relevant studies, summarized their results, and discussed the evidence reports to find consensus. Unenhanced computed tomography (CT) is recommended as the initial test with the use of an attenuation value of ≤10 Hounsfield units (HU) to differentiate between adenomas and non-adenomas. For tumors with a higher baseline attenuation value, we suggest considering delayed contrast-enhanced CT studies. Positron emission tomography (PET) or PET/CT should be considered when CT is inconclusive, whereas fine needle aspiration biopsy may be used only in selected cases suspicious of metastases (after biochemical exclusion of pheochromocytoma). HORMONAL ASSESSMENT: Pheochromocytoma and excessive overt cortisol should be ruled out in all patients, whereas primary aldosteronism has to be considered in hypertensive and/or hypokalemic patients. The 1 mg overnight dexamethasone suppression test is the test recommended for screening of subclinical Cushing's syndrome (SCS) with a threshold at 138 nmol/l for considering this condition. A value of 50 nmol/l virtually excludes SCS with an area of uncertainty between 50 and 138 nmol/l. Surgery is recommended for masses with suspicious radiological aspects and masses causing overt catecholamine or steroid excess. Data are insufficient to make firm recommendations for or against surgery in patients with SCS. However, adrenalectomy may be considered when an adequate medical therapy does not reach the treatment goals of associated diseases potentially linked to hypercortisolism.

9B.08: CARDIAC AND VASCULAR DAMAGE IN PATIENTS WITH PRIMARY ALDOSTERONISM AND ESSENTIAL HYPERTENSION.

PubMed

Bertacchini, F; Paini, A; Salvetti, M; Casella, E; Rosei, C Agabiti; Colonetti, E; Donini, C; Maruelli, G; Rizzoni, D; Rosei, E Agabiti; Muiesan, M L

2015-06-01

Primary aldosteronism is a relatively common condition in hypertensive patients. Only few studies, in small groups of patients, have evaluated large arteries alterations. In some, but not in all studies, positive relationship with vascular damage was observed. To compare the prevalence of cardiac and large arteries vascular organ damage in patients with essential hypertension (EH) or primary aldosteronism (PA). In 243 consecutive patients with no interfering therapy (147 M, mean age 48 ± 11 years) a routine blood sample, including measurement of aldosterone/renin ratio (ARR) and saline load if ARR>30, was obtained. Echocardiography, carotid ultrasound and measurement of pulse wave velocity (PWV) were performed. We considered 3 groups: 48 patients with EH (ARR < 30); 122 patients with positive ARR screening but negative saline load (indeterminate aldosteronism, IA); 73 patients with PA (positive ARR and post saline aldosterone >100ng/ml)(51 % with adrenal adenoma). No differences between groups were observed in age, gender, BMI, BP values (clinic and 24 hours), glucose, lipids and renal function. LVMI was greater in PA vs both IA and EH (PA 45 ± 18, IA 39 ± 12, EH 39 ± 10 gr/m2.7, p < 0,05). Left atrial volume/BSA was significantly greater in PA vs EH (PA 27 ± 10, IA 24 ± 8, EH 23 ± 6 ml/m2, p < 0,05 for PA vs EH). A positive correlation was observed between ARR and LVMI (r = 0,20 p = 0,002), left atrium volume (r = 0,201,p < 0,001) and relative wall thickness (r = 0,394, p < 0,005). Indices of vascular damage did not differ between groups (see table). Aldosterone levels and ARR were not significantly correlated with indices of vascular damage.(Figure is included in full-text article.) : A greater prevalence of cardiac, but not of large arteries damage is observed in PA as compared to EH when a simultaneous assessment of cardiac and vascular OD is performed.

A NEW CLINICAL PREDICTION CRITERION ACCURATELY DETERMINES A SUBSET OF PATIENTS WITH BILATERAL PRIMARY ALDOSTERONISM BEFORE ADRENAL VENOUS SAMPLING.

PubMed

Kocjan, Tomaz; Janez, Andrej; Stankovic, Milenko; Vidmar, Gaj; Jensterle, Mojca

2016-05-01

Adrenal venous sampling (AVS) is the only available method to distinguish bilateral from unilateral primary aldosteronism (PA). AVS has several drawbacks, so it is reasonable to avoid this procedure when the results would not affect clinical management. Our objective was to identify a clinical criterion that can reliably predict nonlateralized AVS as a surrogate for bilateral PA that is not treated surgically. A retrospective diagnostic cross-sectional study conducted at Slovenian national endocrine referral center included 69 consecutive patients (mean age 56 ± 8 years, 21 females) with PA who underwent AVS. PA was confirmed with the saline infusion test (SIT). AVS was performed sequentially during continuous adrenocorticotrophic hormone (ACTH) infusion. The main outcome measures were variables associated with nonlateralized AVS to derive a clinical prediction rule. Sixty-seven (97%) patients had a successful AVS and were included in the statistical analysis. A total of 39 (58%) patients had nonlateralized AVS. The combined criterion of serum potassium ≥3.5 mmol/L, post-SIT aldosterone <18 ng/dL, and either no or bilateral tumor found on computed tomography (CT) imaging had perfect estimated specificity (and thus 100% positive predictive value) for bilateral PA, saving an estimated 16% of the patients (11/67) from unnecessary AVS. The best overall classification accuracy (50/67 = 75%) was achieved using the post-SIT aldosterone level <18 ng/dL alone, which yielded 74% sensitivity and 75% specificity for predicting nonlateralized AVS. Our clinical prediction criterion appears to accurately determine a subset of patients with bilateral PA who could avoid unnecessary AVS and immediately commence with medical treatment.

Adrenal Hormones in Common Bottlenose Dolphins (Tursiops truncatus): Influential Factors and Reference Intervals

PubMed Central

Hart, Leslie B.; Wells, Randall S.; Kellar, Nick; Balmer, Brian C.; Hohn, Aleta A.; Lamb, Stephen V.; Rowles, Teri; Zolman, Eric S.; Schwacke, Lori H.

2015-01-01

Inshore common bottlenose dolphins (Tursiops truncatus) are exposed to a broad spectrum of natural and anthropogenic stressors. In response to these stressors, the mammalian adrenal gland releases hormones such as cortisol and aldosterone to maintain physiological and biochemical homeostasis. Consequently, adrenal gland dysfunction results in disruption of hormone secretion and an inappropriate stress response. Our objective herein was to develop diagnostic reference intervals (RIs) for adrenal hormones commonly associated with the stress response (i.e., cortisol, aldosterone) that account for the influence of intrinsic (e.g., age, sex) and extrinsic (e.g., time) factors. Ultimately, these reference intervals will be used to gauge an individual’s response to chase-capture stress and could indicate adrenal abnormalities. Linear mixed models (LMMs) were used to evaluate demographic and sampling factors contributing to differences in serum cortisol and aldosterone concentrations among bottlenose dolphins sampled in Sarasota Bay, Florida, USA (2000–2012). Serum cortisol concentrations were significantly associated with elapsed time from initial stimulation to sample collection (p<0.05), and RIs were constructed using nonparametric methods based on elapsed sampling time for dolphins sampled in less than 30 minutes following net deployment (95% RI: 0.91–4.21 µg/dL) and following biological sampling aboard a research vessel (95% RI: 2.32–6.68 µg/dL). To examine the applicability of the pre-sampling cortisol RI across multiple estuarine stocks, data from three additional southeast U.S. sites were compared, revealing that all of the dolphins sampled from the other sites (N = 34) had cortisol concentrations within the 95th percentile RI. Significant associations between serum concentrations of aldosterone and variables reported in previous studies (i.e., age, elapsed sampling time) were not observed in the current project (p<0.05). Also, approximately 16% of

Adrenal Hormones in Common Bottlenose Dolphins (Tursiops truncatus): Influential Factors and Reference Intervals.

PubMed

Hart, Leslie B; Wells, Randall S; Kellar, Nick; Balmer, Brian C; Hohn, Aleta A; Lamb, Stephen V; Rowles, Teri; Zolman, Eric S; Schwacke, Lori H

2015-01-01

Inshore common bottlenose dolphins (Tursiops truncatus) are exposed to a broad spectrum of natural and anthropogenic stressors. In response to these stressors, the mammalian adrenal gland releases hormones such as cortisol and aldosterone to maintain physiological and biochemical homeostasis. Consequently, adrenal gland dysfunction results in disruption of hormone secretion and an inappropriate stress response. Our objective herein was to develop diagnostic reference intervals (RIs) for adrenal hormones commonly associated with the stress response (i.e., cortisol, aldosterone) that account for the influence of intrinsic (e.g., age, sex) and extrinsic (e.g., time) factors. Ultimately, these reference intervals will be used to gauge an individual's response to chase-capture stress and could indicate adrenal abnormalities. Linear mixed models (LMMs) were used to evaluate demographic and sampling factors contributing to differences in serum cortisol and aldosterone concentrations among bottlenose dolphins sampled in Sarasota Bay, Florida, USA (2000-2012). Serum cortisol concentrations were significantly associated with elapsed time from initial stimulation to sample collection (p<0.05), and RIs were constructed using nonparametric methods based on elapsed sampling time for dolphins sampled in less than 30 minutes following net deployment (95% RI: 0.91-4.21 µg/dL) and following biological sampling aboard a research vessel (95% RI: 2.32-6.68 µg/dL). To examine the applicability of the pre-sampling cortisol RI across multiple estuarine stocks, data from three additional southeast U.S. sites were compared, revealing that all of the dolphins sampled from the other sites (N = 34) had cortisol concentrations within the 95th percentile RI. Significant associations between serum concentrations of aldosterone and variables reported in previous studies (i.e., age, elapsed sampling time) were not observed in the current project (p<0.05). Also, approximately 16% of Sarasota Bay

Aldosterone and the conquest of land.

PubMed

Colombo, L; Dalla Valle, L; Fiore, C; Armanini, D; Belvedere, P

2006-04-01

The sequence of the phylogenetic events that preceded the appearance of aldosterone in vertebrates is described, starting from the ancestral conversion of cytochrome P450s from oxygen detoxification to xenobiotic detoxification and synthesis of oxygenated endobiotics with useful functions in intercellular signalling, such as steroid hormones. At the end of the Silurian period [438-408 million yr ago, (Mya)], a complete set of cytochrome P450s for corticoid synthesis was presumably already available, except for mitochondrial cytochrome P450c18 or aldosterone synthase encoded by CYP11B2. This gene arose by duplication of the CYP11B gene in the sarcopterygian or lobe-finned fish/tetrapod line after its divergence from the actinopterygian or ray-finned fish line 420 Mya, but before the beginning of the colonization of land by tetrapods in the late Devonian period, around 370 Mya. The fact that aldosterone is already present in Dipnoi, which occupy an evolutionary transition between water- and air-breathing but are fully aquatic, suggests that the role of this steroid was to potentiate the corticoid response to hypoxia, rather than to prevent dehydration out of the water. In terrestrial amphibians, there is no differentiation between the secretion rates and gluco- and mineralocorticoid effects of aldosterone and corticosterone. In sauropsids, plasma aldosterone concentrations are much lower than in amphibians, but regulation of salt/water balance is dependent upon both aldosterone and corticosterone, though sometimes with opposed actions. In terrestrial mammals, aldosterone acquires a specific mineralocorticoid function, because its interaction with the mineralocorticoid receptor is protected by the coexpression of the enzyme 11beta-hydroxysteroid dehydrogenase type 2, which inactivates both cortisol and corticosterone. There is evidence that aldosterone can be also synthesized extra-adrenally in brain neurons and cardiac myocytes, which lack this protection and where

Aldosterone and parathyroid hormone: a precarious couple for cardiovascular disease.

PubMed

Tomaschitz, Andreas; Ritz, Eberhard; Pieske, Burkert; Fahrleitner-Pammer, Astrid; Kienreich, Katharina; Horina, Jörg H; Drechsler, Christiane; März, Winfried; Ofner, Michael; Pieber, Thomas R; Pilz, Stefan

2012-04-01

Animal and human studies support a clinically relevant interaction between aldosterone and parathyroid hormone (PTH) levels and suggest an impact of the interaction on cardiovascular (CV) health. This review focuses on mechanisms behind the bidirectional interactions between aldosterone and PTH and their potential impact on the CV system. There is evidence that PTH increases the secretion of aldosterone from the adrenals directly as well as indirectly by activating the renin-angiotensin system. Upregulation of aldosterone synthesis might contribute to the higher risk of arterial hypertension and of CV damage in patients with primary hyperparathyroidism. Furthermore, parathyroidectomy is followed by decreased blood pressure levels and reduced CV morbidity as well as lower renin and aldosterone levels. In chronic heart failure, the aldosterone activity is inappropriately elevated, causing salt retention; it has been argued that the resulting calcium wasting causes secondary hyperparathyroidism. The ensuing intracellular calcium overload and oxidative stress, caused by PTH and amplified by the relative aldosterone excess, may increase the risk of CV events. In the setting of primary aldosteronism, renal and faecal calcium loss triggers increased PTH secretion which in turn aggravates aldosterone secretion and CV damage. This sequence explains why adrenalectomy and blockade of the mineralocorticoid receptor tend to decrease PTH levels in patients with primary aldosteronism. In view of the reciprocal interaction between aldosterone and PTH and the potentially ensuing CV damage, studies are urgently needed to evaluate diagnostic and therapeutic strategies addressing the interaction between the two hormones.

Regulation of extrarenal potassium homeostasis by adrenal hormones in rats.

PubMed

Bia, M J; Tyler, K A; DeFronzo, R A

1982-06-01

The effect of chronic (7-10 days) adrenal insufficiency on extrarenal potassium tolerance was examined by infusing potassium into rats after acute nephrectomy. The increment in plasma potassium concentration was significantly higher in glucocorticoid-replaced adrenalectomized rats versus controls (max delta PK 3.59 +/-0.11 vs. 2.93 +/- 0.08 meq/liter; P less than 0.001). The impairment in extrarenal potassium tolerance in adrenalectomized rats could not be attributed to acidemia, hypotension, changes in plasma insulin or glucose concentration, or potassium retention prior to study. Acute replacement with aldosterone resulted in significant improvement in the rise in plasma potassium after KCl (max delta PK 3.18 +/- 0.06 meq/liter; P less than 0.005 compared with aldosterone-deficient adrenalectomized rats but higher than in controls, P less than 0.02). If given on a chronic basis, aldosterone replacement led to a complete correction of the defect (max delta PK = 2.89 +/- 0.08 meq/liter). Acute epinephrine replacement in adrenalectomized rats also returned potassium tolerance to normal (max delta PK = 3.02 +/- 0.10 meq/liter). The results demonstrate that extrarenal potassium tolerance is impaired in chronic adrenal insufficiency and suggest that both aldosterone and epinephrine deficiency may contribute to the defect, since replacement with either hormone returns potassium tolerance toward normal. Accordingly, both aldosterone and epinephrine have important extrarenal mechanisms of action.

The Potassium Channel, Kir3.4 Participates in Angiotensin II-Stimulated Aldosterone Production by a Human Adrenocortical Cell Line

PubMed Central

Oki, Kenji; Plonczynski, Maria W.; Lam, Milay Luis; Gomez-Sanchez, Elise P.

2012-01-01

Angiotensin II (A-II) regulation of aldosterone secretion is initiated by inducing cell membrane depolarization, thereby increasing intracellular calcium and activating the calcium calmodulin/calmodulin kinase cascade. Mutations in the selectivity filter of the KCNJ5 gene coding for inward rectifying potassium channel (Kir)3.4 has been found in about one third of aldosterone-producing adenomas. These mutations result in loss of selectivity of the inward rectifying current for potassium, which causes membrane depolarization and opening of calcium channels and activation of the calcium calmodulin/calmodulin kinase cascade and results in an increase in aldosterone secretion. In this study we show that A-II and a calcium ionophore down-regulate the expression of KCNJ5 mRNA and protein. Activation of Kir3.4 by naringin inhibits A-II-stimulated membrane voltage and aldosterone secretion. Overexpression of KCNJ5 in the HAC15 cells using a lentivirus resulted in a decrease in membrane voltage, intracellular calcium, expression of steroidogenic acute regulatory protein, 3-β-hydroxysteroid dehydrogenase 3B2, cytochrome P450 11B1 and cytochrome P450 11B2 mRNA, and aldosterone synthesis. In conclusion, A-II appears to stimulate aldosterone secretion by depolarizing the membrane acting in part through the regulation of the expression and activity of Kir3.4. PMID:22798349

Mechanisms of Hypertension: The Expanding Role of Aldosterone

PubMed Central

FREEL, E. MARIE; CONNELL, JOHN M.C.

2005-01-01

Hypertension is a common disorder that affects a large heterogeneous patient population. Subgroups can be identified on the basis of their responses to hormonal and biologic stimuli. These subgroups include low-renin hypertensives and nonmodulators. Aldosterone, the principal human mineralocorticoid, is increasingly recognized as playing a significant role in cardiovascular morbidity, and its role in hypertension has recently been reevaluated with studies that suggest that increased aldosterone biosynthesis (as defined by an elevated aldosterone to renin ratio) is a key phenotype in up to 15% of individuals with hypertension. It was reported previously that a polymorphism of the gene (C to T conversion at position −344) encoding aldosterone synthase is associated with hypertension, particularly in individuals with a high ratio. However, the most consistent association with this variant is a relative impairment of adrenal 11β-hydroxylation. This review explores the evidence for this and provides a hypothesis linking impaired 11β-hydroxylation and hypertension with a raised aldosterone to renin ratio. It is also speculated that there is substantial overlap between this group of patients and previously identified low-renin hypertensives and nonmodulators. Thus, these groups may form a neurohormonal spectrum reflecting different stages of hypertension or indeed form sequential steps in the natural history of hypertension in genetically susceptible individuals. PMID:15284285

Anatomical Variations of the Right Adrenal Vein: Concordance Between Multidetector Computed Tomography and Catheter Venography.

PubMed

Omura, Kensuke; Ota, Hideki; Takahashi, Yuuki; Matsuura, Tomonori; Seiji, Kazumasa; Arai, Yoichi; Morimoto, Ryo; Satoh, Fumitoshi; Takase, Kei

2017-03-01

Adrenal venous sampling is the most reliable diagnostic procedure to determine surgical indications in primary aldosteronism. Because guidelines recommend multidetector computed tomography (CT) to evaluate the adrenal gland, some past reports used multidetector CT as a guide for adrenal venous sampling. However, the detailed anatomy of the right adrenal vein and its relationship with an accessory hepatic vein remains uncertain. The purpose of this study was to describe detailed anatomical variations of the right adrenal vein and to determine the concordance between CT and catheter venography in patients with primary aldosteronism. In total, 440 consecutive patients who underwent adrenal venous sampling were included. Four-phase dynamic CT was performed. Anatomical locations and variations of the right adrenal vein and its relationship with the accessory hepatic vein were compared with catheter venographic findings. Successful catheterization was achieved in 437 patients (99%). The right adrenal vein was visualized in the late arterial phase with CT in 420 patients (95%). The right adrenal vein formed a common trunk with the accessory hepatic vein in 87 patients (20%). CT identified the correct craniocaudal level of the orifice in 354 patients (84%). Anatomical variations, location, and angle of inflow of the right adrenal vein based on CT demonstrated high concordance with catheter venography. CT may provide useful information for preparation before adrenal venous sampling. © 2017 American Heart Association, Inc.

Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors.

PubMed

Fassnacht, Martin; Arlt, Wiebke; Bancos, Irina; Dralle, Henning; Newell-Price, John; Sahdev, Anju; Tabarin, Antoine; Terzolo, Massimo; Tsagarakis, Stylianos; Dekkers, Olaf M

2016-08-01

: By definition, an adrenal incidentaloma is an asymptomatic adrenal mass detected on imaging not performed for suspected adrenal disease. In most cases, adrenal incidentalomas are nonfunctioning adrenocortical adenomas, but may also represent conditions requiring therapeutic intervention (e.g. adrenocortical carcinoma, pheochromocytoma, hormone-producing adenoma or metastasis). The purpose of this guideline is to provide clinicians with best possible evidence-based recommendations for clinical management of patients with adrenal incidentalomas based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. We predefined four main clinical questions crucial for the management of adrenal incidentaloma patients, addressing these four with systematic literature searches: (A) How to assess risk of malignancy?; (B) How to define and manage low-level autonomous cortisol secretion, formerly called 'subclinical' Cushing's syndrome?; (C) Who should have surgical treatment and how should it be performed?; (D) What follow-up is indicated if the adrenal incidentaloma is not surgically removed? SELECTED RECOMMENDATIONS: (i) At the time of initial detection of an adrenal mass establishing whether the mass is benign or malignant is an important aim to avoid cumbersome and expensive follow-up imaging in those with benign disease. (ii) To exclude cortisol excess, a 1mg overnight dexamethasone suppression test should be performed (applying a cut-off value of serum cortisol ≤50nmol/L (1.8µg/dL)). (iii) For patients without clinical signs of overt Cushing's syndrome but serum cortisol levels post 1mg dexamethasone >138nmol/L (>5µg/dL), we propose the term 'autonomous cortisol secretion'. (iv) All patients with '(possible) autonomous cortisol' secretion should be screened for hypertension and type 2 diabetes mellitus, to ensure these are appropriately treated. (v) Surgical treatment should be considered in an individualized approach in patients with

Adrenal tuberculosis in Cushing's disease with bilateral macronodular adrenocortical hyperplasia.

PubMed

Kwon, Hyuk-Sang; Kim, Sang-Il; Yoo, Soon-Jib; Yoon, Kun-Ho; Lee, Kwang-Woo; Kang, Moon-Won; Son, Ho-Young; Kang, Sung-Koo; Cha, Bong-Yun

2006-04-01

Cushing's disease is a disorder of hypercortisolism caused by a pituitary micro- or macro-adenoma. Most patients with Cushing's disease have a bilateral adrenal enlargement, which depends on the duration of the disease, as a result of the long standing ACTH stimulation of both adrenal glands. However, in macronodular adrenocortical hyperplasia (MNH) that is caused by Cushing's disease, if the MNH gains autonomy, a bilateral adrenalectomy, as well as the removal of pituitary adenoma, is often essential. We encountered a patient diagnosed with Cushing's disease with bilateral adrenal tuberculosis simulating MNH. She had taken anti-tuberculosis medications one year prior to admission due to spinal tuberculosis. Sellar MRI revealed a pituitary macroadenoma, but adrenal CT showed enlargement in both adrenal glands that appeared to be MNH. A hormonal study and bilateral inferior petrosal sinus sampling revealed Cushing's disease. Therefore, she underwent trans-sphenoidal surgery of the pituitary mass. The pituitary surgery was successful and the serum cortisol returned to normal range. However, the adrenal mass rapidly enlarged after removing the pituitary tumor without showing evidence of a recurrence or adrenal autonomy of hypercortisolism. Accordingly, a laparoscopic left adrenalectomy was performed to examine the nature of the mass. The resected left adrenal gland was pathologically determined to have a lesion of tuberculosis with some part of the intact cortex. So we assumed that the cause of rapid adrenal enlargement might be due to adrenal tuberculosis. In summary, to the best of our knowledge, this is the first case of Cushing's disease coexisting with both adrenal tuberculosis simulating a bilateral MNH.

Principles and management of adrenal cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Javadpour, N.

1987-01-01

This book provides information on adrenal diseases of latest developments and guides the clinicians in the care of their patients. The book is divided into two parts. The first section gives an overview of the embryology, anatomy, physiology, markers, pathology, imaging and the current progress in the field. The second edition covers specific diseases of the adrenal cortex and medulla. The increasingly significant roles played by steroids, catecholamines, blockers, computed tomography and magnetic resonance are elucidated and discussed. The contents include: Overview of progress; current problems, and perspectives - embryology anatomy, physiology, and biologic markers; pathology; advances in diagnosis; imagingmore » techniques; adrenal disorders in childhood; primary aldosteronism; Cushing's syndrome; carcinoma; pheochromocytoma; neuroblastoma; metastatic disease; surgical management; and subject index.« less

Adrenal cortical oncocytoma mimicking pheochromocytoma.

PubMed

Kiriakopoulos, Andreas; Papaioannou, Dimitrios; Linos, Dimitrios

2011-01-01

Adrenal tumors present with clinical features and signs unique to their specific hormonal hypersecretion. However, there have been cases in which the clinical expression has been in conflict with the histologic features of the tumor. In this communication we report an unusual clinical presentation of an adrenal cortical tumor with histologic features of an oncocytoma that clinically mimicked a pheochromocytoma. A 49-year old man was referred to our Unit due to type B aortic dissection and a mass of the left adrenal gland. Computed tomography and magnetic resonance imaging confirmed the presence of aortic dissection extending from the left subclavian artery to both iliac arteries and also revealed a 6 cm tumor on the left adrenal gland. Preoperative endocrine evaluation showed a near tenfold increase of urinary vanillylmandelic acid (VMA) and metanephrine values. Transperitoneal laparoscopic adrenalectomy was successfully performed. The adrenal tumor proved to be an adrenal cortical neoplasm with histologic features of oncocytoma. Although the case of an adrenal cortical adenoma clinically mimicking a pheochromocytoma has been described in the literature, to the best of our knowledge, there has been no previous report of an adrenal cortical neoplasm with predominant features of oncocytoma.

Co-secretion of aldosterone and cortisol by an adrenocortical carcinoma.

PubMed

Kurtulmus, Neslihan; Yarman, Sema; Azizlerli, Halil; Kapran, Yersu

2004-01-01

We report a rare case of adrenocortical carcinoma. A 26-year-old woman presented with hypokalemia and hypertension due to hyperaldosteronism. She had no signs of Cushing's syndrome. Endocrinological data showed excess of aldosterone production and nonsupressible cortisol production on 2 mg of dexamethasone. Magnetic resonance imaging showed left adrenal tumor. Transabdominal left adrenalectomy was performed and histopathological diagnosis was adrenocortical carcinoma. Her blood pressure and hypokalemia returned to normal after adrenalectomy. There is no recurrence after 36 months. We want to emphasis the importance of adrenal tests before the operation even if there are no signs of excess cortisol production.

Imaging of adrenal incidentalomas with PET using (11)C-metomidate and (18)F-FDG.

PubMed

Minn, Heikki; Salonen, Anna; Friberg, Johan; Roivainen, Anne; Viljanen, Tapio; Långsjö, Jaakko; Salmi, Jorma; Välimäki, Matti; Någren, Kjell; Nuutila, Pirjo

2004-06-01

Our aim was to evaluate the use of PET with (11)C-metomidate and (18)F-FDG for the diagnosis of adrenal incidentalomas. Twenty-one patients underwent hormonal screening before dynamic imaging of the upper abdomen with (11)C-metomidate, and for 19 of these 21 patients, static (18)F-FDG imaging followed. Uptake of (11)C-metomidate and (18)F-FDG in incidentalomas was quantified and correlated with the hormonal work-up and the mass size on CT (median, 2.5 cm; range, 2-10 cm). The final diagnoses were hormonally active adenoma (n = 7), nonsecretory adenoma (n = 5), adrenocortical carcinoma (n = 1), pheochromocytoma (n = 2), benign noncortical tumor (n = 2), normal adrenal (n = 1), and malignant noncortical tumor (n = 3). Diagnosis was established at surgery (n = 9), percutaneous biopsy (n = 4), or follow-up (n = 8). The highest uptake of (11)C-metomidate, expressed as standardized uptake value (SUV), was found in adrenocortical carcinoma (SUV = 28.0), followed by active adenomas (median SUV = 12.7), nonsecretory adenomas (median SUV = 12.2), and noncortical tumors (median SUV = 5.7). Patients with adenomas had significantly higher tumor-to-normal-adrenal (11)C-metomidate SUV ratios than did patients with noncortical tumors. (18)F-FDG detected 2 of 3 noncortical malignancies but failed to detect adrenal metastases from renal cell carcinoma. All inactive and most active adenomas were difficult to detect with (18)F-FDG against background activity, whereas both pheochromocytomas and adrenocortical carcinoma showed slightly increased uptake of (18)F-FDG. There was no correlation between uptake of (11)C-metomidate or (18)F-FDG and mass size. (11)C-Metomidate is a promising PET tracer to identify incidentalomas of adrenocortical origin. (18)F-FDG should be reserved for patients with a moderate to high likelihood of neoplastic disease.

Prenatal Testosterone Exposure Decreases Aldosterone Production but Maintains Normal Plasma Volume and Increases Blood Pressure in Adult Female Rats.

PubMed

More, Amar S; Mishra, Jay S; Hankins, Gary D; Kumar, Sathish

2016-08-01

Plasma testosterone levels are elevated in pregnant women with preeclampsia and polycystic ovaries; their offspring are at increased risk for hypertension during adult life. We tested the hypothesis that prenatal testosterone exposure induces dysregulation of the renin-angiotensin-aldosterone system, which is known to play an important role in water and electrolyte balance and blood pressure regulation. Female rats (6 mo old) prenatally exposed to testosterone were examined for adrenal expression of steroidogenic genes, telemetric blood pressure, blood volume and Na(+) and K(+) levels, plasma aldosterone, angiotensin II and vasopressin levels, and vascular responses to angiotensin II and arg(8)-vasopressin. The levels of Cyp11b2 (aldosterone synthase), but not the other adrenal steroidogenic genes, were decreased in testosterone females. Accordingly, plasma aldosterone levels were lower in testosterone females. Plasma volume and serum and urine Na(+) and K(+) levels were not significantly different between control and testosterone females; however, prenatal testosterone exposure significantly increased plasma vasopressin and angiotensin II levels and arterial pressure in adult females. In testosterone females, mesenteric artery contractile responses to angiotensin II were significantly greater, while contractile responses to vasopressin were unaffected. Angiotensin II type-1 receptor expression was increased, while angiotensin II type-2 receptor was decreased in testosterone arteries. These results suggest that prenatal testosterone exposure downregulates adrenal Cyp11b2 expression, leading to decreased plasma aldosterone levels. Elevated angiotensin II and vasopressin levels along with enhanced vascular responsiveness to angiotensin II may serve as an underlying mechanism to maintain plasma volume and Na(+) and K(+) levels and mediate hypertension in adult testosterone females. © 2016 by the Society for the Study of Reproduction, Inc.

Long-term treatment with aldosterone slows the progression of age-related hearing loss.

PubMed

Halonen, Joshua; Hinton, Ashley S; Frisina, Robert D; Ding, Bo; Zhu, Xiaoxia; Walton, Joseph P

2016-06-01

Age-related hearing loss (ARHL), clinically referred to as presbycusis, is one of the three most prevalent chronic medical conditions of our elderly, with the majority of persons over the age of 60 suffering from some degree of ARHL. The progressive loss of auditory sensitivity and perceptual capability results in significant declines in workplace productivity, quality of life, cognition and abilities to communicate effectively. Aldosterone is a mineralocorticoid hormone produced in the adrenal glands and plays a role in the maintenance of key ion pumps, including the Na-K(+)-Cl co-transporter 1 or NKCC1, which is involved in homeostatic maintenance of the endocochlear potential. Previously we reported that aldosterone (1 μM) increases NKCC1 protein expression in vitro and that this up-regulation of NKCC1 was not dose-dependent (dosing range from 1 nM to 100 μM). In the current study we measured behavioral and electrophysiological hearing function in middle-aged mice following long-term systemic treatment with aldosterone. We also confirmed that blood pressure remained stable during treatment and that NKCC1 protein expression was upregulated. Pre-pulse inhibition of the acoustic startle response was used as a functional measure of hearing, and the auditory brainstem response was used as an objective measure of peripheral sensitivity. Long-term treatment with aldosterone improved both behavioral and physiological measures of hearing (ABR thresholds). These results are the first to demonstrate a protective effect of aldosterone on age-related hearing loss and pave the way for translational drug development, using aldosterone as a key component to prevent or slow down the progression of ARHL. Copyright © 2016 Elsevier B.V. All rights reserved.

Aldosterone and parathyroid hormone interactions as mediators of metabolic and cardiovascular disease.

PubMed

Tomaschitz, Andreas; Ritz, Eberhard; Pieske, Burkert; Rus-Machan, Jutta; Kienreich, Katharina; Verheyen, Nicolas; Gaksch, Martin; Grübler, Martin; Fahrleitner-Pammer, Astrid; Mrak, Peter; Toplak, Hermann; Kraigher-Krainer, Elisabeth; März, Winfried; Pilz, Stefan

2014-01-01

Inappropriate aldosterone and parathyroid hormone (PTH) secretion is strongly linked with development and progression of cardiovascular (CV) disease. Accumulating evidence suggests a bidirectional interplay between parathyroid hormone and aldosterone. This interaction may lead to a disproportionally increased risk of CV damage, metabolic and bone diseases. This review focuses on mechanisms underlying the mutual interplay between aldosterone and PTH as well as their potential impact on CV, metabolic and bone health. PTH stimulates aldosterone secretion by increasing the calcium concentration in the cells of the adrenal zona glomerulosa as a result of binding to the PTH/PTH-rP receptor and indirectly by potentiating angiotensin 2 induced effects. This may explain why after parathyroidectomy lower aldosterone levels are seen in parallel with improved cardiovascular outcomes. Aldosterone mediated effects are inappropriately pronounced in conditions such as chronic heart failure, excess dietary salt intake (relative aldosterone excess) and primary aldosteronism. PTH is increased as a result of (1) the MR (mineralocorticoid receptor) mediated calciuretic and magnesiuretic effects with a trend of hypocalcemia and hypomagnesemia; the resulting secondary hyperparathyroidism causes myocardial fibrosis and disturbed bone metabolism; and (2) direct effects of aldosterone on parathyroid cells via binding to the MR. This adverse sequence is interrupted by mineralocorticoid receptor blockade and adrenalectomy. Hyperaldosteronism due to klotho deficiency results in vascular calcification, which can be mitigated by spironolactone treatment. In view of the documented reciprocal interaction between aldosterone and PTH as well as the potentially ensuing target organ damage, studies are needed to evaluate diagnostic and therapeutic strategies to address this increasingly recognized pathophysiological phenomenon. © 2013.

RGS2 is regulated by angiotensin II and functions as a negative feedback of aldosterone production in H295R human adrenocortical cells.

PubMed

Romero, Damian G; Plonczynski, Maria W; Gomez-Sanchez, Elise P; Yanes, Licy L; Gomez-Sanchez, Celso E

2006-08-01

Regulator of G protein signaling (RGS) proteins interact with Galpha-subunits of heterotrimeric G proteins, accelerating the rate of GTP hydrolysis and finalizing the intracellular signaling triggered by the G protein-coupled receptor-ligand interaction. Angiotensin (Ang) II interacts with its G protein-coupled receptor in zona glomerulosa adrenal cells and triggers a cascade of intracellular signals that regulates steroidogenesis and proliferation. We studied Ang II-mediated regulation of RGS2, the role of RGS2 in steroidogenesis, and the intracellular signal events involved in H295R human adrenal cells. We report that both H295R cells and human adrenal gland express RGS2 mRNA. In H295R cells, Ang II caused a rapid and transient increase in RGS2 mRNA levels quantified by real-time RT-PCR. Ang II effects were mimicked by calcium ionophore A23187 and blocked by calcium channel blocker nifedipine. Ang II effects also were blocked by calmodulin antagonists (W-7 and calmidazolium) and calcium/calmodulin-dependent kinase antagonist KN-93. RGS2 overexpression by retroviral infection in H295R cells caused a decrease in Ang II-stimulated aldosterone secretion but did not modify cortisol secretion. In reporter assays, RGS2 decreased Ang II-mediated aldosterone synthase up-regulation. These results suggest that Ang II up-regulates RGS2 mRNA by the calcium/calmodulin-dependent kinase pathway in H295R cells. RGS2 overexpression specifically decreases aldosterone secretion through a decrease in Ang II-mediated aldosterone synthase-induced expression. In conclusion, RGS2 expression is induced by Ang II to terminate the intracellular signaling cascade generated by Ang II. RGS2 alterations in expression levels or functionality could be implicated in deregulations of Ang II signaling and abnormal aldosterone secretion by the adrenal gland.

Very low-density lipoprotein (VLDL)-induced signals mediating aldosterone production.

PubMed

Tsai, Ying-Ying; Rainey, William E; Bollag, Wendy B

2017-02-01

Aldosterone, secreted by the adrenal zona glomerulosa, enhances sodium retention, thus increasing blood volume and pressure. Excessive production of aldosterone results in high blood pressure and contributes to cardiovascular and renal disease, stroke and visual loss. Hypertension is also associated with obesity, which is correlated with other serious health risks as well. Although weight gain is associated with increased blood pressure, the mechanism by which excess fat deposits increase blood pressure remains unclear. Several studies have suggested that aldosterone levels are elevated with obesity and may represent a link between obesity and hypertension. In addition to hypertension, obese patients typically have dyslipidemia, including elevated serum levels of very low-density lipoprotein (VLDL). VLDL, which functions to transport triglycerides from the liver to peripheral tissues, has been demonstrated to stimulate aldosterone production. Recent studies suggest that the signaling pathways activated by VLDL are similar to those utilized by AngII. Thus, VLDL increases cytosolic calcium levels and stimulates phospholipase D (PLD) activity to result in the induction of steroidogenic acute regulatory (StAR) protein and aldosterone synthase (CYP11B2) expression. These effects seem to be mediated by the ability of VLDL to increase the phosphorylation (activation) of their regulatory transcription factors, such as the cAMP response element-binding (CREB) protein family of transcription factors. Thus, research into the pathways by which VLDL stimulates aldosterone production may identify novel targets for the development of therapies for the treatment of hypertension, particularly those associated with obesity, and other aldosterone-modulated pathologies. © 2017 Society for Endocrinology.

Down-regulation of E-cadherin and catenins in human pituitary growth hormone-producing adenomas.

PubMed

Sano, Toshiaki; Rong, Qian Zhi; Kagawa, Noriko; Yamada, Shozo

2004-01-01

Growth hormone (GH)-producing pituitary adenomas can be ultrastructurally divided into two major types: densely granulated and sparsely granulated. The latter type of adenoma characteristically exhibits globular accumulations of cytokeratin filaments known as fibrous bodies, which are immunohistochemically identifiable as juxtanuclear dot-like immunoreactivity. We hypothesize that the formation of fibrous body might be related to dysfunction of adhesion molecules, because of the functional relationship between intermediate filaments and the cadherin-catenin complex and frequent observation of loss of cohesiveness of the adenoma cells. Our recent immunohistochemical study showed that expression of E-cadherin and its undercoat proteins, alpha-, beta- and gamma-catenin, in GH cell adenomas with prominent fibrous bodies was significantly reduced compared with GH cell adenomas without fibrous bodies and the normal adenohypophysial cells. Although no mutation of exon 3 of the beta-catenin gene was found in any GH cell adenomas with fibrous bodies, methylation-specific polymerase chain reaction analysis revealed that the E-cadherin promoter region was methylated in 37.5% of these adenomas, two of which displayed total methylation, but not in GH cell adenomas without fibrous bodies. We conclude that the decreased expression of the E-cadherin-catenin complex and methylation of the E-cadherin gene promoter region are events associated with the formation of fibrous bodies in GH cell adenomas. It remains to be clarified to explain the mechanism by which down-regulation of adhesion molecules is involved in the abnormal assembly of intermediate filaments.

Does the corticoadrenal adenoma with ''pre-Cushing's syndrome'' exist

DOE Office of Scientific and Technical Information (OSTI.GOV)

Charbonnel, B.; Chatal, J.F.; Ozanne, P.

1981-12-01

An adrenal tumor was discovered fortuitously in a patient with no clinical features of Cushing's syndrome. On adrenal imaging, there was good uptake in the nodule but no visualization of the contralateral adrenal. The latter was seen, however, in a second scan performed under ACTH treatment. In the hormone assessment, basal cortisol and 17-hydroxycorticoids were normal and cortisol diurnal variation was near normal, but a dexamethasone suppression test and ACTH responses to metyrapone and insulin hypoglycemia were abnormal. Eight months after excision of a spongiocytic-type adenoma, the remaining adrenal was visible on scintigram and the hormonal tests were normal. Thismore » pattern suggests that the clinical Cushing's syndrome was enough to partially suppress ACTH and, consequently, visualization of the contralateral gland.« less

Interactions Between Adrenal and Calcium-Regulatory Hormones in Human Health

PubMed Central

Brown, Jenifer M.; Vaidya, Anand

2014-01-01

Purpose of Review To summarize evidence characterizing the interactions between adrenal- and calcium-regulating hormones, and the relevance of these interactions to human cardiovascular and skeletal health. Recent Findings Human studies support the regulation of parathyroid hormone (PTH) by the renin-angiotensin-aldosterone system (RAAS): angiotensin II may stimulate PTH secretion via an acute and direct mechanism, whereas aldosterone may exert a chronic stimulation of PTH secretion. Studies in primary aldosteronism, congestive heart failure, and chronic kidney disease have identified associations between hyperaldosteronism, hyperparathyroidism, and bone loss, which appear to improve when inhibiting the RAAS. Conversely, elevated PTH and insufficient vitamin D status have been associated with adverse cardiovascular outcomes, which may be mediated by the RAAS. Studies of primary hyperparathyroidism implicate PTH-mediated stimulation of the RAAS, and recent evidence shows that the vitamin D-vitamin D receptor (VDR) complex may negatively regulate renin expression and RAAS activity. Ongoing human interventional studies are evaluating the influence of RAAS inhibition on PTH and the influence of VDR agonists on RAAS activity. Summary While previously considered independent endocrine systems, emerging evidence supports a complex web of interactions between adrenal and calcium-regulating hormones, with implications for human cardiovascular and skeletal health. PMID:24694551

Targeted Molecular Imaging in Adrenal Disease—An Emerging Role for Metomidate PET-CT

PubMed Central

Mendichovszky, Iosif A.; Powlson, Andrew S.; Manavaki, Roido; Aigbirhio, Franklin I.; Cheow, Heok; Buscombe, John R.; Gurnell, Mark; Gilbert, Fiona J.

2016-01-01

Adrenal lesions present a significant diagnostic burden for both radiologists and endocrinologists, especially with the increasing number of adrenal ‘incidentalomas’ detected on modern computed tomography (CT) or magnetic resonance imaging (MRI). A key objective is the reliable distinction of benign disease from either primary adrenal malignancy (e.g., adrenocortical carcinoma or malignant forms of pheochromocytoma/paraganglioma (PPGL)) or metastases (e.g., bronchial, renal). Benign lesions may still be associated with adverse sequelae through autonomous hormone hypersecretion (e.g., primary aldosteronism, Cushing’s syndrome, phaeochromocytoma). Here, identifying a causative lesion, or lateralising the disease to a single adrenal gland, is key to effective management, as unilateral adrenalectomy may offer the potential for curing conditions that are typically associated with significant excess morbidity and mortality. This review considers the evolving role of positron emission tomography (PET) imaging in addressing the limitations of traditional cross-sectional imaging and adjunctive techniques, such as venous sampling, in the management of adrenal disorders. We review the development of targeted molecular imaging to the adrenocortical enzymes CYP11B1 and CYP11B2 with different radiolabeled metomidate compounds. Particular consideration is given to iodo-metomidate PET tracers for the diagnosis and management of adrenocortical carcinoma, and the increasingly recognized utility of 11C-metomidate PET-CT in primary aldosteronism. PMID:27869719

A Case of Cushing's Syndrome with Multiple Adrenocortical Adenomas Composed of Compact Cells and Clear Cells.

PubMed

Asakawa, Masahiro; Yoshimoto, Takanobu; Ota, Mitsutane; Numasawa, Mitsuyuki; Sasahara, Yuriko; Takeuchi, Takato; Nakano, Yujiro; Oohara, Norihiko; Murakami, Masanori; Bouchi, Ryotaro; Minami, Isao; Tsuchiya, Kyoichiro; Hashimoto, Koshi; Izumiyama, Hajime; Kawamura, Naoko; Kihara, Kazunori; Negi, Mariko; Akashi, Takumi; Eishi, Yoshinobu; Sasano, Hironobu; Ogawa, Yoshihiro

2016-06-01

A 58-year-old woman was referred to our hospital for Cushingoid features and diagnosed as adrenal Cushing's syndrome due to a right adrenocortical mass (60 × 55 mm). The mass was composed of three different tumors; the first one was homogeneously lipid-poor neoplasm measuring 20 × 13 mm located at the most dorsal region, the second one was heterogeneous and lipid-rich tumor containing multiple foci of calcification measuring 50 × 32 mm located at the central region, and the last one was heterogeneous harboring dilated and tortuous vessels and lipid-poor one measuring 35 × 18 mm at the most ventral region of the adrenal gland. A right adrenalectomy was subsequently performed by open surgery. Macroscopic and microscopic analyses revealed that all three tumors were adrenocortical adenomas; the first one represents a pigmented adrenocortical adenoma, the second one adrenocortical adenoma associated with degeneration, and the third one adrenocortical adenoma harboring extensive degeneration. Immunohistochemical analysis of the steroidogenic enzymes also revealed that all of the tumors had the capacity of synthesizing cortisol. This is a very rare case of Cushing's syndrome caused by multiple adrenocortical adenomas including a pigmented adenoma. Immunohistochemical analysis of steroidogenic enzymes contributed to understanding of steroidogenesis in each of these three different adrenocortical adenomas in this case.

Adrenal incidentaloma caused by extramedullary haematopoiesis: conservative management is optimal.

PubMed

Sekar, Suganya; Burad, Deepak; Abraham, Aby; Paul, Mazhuvanchary Jacob

2015-09-21

We present a thalassaemic patient with extramedullary haematopoiesis in the adrenal gland, which is one of the rare sites of involvement. A 29-year-old man presented with a history of anaemia since childhood which required blood transfusion recently. On examination, he had pallor, icterus and splenomegaly with no other palpable abdominal mass. He was diagnosed to have β-thalassaemia. Ultrasonography of the abdomen showed an incidental right adrenal mass with splenomegaly; CT revealed a large right adrenal mass with heterogeneous density. Adrenal adenoma, carcinoma and extramedullary haematopoiesis were considered in the differential diagnosis. After excluding a functioning tumour, the diagnosis was confirmed by ultrasound-guided biopsy. Since the patient was asymptomatic, the adrenal lesion was managed conservatively. 2015 BMJ Publishing Group Ltd.

Effects of Carbenoxolone on the Canine Pituitary-Adrenal Axis.

PubMed

Teshima, Takahiro; Matsumoto, Hirotaka; Okusa, Tomoko; Nakamura, Yumi; Koyama, Hidekazu

2015-01-01

Cushing's disease caused by pituitary corticotroph adenoma is a common endocrine disease in dogs. A characteristic biochemical feature of corticotroph adenomas is their relative resistance to suppressive negative feedback by glucocorticoids. The abnormal expression of 11beta-hydroxysteroid dehydrogenase (11HSD), which is a cortisol metabolic enzyme, is found in human and murine corticotroph adenomas. Our recent studies demonstrated that canine corticotroph adenomas also have abnormal expression of 11HSD. 11HSD has two isoforms in dogs, 11HSD type1 (HSD11B1), which converts cortisone into active cortisol, and 11HSD type2 (HSD11B2), which converts cortisol into inactive cortisone. It has been suggested that glucocorticoid resistance in corticotroph tumors is related to the overexpression of HSD11B2. Therefore it was our aim to investigate the effects of carbenoxolone (CBX), an 11HSD inhibitor, on the healthy dog's pituitary-adrenal axis. Dogs were administered 50 mg/kg of CBX twice each day for 15 days. During CBX administration, no adverse effects were observed in any dogs. The plasma adrenocorticotropic hormone (ACTH), and serum cortisol and cortisone concentrations were significantly lower at day 7 and 15 following corticotropin releasing hormone stimulation. After completion of CBX administration, the HSD11B1 mRNA expression was higher, and HSD11B2 mRNA expression was significantly lower in the pituitaries. Moreover, proopiomelanocortin mRNA expression was lower, and the ratio of ACTH-positive cells in the anterior pituitary was also significantly lower after CBX treatment. In adrenal glands treated with CBX, HSD11B1 and HSD11B2 mRNA expression were both lower compared to normal canine adrenal glands. The results of this study suggested that CBX inhibits ACTH secretion from pituitary due to altered 11HSD expressions, and is potentially useful for the treatment of canine Cushing's disease.

Effects of selective type I and II adrenal steroid agonists on immune cell distribution.

PubMed

Miller, A H; Spencer, R L; hassett, J; Kim, C; Rhee, R; Ciurea, D; Dhabhar, F; McEwen, B; Stein, M

1994-11-01

Adrenal steroids exert their effects through two distinct adrenal steroid receptor subtypes; the high affinity type I, or mineralocorticoid, receptor and the lower affinity type II, or glucocorticoid, receptor. Adrenal steroids have well known effects on immune cell distribution, and although both type I and II receptors are expressed in immune cells and tissues, few data exist on the relative effects mediated through these two receptor subtypes. Accordingly, we administered selective type I and II adrenal steroid receptor agonists to young adult male Sprague-Dawley rats for 7 days and then measured immune cell distribution in the peripheral blood and spleen. Results were compared with those of similar studies using the naturally occurring glucocorticoid of the rat, corticosterone, which binds both type I and II receptors. The majority of the well characterized effects of adrenal steroids on peripheral blood immune cells (increased neutrophils and decreased lymphocytes and monocytes) were reproduced by the type II receptor agonist, RU28362. RU28362 decreased the numbers of all lymphocyte subsets [T-cells, B-cells, and natural killer (NK) cells] to very low absolute levels. The largest relative decrease (i.e. in percentage) was seen in B-cells, whereas NK cells exhibited the least relative decrease and actually showed a 2-fold increase in relative percentage during RU28362 treatment. Similar to RU28362, the type I receptor agonist, aldosterone, significantly reduced the number of lymphocytes and monocytes. In contrast to RU28362, however, aldosterone significantly decreased the number of neutrophils. Moreover, aldosterone decreased the number of T-helper cells and NK cells, while having no effect on the number of B-cells or T-suppressor/cytotoxic cells. Corticosterone at physiologically relevant concentrations had potent effects on immune cell distribution, which were indistinguishable from those of the type II receptor agonist, RU28362. Taken together, these

Cushing's syndrome associated with a bronchial adenoma. Possible periodic hormonogenesis.

PubMed

Shapiro, M S; Gutman, A; Bruderman, I; Myers, B; Griffel, W B

1975-09-01

Diagnostic and therapeutic problems in a patient with ectopic ACTH syndrome caused by a malignant bronchial adenoma are discussed. Persistent Cushing's syndrome was present following apparent total adrenalectomy, but radioactive scanning with 131I-19-iodocholesterol showed the presence of residual adrenal tissue in the right suprarenal bed. Amelioration of the hypercortisolism occurred after removal of the bronchial adenoma. A paradoxical elevation of adrenocortical activity followed administration of dexamethasone and data are presented which suggest that periodic secretion of ACTH accounted for this phenomenon.

The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline.

PubMed

Funder, John W; Carey, Robert M; Mantero, Franco; Murad, M Hassan; Reincke, Martin; Shibata, Hirotaka; Stowasser, Michael; Young, William F

2016-05-01

recommend that all patients with primary aldosteronism undergo adrenal computed tomography as the initial study in subtype testing and to exclude adrenocortical carcinoma. We recommend that an experienced radiologist should establish/exclude unilateral primary aldosteronism using bilateral adrenal venous sampling, and if confirmed, this should optimally be treated by laparoscopic adrenalectomy. We recommend that patients with bilateral adrenal hyperplasia or those unsuitable for surgery should be treated primarily with a mineralocorticoid receptor antagonist.

Cardiac Hypertrophy and Fibrosis in the Metabolic Syndrome: A Role for Aldosterone and the Mineralocorticoid Receptor

PubMed Central

Essick, Eric E.; Sam, Flora

2011-01-01

Obesity and hypertension, major risk factors for the metabolic syndrome, render individuals susceptible to an increased risk of cardiovascular complications, such as adverse cardiac remodeling and heart failure. There has been much investigation into the role that an increase in the renin-angiotensin-aldosterone system (RAAS) plays in the pathogenesis of metabolic syndrome and in particular, how aldosterone mediates left ventricular hypertrophy and increased cardiac fibrosis via its interaction with the mineralocorticoid receptor (MR). Here, we review the pertinent findings that link obesity with elevated aldosterone and the development of cardiac hypertrophy and fibrosis associated with the metabolic syndrome. These studies illustrate a complex cross-talk between adipose tissue, the heart, and the adrenal cortex. Furthermore, we discuss findings from our laboratory that suggest that cardiac hypertrophy and fibrosis in the metabolic syndrome may involve cross-talk between aldosterone and adipokines (such as adiponectin). PMID:21747976

Genomic and rapid effects of aldosterone: what we know and do not know thus far.

PubMed

Hermidorff, Milla Marques; de Assis, Leonardo Vinícius Monteiro; Isoldi, Mauro César

2017-01-01

Aldosterone is the most known mineralocorticoid hormone synthesized by the adrenal cortex. The genomic pathway displayed by aldosterone is attributed to the mineralocorticoid receptor (MR) signaling. Even though the rapid effects displayed by aldosterone are long known, our knowledge regarding the receptor responsible for such event is still poor. It is intense that the debate whether the MR or another receptor-the "unknown receptor"-is the receptor responsible for the rapid effects of aldosterone. Recently, G protein-coupled estrogen receptor-1 (GPER-1) was elegantly shown to mediate some aldosterone-induced rapid effects in several tissues, a fact that strongly places GPER-1 as the unknown receptor. It has also been suggested that angiotensin receptor type 1 (AT1) also participates in the aldosterone-induced rapid effects. Despite this open question, the relevance of the beneficial effects of aldosterone is clear in the kidneys, colon, and CNS as aldosterone controls the important water reabsorption process; on the other hand, detrimental effects displayed by aldosterone have been reported in the cardiovascular system and in the kidneys. In this line, the MR antagonists are well-known drugs that display beneficial effects in patients with heart failure and hypertension; it has been proposed that MR antagonists could also play an important role in vascular disease, obesity, obesity-related hypertension, and metabolic syndrome. Taken altogether, our goal here was to (1) bring a historical perspective of both genomic and rapid effects of aldosterone in several tissues, and the receptors and signaling pathways involved in such processes; and (2) critically address the controversial points within the literature as regarding which receptor participates in the rapid pathway display by aldosterone.

Adrenal steroidogenesis after B lymphocyte depletion therapy in new-onset Addison's disease.

PubMed

Pearce, Simon H S; Mitchell, Anna L; Bennett, Stuart; King, Phil; Chandran, Sukesh; Nag, Sath; Chen, Shu; Smith, Bernard Rees; Isaacs, John D; Vaidya, Bijay

2012-10-01

A diagnosis of Addison's disease means lifelong dependence on daily glucocorticoid and mineralocorticoid therapy and is associated with increased morbidity and mortality as well as a risk of unexpected adrenal crisis. The objective of the study was to determine whether immunomodulatory therapy at an early stage of autoimmune Addison's disease could lead to preservation or improvement in adrenal steroidogenesis. This was an open-label, pilot study of B lymphocyte depletion therapy in new-onset idiopathic primary adrenal failure. Doses of iv rituximab (1 g) were given on d 1 and 15, after pretreatment with 125 mg iv methylprednisolone. Six patients (aged 17-47 yr; four females) were treated within 4 wk of the first diagnosis of idiopathic primary adrenal failure. Dynamic testing of adrenal function was performed every 3 months for at least 12 months. Serum cortisol levels declined rapidly and were less than 100 nmol/liter (3.6 μg/dl) in all patients by 3 months after B lymphocyte depletion. Serum cortisol and aldosterone concentrations remained low in five of the six patients throughout the follow-up period. However, a single patient had sustained improvement in both serum cortisol [peak 434 nmol/liter (15.7 μg/dl)] and aldosterone [peak 434 pmol/liter (15.7 ng/dl)] secretion. This patient was able to discontinue steroid medications 15 months after therapy and remains well, with improving serum cortisol levels 27 months after therapy. New-onset autoimmune Addison's disease should be considered as a potentially reversible condition in some patients. Future studies of immunomodulation in autoimmune Addison's disease may be warranted.

60 YEARS OF POMC: Adrenal and extra-adrenal functions of ACTH.

PubMed

Gallo-Payet, Nicole

2016-05-01

The pituitary adrenocorticotropic hormone (ACTH) plays a pivotal role in homeostasis and stress response and is thus the major component of the hypothalamo-pituitary-adrenal axis. After a brief summary of ACTH production from proopiomelanocortin (POMC) and on ACTH receptor properties, the first part of the review covers the role of ACTH in steroidogenesis and steroid secretion. We highlight the mechanisms explaining the differential acute vs chronic effects of ACTH on aldosterone and glucocorticoid secretion. The second part summarizes the effects of ACTH on adrenal growth, addressing its role as either a mitogenic or a differentiating factor. We then review the mechanisms involved in steroid secretion, from the classical Cyclic adenosine monophosphate second messenger system to various signaling cascades. We also consider how the interaction between the extracellular matrix and the cytoskeleton may trigger activation of signaling platforms potentially stimulating or repressing the steroidogenic potency of ACTH. Finally, we consider the extra-adrenal actions of ACTH, in particular its role in differentiation in a variety of cell types, in addition to its known lipolytic effects on adipocytes. In each section, we endeavor to correlate basic mechanisms of ACTH function with the pathological consequences of ACTH signaling deficiency and of overproduction of ACTH. © 2016 Society for Endocrinology.

[Primary hyperaldosteronism due to unilateral adrenal hyperplasia with surgical resolution].

PubMed

Rubio-Puchol, O; Garzón-Pastor, S; Salom-Vendrell, C; Hernández-Mijares, A

Unilateral adrenal hyperplasia is a rare cause of primary hyperaldosteronism (around a 3%) that has surgical treatment. A case of a patient with hypertension resistant to conventional therapy in treatment with 7 drugs who presented with primary hyperaldosteronism due to unilateral adrenal hyperplasia is presented. A left adrenalectomy was performed, and the patient had a good clinical response, with no need of any drug after 2 years of surgery. Unilateral adrenal hyperplasia is a different entity and it is not an asymmetric variant of the bilateral adrenal hyperplasia. In the study of patients with primary hyperaldosteronism and imaging tests with absence of adenoma is a diagnosis that must be considered before cataloguing patients with bilateral adrenal hyperplasia and start a medical treatment, because unilateral adrenal hyperplasia would have a surgical resolution. Copyright © 2016 SEH-LELHA. Publicado por Elsevier España, S.L.U. All rights reserved.

Double pituitary adenomas: six surgical cases.

PubMed

Sano, T; Horiguchi, H; Xu, B; Li, C; Hino, A; Sakaki, M; Kannuki, S; Yamada, S

1999-05-01

While double pituitary adenomas have been found in approximately 1% of autopsy pituitaries, those in surgically resected material have been only rarely reported. We report herein 6 cases of double pituitary adenomas, which consisted of two histologically and/or immunohistochemically different areas among approximately 450 surgical specimens. Five out of 6 patients were men and the age was ranged between 18 and 61 years old. All these 6 patients presented acromegaly or acrogigantism and hyperprolactinemia was noted in 3 patients. In 2 patients (cases 1 and 2) the two adenomas belonged to different adenoma groups (GH-PRL-TSH group and FSH/LH group), while in the remaining 4 patients (cases 3-6) the two adenomas belonged to the same group (GH-PRL-TSH group). Thus, in all patients at least one of the two adenomas was GH-producing adenoma. Reasons for a high incidence of GH-producing adenomas in surgically resected double pituitary adenomas may include the presence of a variety of histologic subtypes among GH-producing adenomas and the advantage of cytokeratin immunostaining to distinguish these subtypes. In regard to pathogenesis of double pituitary adenomas, adenomas in cases 1 and 2 may be of multicentric occurrence, while those in cases 3-6 may occur through different clonal proliferation within originally one adenoma, resulting in diverse phenotypic expressions. Since there were patients with familial MEN 1 (case 2) and familial pituitary adenoma unrelated MEN 1 (case 3), genetic background should be also considered. Double pituitary adenomas in surgically resected material may not be so infrequent. Further molecular analysis will provide new insights into understanding the pathogenesis of pituitary adenomas and their mechanisms of multidirectional phenotypic diffrentiation.

[Adrenal incidentaloma: a clinical problem related to imaging].

PubMed

de Bruijne, E L E; Burgmans, J P J; Krestin, G P; Pols, H A P; van den Meiracker, A H; de Herder, W W

2005-08-13

Two female patients, 68 and 67 years of age, were referred for right abdominal pain and pyelonephritis, respectively. During the diagnostic work-up, an unsuspected adrenal mass was found in both patients. Hormonal evaluation and imaging showed a benign non-hyperactive functioning adenoma in one patient and a pheochromocytoma in the other. Both patients were successfully treated with endoscopic adrenalectomy. Wider application and improvement of abdominal imaging procedures have caused an increase of incidentally detected adrenal masses, posing a common clinical problem. Typically, a diagnosis can be made on the basis of the characteristic radiological image. The exact nature of the defect is often unclear and further evaluation is required to determine functionality and possible malignancy. An algorithm is presented for the management of adrenal incidentalomas.

Adrenal Steroidogenesis after B Lymphocyte Depletion Therapy in New-Onset Addison's Disease

PubMed Central

Mitchell, Anna L.; Bennett, Stuart; King, Phil; Chandran, Sukesh; Nag, Sath; Chen, Shu; Smith, Bernard Rees; Isaacs, John D.; Vaidya, Bijay

2012-01-01

Context: A diagnosis of Addison's disease means lifelong dependence on daily glucocorticoid and mineralocorticoid therapy and is associated with increased morbidity and mortality as well as a risk of unexpected adrenal crisis. Objective: The objective of the study was to determine whether immunomodulatory therapy at an early stage of autoimmune Addison's disease could lead to preservation or improvement in adrenal steroidogenesis. Design and Intervention: This was an open-label, pilot study of B lymphocyte depletion therapy in new-onset idiopathic primary adrenal failure. Doses of iv rituximab (1 g) were given on d 1 and 15, after pretreatment with 125 mg iv methylprednisolone. Patients and Main Outcome Measures: Six patients (aged 17–47 yr; four females) were treated within 4 wk of the first diagnosis of idiopathic primary adrenal failure. Dynamic testing of adrenal function was performed every 3 months for at least 12 months. Results: Serum cortisol levels declined rapidly and were less than 100 nmol/liter (3.6 μg/dl) in all patients by 3 months after B lymphocyte depletion. Serum cortisol and aldosterone concentrations remained low in five of the six patients throughout the follow-up period. However, a single patient had sustained improvement in both serum cortisol [peak 434 nmol/liter (15.7 μg/dl)] and aldosterone [peak 434 pmol/liter (15.7 ng/dl)] secretion. This patient was able to discontinue steroid medications 15 months after therapy and remains well, with improving serum cortisol levels 27 months after therapy. Conclusion: New-onset autoimmune Addison's disease should be considered as a potentially reversible condition in some patients. Future studies of immunomodulation in autoimmune Addison's disease may be warranted. PMID:22767640

Application of a protocol for magnetic resonance spectroscopy of adrenal glands: an experiment with over 100 cases.

PubMed

Melo, Homero José de Farias E; Goldman, Suzan M; Szejnfeld, Jacob; Faria, Juliano F; Huayllas, Martha K P; Andreoni, Cássio; Kater, Cláudio E

2014-01-01

To evaluate a protocol for two-dimensional (2D) hydrogen proton (1H) magnetic resonance spectroscopy (MRS) (Siemens Medical Systems; Erlangen, Germany) in the detection of adrenal nodules and differentiation between benign and malignant masses (adenomas, pheochromocytomas, carcinomas and metastases). A total of 118 patients (36 men; 82 women) (mean age: 57.3 ± 13.3 years) presenting with 138 adrenal nodules/masses were prospectively assessed. A multivoxel system was utilized with a 2D point-resolved spectroscopy/chemical shift imaging sequence. The following ratios were calculated: choline (Cho)/creatine (Cr), 4.0-4.3/Cr, lipid (Lip)/Cr, Cho/Lip and lactate (Lac)/Cr. 2D-1H-MRS was successful in 123 (89.13%) lesions. Sensitivity and specificity values observed for the ratios and cutoff points were the following: Cho/Cr ≥ 1.2, 100% sensitivity, 98.2% specificity (differences between adenomas/pheochromocytomas and carcinomas/ metastases); 4.0-4.3 ppm/Cr ≥ 1.5, 92.3% sensitivity, 96.9% specificity (differences between carcinomas/pheochromocytomas and adenomas/metastases); Lac/Cr ≤ -7.449, 90.9% sensitivity and 77.8% specificity (differences between pheochromocytomas and carcinomas/adenomas). Information provided by 2D-1H-MRS were effective and allowed for the differentiation between adrenal masses and nodules in most cases of lesions with > 1.0 cm in diameter.

Adrenal Fatigue

MedlinePlus

... unlikely to cover the costs. What is the theory behind adrenal fatigue? Supporters of adrenal fatigue believe ... by producing hormones like cortisol. According to the theory of adrenal fatigue, when people are faced with ...

[Adrenal hormones in the formation of atherosclerotic precursors in adolescents with primary arterial hypertension].

PubMed

Bogmat, L F

1993-01-01

The components of blood lipid spectrum (total cholesterol, triglycerides and high density lipoprotein cholesterol) were studied in 131 adolescents (12-18 years old) with primary arterial hypertension at various levels of adrenal hormones (hydrocortisone and aldosterone) and blood plasma renin activity. The optimal ratio of lipid components in blood was detected if concentrations of adrenal hormones and blood plasma renin activity were low. Hyperfunction of the adrenal cortex in teen-agers contributed both to the development of hypertension and to atherosclerotic changes in vessels. This suggests that definite forms of hypertension occurred in adults, with specific impairments in the metabolism of blood serum lipids, were developed during the juvenile age.

Congenital primary adrenal insufficiency and selective aldosterone defects presenting as salt-wasting in infancy: a single center 10-year experience.

PubMed

Bizzarri, Carla; Olivini, Nicole; Pedicelli, Stefania; Marini, Romana; Giannone, Germana; Cambiaso, Paola; Cappa, Marco

2016-08-02

Salt-wasting represents a relatively common cause of emergency admission in infants and may result in life-threatening complications. Neonatal kidneys show low glomerular filtration rate and immaturity of the distal nephron leading to reduced ability to concentrate urine. A retrospective chart review was conducted for infants hospitalized in a single Institution from 1(st) January 2006 to 31(st) December 2015. The selection criterion was represented by the referral to the Endocrinology Unit for hyponatremia (serum sodium <130 mEq/L) of suspected endocrine origin at admission. Fifty-one infants were identified. In nine infants (17.6 %) hyponatremia was related to unrecognized chronic gastrointestinal or renal salt losses or reduced sodium intake. In 10 infants (19.6 %) hyponatremia was related to central nervous system diseases. In 19 patients (37.3 %) the final diagnosis was congenital adrenal hyperplasia (CAH). CAH was related to 21-hydroxylase deficiency in 18 patients, and to 3β-Hydroxysteroid dehydrogenase (3βHSD) deficiency in one patient. Thirteen patients (25.5 %) were affected by different non-CAH salt-wasting forms of adrenal origin. Four familial cases of X-linked adrenal hypoplasia congenita due to NROB1 gene mutation were identified. Two unrelated girls showed aldosterone synthase deficiency due to mutation of the CYP11B2 gene. Two unrelated infants were affected by familial glucocorticoid deficiency due to MC2R gene mutations. One girl showed pseudohypoaldosteronism related to mutations of the SCNN1G gene encoding for the epithelial sodium channel. Transient pseudohypoaldosteronism was identified in two patients with renal malformations. In two infants the genetic aetiology was not identified. Emergency management of infants presenting with salt wasting requires correction of water losses and treatment of electrolyte imbalances. Nevertheless, the differential diagnosis may be difficult in emergency settings, and sometimes hospitalized infants

Assessment of adrenal function by measurement of salivary steroids in response to corticotrophin in patients infected with human immunodeficiency virus.

PubMed

Cardoso, Estela; Persi, Gabriel; González, Natalia; Tumilasci, Omar; Arregger, Alejandro; Burgos, Myriam; Rodríguez, Viviana; Molina, Ana; Contreras, Liliana N

2007-04-01

Adrenal insufficiency has been reported among critically ill HIV-infected patients. This is the first study that attempts to detect subclinical hypoadrenal states in non-critical HIV patients through salivary steroids in response to intramuscular low-dose ACTH injection. We studied 21 ambulatory adult HIV-infected patients without specific clinical signs or symptoms of adrenal insufficiency. Normal salivary flow-rate and salivary alpha-amylase activity confirmed adequate salivary gland function. Salivary cortisol (SAF) and salivary aldosterone (SAL) were obtained at baseline and 30 min after the injection of 25 microg of ACTH in the deltoid muscle (LDT(s)). Assessment of salivary steroids after stimulation with 250 microg of intramuscular ACTH (HDT(s)) was performed on those who hyporesponded to LDT(s). Basal blood samples were drawn for steroids, renin and ACTH measurements. At baseline SAF and SAL correlated significantly (p=0.0001) with basal serum cortisol and aldosterone (r=0.70 and 0.91, respectively). Plasma ACTH and renin concentrations were within the normal range in all patients. Eight of the twenty-one HIV(+) patients were LDT(s) hyporesponders in either SAF (n:1) or SAL (n:7). LDT(s) repeated in six cases after a year reconfirmed the impairment of aldosterone secretion. LDT(s) hyporesponders had normal steroid responses to HDT(s). LDT(s) is a simple, safe, well-accepted and non-invasive approach to assess adrenal function in HIV-infected ambulatory patients. It revealed subnormal cortisol (5%) and aldosterone responses (33%) when HDT(s) results were normal.

Saline suppression test parameters may predict bilateral subtypes of primary aldosteronism.

PubMed

Hashimura, Hikaru; Shen, Jimmy; Fuller, Peter J; Chee, Nicholas Y N; Doery, James C G; Chong, Winston; Choy, Kay Weng; Gwini, Stella May; Yang, Jun

2018-06-06

The saline suppression test (SST) serves to confirm the diagnosis of primary aldosteronism (PA) while adrenal vein sampling (AVS) is used to determine whether the aldosterone hypersecretion is unilateral or bilateral. An accurate prediction of bilateral PA based on SST results could reduce the need for AVS. We sought to identify SST parameters that reliably predict bilateral PA. The results from 121 patients undergoing SSTs at Monash Health from January 2010 to January 2018 including screening blood tests, imaging, AVS and histopathology results were evaluated. Patients were subtyped into unilateral or bilateral PA based on AVS and surgical outcomes. Of 113 patients with confirmed PA, 33 had unilateral disease while 42 had bilateral disease. In those with bilateral disease, plasma aldosterone concentration (PAC) was significantly lower post-SST, together with a significant fall in the aldosterone-renin ratio (ARR). The combination of PAC <300 pmol/L and a reduction in ARR post-SST provided 96.8% specificity in predicting bilateral disease. Eighteen out of 39 patients (49%) with bilateral PA could have avoided AVS using these criteria. A combination of PAC <300 pmol/L and a lower ARR post-SST could reliably predict bilateral PA. An independent cohort will be needed to validate these findings. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Is biochemical screening for pheochromocytoma in adrenal incidentalomas expressing low unenhanced attenuation on computed tomography necessary?

PubMed

Sane, T; Schalin-Jäntti, C; Raade, M

2012-06-01

Pheochromocytomas are characterized by a high attenuation value on unenhanced computed tomography (CT). It is not known whether pheochromocytoma could be ruled out as a cause of adrenal incidentalomas on the basis of unenhanced attenuation values only. We retrospectively evaluated the outcome of routine biochemical screening for pheochromocytoma in a series of adrenal incidentalomas in relationship to the unenhanced attenuation values on CT. An unenhanced CT was available in 174 of 184 patients with 214 adrenal incidentalomas. All patients were screened for pheochromocytoma with 24-h urinary metanephrines and normetanephrines and for hypercortisolism (1 mg dexamethasone test and ACTH). Hypertensive patients were screened for aldosterone overproduction (aldosterone to renin ratio and 24 h urinary aldosterone). The results were compared between incidentalomas with high [≥10 Hounsfield units (HU)] and low (<10 HU) unenhanced attenuation values. One hundred forty-six incidentalomas in 115 patients had an unenhanced HU less than 10. None of these patients had elevated 24-h fractionated urinary metanephrines or normetanephrines suggesting pheochromocytoma. Sixty-eight incidentalomas in 59 patients had an unenhanced HU of 10 or greater, and nine (15.2%) of these patients had surgically and histologically verified pheochromocytoma. Incidentalomas with a HU of 10 or greater were significantly larger (2.6 ± 1.5 vs. 2.3 ± 1.2 cm; P < 0.001), more often functional (27.9 vs. 8.9%, P < 0.001), and more often operated (44.1 vs. 10.2%; P < 0.001) than those with a Hounsfield unit less than 10. The results of this study indicate that routine biochemical screening of pheochromocytoma in small homogenous adrenal incidentalomas characterized by an unenhanced Hounsfield unit value less than 10 HU may not be necessary.

Clinicopathological features of growth hormone-producing pituitary adenomas: difference among various types defined by cytokeratin distribution pattern including a transitional form.

PubMed

Obari, Abdulkader; Sano, Toshiaki; Ohyama, Kenichi; Kudo, Eiji; Qian, Zhi Rong; Yoneda, Akiko; Rayhan, Nasim; Mustafizur Rahman, Muhammad; Yamada, Shozo

2008-01-01

Pituitary adenomas producing almost exclusively growth hormones (GH) have been ultrastructurally classified into two distinct types: densely granulated somatotroph (DG) adenomas and sparsely granulated (SG) adenomas. Fibrous body (FB), an intracytoplasmic globular aggregation of cytokeratin (CK) filaments, is a hallmark of SG adenomas. Under light microscope, FB could be identified by CK immunohistochemistry as a dot-pattern immunoreaction versus a perinuclear pattern for cells without FB. However, it has been noted that numerous adenomas contain mixed populations of the two patterns. To clarify clinicopathological characteristics of the adenomas with mixed populations ("intermediate type" adenomas) and to confirm clinicopathological differences between strictly defined DG-type and SG-type adenomas, we performed this study on 104 GH cell adenomas. Having segregated "intermediate-type" adenomas (26 cases), we found significant differences between typical DG-type (47 cases) and SG-type adenomas (31 cases); SG-type adenomas had younger ages (44 vs. 50), higher frequency of macroadenomas (86% vs. 58%), invasiveness (65% vs. 38%), advanced grades (3 or 4) in Knosp's classification (50% vs. 24%), and weaker immunoreaction for GH, beta-TSH, alpha-subunit, E-cadherin, and beta-catenin. Clinicopathological characteristics of "intermediate-type" adenomas were identical to those of DG-type adenomas. These findings confirm that SG-type adenoma is a distinct section of GH cell adenomas with special properties and biological behavior, and suggest that intermediate-phenotype adenomas are enrolled in DG-type adenomas. Special properties and biological behavior of SG-type adenomas may appear after the majority of tumor cells possess a fully developed fibrous body.

Effects of acrolein on aldosterone release from zona glomerulosa cells in male rats.

PubMed

Wang, Kai-Lee; Huang, Wen-Ching; Chou, Jou-Chun; Weng, Ting-Chun; Hu, Sindy; Lieu, Fu-Kong; Lai, Wei-Ho; Idova, Galina; Wang, Paulus S; Wang, Shyi-Wu

2016-07-01

A positive correlation between smoking and hypertension has been well established. Acrolein is a major toxic volatile compound found in cigarette smoke. Human exposure to low levels of acrolein is unavoidable due to its production in daily activities, such as smoke from industrial, hot oil cooking vapors, and exhaust fumes from vehicles. The toxicity and the action mechanism of acrolein to induce apoptosis have been extensively studied, but the effects of acrolein on hypertension are still unknown. The present study aimed to examine the effects of acrolein on aldosterone release both in vivo and in vitro. Male rats were divided into three groups, and intraperitoneally injected with normal saline, or acrolein (2mg/kg) for 1 (group A-1) or 3 (group A-3) days, respectively. After sacrificing, rat blood samples were obtained to measure plasma aldosterone and angiotensin II (Ang II) levels. Zona glomerulosa (ZG) cells were prepared from rat adrenal cortex, and were incubated with or without stimulants. We found that the serum aldosterone was increased by 1.2-fold (p<0.05) in A-3 group as compared to control group. Basal aldosterone release from ZG cells in A-3 group was also increased significantly. Moreover, acrolein enhanced the stimulatory effects of Ang II and 8-bromo-cyclic AMP on aldosterone secretion from ZG cells prepared in both A-1 and A-3 groups. Furthermore, the enzyme activity of P450scc, the rate-limiting step of aldosterone synthesis, was elevated after acrolein injection. Plasma level of Ang II was increased in both A-1 and A-3 groups. These results suggested that acrolein exposure increased aldosterone production, at least in part, through elevating the level of plasma Ang II and stimulating steroidogenesis pathways. Copyright © 2016 Elsevier Inc. All rights reserved.

Impact of New Quick Gold Nanoparticle-Based Cortisol Assay During Adrenal Vein Sampling for Primary Aldosteronism.

PubMed

Yoneda, Takashi; Karashima, Shigehiro; Kometani, Mitsuhiro; Usukura, Mikiya; Demura, Masashi; Sanada, Junichirou; Minami, Tetsuya; Koda, Wataru; Gabata, Toshifumi; Matsui, Osamu; Idegami, Koutarou; Takamura, Yuzuru; Tamiya, Eiichi; Oe, Masashi; Nakai, Masuo; Mori, Shunsuke; Terayama, Noboru; Matsuda, Yuichi; Kamemura, Kouhei; Fujii, Sumie; Seta, Takashi; Sawamura, Toshitaka; Okuda, Rika; Takeda, Yoshimichi; Hayashi, Kenshi; Yamagishi, Masakazu; Takeda, Yoshiyu

2016-06-01

Adrenal vein sampling (AVS) is essential for identifying a surgically curable form of primary aldosteronism (PA), but accurate placement of the sampling catheter is technically challenging. Intraprocedural cortisol measurement can confirm the catheter's position, thereby increasing the AVS success rate. We developed a quick cortisol assay (QCA) that uses immunochromatography and gold nanoparticles and can be performed either semiquantitatively or quantitatively. The assay was evaluated in two studies. In a single-center study, PA patients were assigned to undergo AVS incorporating the semiquantitative QCA (n = 30), the quantitative QCA (n = 30), or without the QCA (n = 30), and the rates of successful AVS were determined. In a prospective multicenter randomized, controlled study, the success rates of AVS performed with (n = 148) or without (n = 145) the semiquantitative QCA were determined. Cortisol concentrations were measured during AVS in 6 minutes or less in the radiology suite, without additional technical assistance, and significantly correlated with a conventional reference assay (R(2) = 0.994; P < .001). In the single-center study, the differences in the AVS success rates associated with semiquantitative and quantitative QCAs were not significant (both 93%); however, the success rates were significantly higher than the rate of successful AVS performed without using the QCA (63%; P < .001). The success rate of AVS performed in the multicenter study was 94% for the semiquantitative QCA, which was significantly higher than the rate for the patients without QCA (60%; P < .001). Our novel QCA was rapidly and easily performed at the point of care and improved the rate of successful AVS.

Gastric inhibitory polypeptide-dependent cortisol hypersecretion--a new cause of Cushing's syndrome.

PubMed

Lacroix, A; Bolté, E; Tremblay, J; Dupré, J; Poitras, P; Fournier, H; Garon, J; Garrel, D; Bayard, F; Taillefer, R

1992-10-01

Corticotropin-independent nodular adrenal hyperplasia is a rare cause of Cushing's syndrome, and the factors responsible for the adrenal hyperplasia are not known. We studied a 48-year-old woman with Cushing's syndrome, nodular adrenal hyperplasia, and undetectable plasma corticotropin concentrations in whom food stimulated cortisol secretion. Cortisol secretion had an inverse diurnal rhythm in this patient, with low-to-normal fasting plasma cortisol concentrations and elevated postprandial cortisol concentrations that could not be suppressed with dexamethasone. The cortisol concentrations increased in response to oral glucose (4-fold increase) and a lipid-rich meal (4.8-fold increase) or a protein-rich meal (2.6-fold increase), but not intravenous glucose. The infusion of somatostatin blunted the plasma cortisol response to oral glucose. Intravenous infusion of gastric inhibitory polypeptide (GIP) for one hour increased the plasma cortisol concentration in the patient but not in four normal subjects. Fasting plasma GIP concentrations in the patient were similar to those in the normal subjects; feeding the patient test meals induced increases in plasma GIP concentrations that paralleled those in plasma cortisol concentrations. Cell suspensions of adrenal tissue from the patient produced more cortisol when stimulated by GIP than when stimulated by corticotropin. In contrast, adrenal cells from normal adults and fetuses or patients with cortisol-producting or aldosterone-producing adenomas responded to corticotropin but not to GIP. Nodular adrenal hyperplasia and Cushing's syndrome may be food-dependent as a result of abnormal responsiveness of adrenal cells to physiologic secretion of GIP. "Illicit" (ectopic) expression of GIP receptors on adrenal cells presumably underlies this disorder.

Case report of a bilateral adrenal myelolipoma associated with Cushing disease.

PubMed

Park, Se Yoon; Kwak, Mi Kyung; Kim, Hye Jeong; Park, Hyeong Kyu; Suh, Kyo-Il; Yoo, Myung Hi; Jin, So Young; Yun, Sumi; Byun, Dong Won

2017-12-01

Adrenal myelolipomas are rare benign tumors, composed of a variable mixture of mature adipose tissue and hematopoietic tissue. These tumors are frequently detected incidentally and are usually asymptomatic, and hormonally inactive. During a routine health checkup, a 52-year-old man was found to have a tumor on the bilateral adrenal glands. Abdominal computed tomography revealed a well-defined, heterogeneously enhanced bilateral adrenal mass, suggesting a myelolipoma. The hormonal evaluation revealed adrenocorticotropic hormone (ACTH) dependent Cushing syndrome. The patient underwent left adrenalectomy, and transsphenoidal resection of a pituitary mass. The final diagnosis was adrenal myelolipoma associated with Cushing disease. Growth of right adrenal myelolipoma was detected during the 7-year follow-up. There were enhancing pituitary lesions in repeat magnetic resonance imaging of the sellar region, which implies persistent or recurrent pituitary adenoma. This case reinforces relationship between Cushing disease and adrenal myelolipoma. To the best of our knowledge, this is the first reported pathologically confirmed bilateral adrenal myelolipoma associated with Cushing disease. This report supports the idea that ACTH is associated with the development of adrenal myelolipoma. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

Standards of ultrasound imaging of the adrenal glands

PubMed Central

Jakubowski, Wiesław S.; Dobruch-Sobczak, Katarzyna; Kasperlik-Załuska, Anna A.

2015-01-01

Adrenal glands are paired endocrine glands located over the upper renal poles. Adrenal pathologies have various clinical presentations. They can coexist with the hyperfunction of individual cortical zones or the medulla, insufficiency of the adrenal cortex or retained normal hormonal function. The most common adrenal masses are tumors incidentally detected in imaging examinations (ultrasound, tomography, magnetic resonance imaging), referred to as incidentalomas. They include a range of histopathological entities but cortical adenomas without hormonal hyperfunction are the most common. Each abdominal ultrasound scan of a child or adult should include the assessment of the suprarenal areas. If a previously non-reported, incidental solid focal lesion exceeding 1 cm (incidentaloma) is detected in the suprarenal area, computed tomography or magnetic resonance imaging should be conducted to confirm its presence and for differentiation and the tumor functional status should be determined. Ultrasound imaging is also used to monitor adrenal incidentaloma that is not eligible for a surgery. The paper presents recommendations concerning the performance and assessment of ultrasound examinations of the adrenal glands and their pathological lesions. The article includes new ultrasound techniques, such as tissue harmonic imaging, spatial compound imaging, three-dimensional ultrasound, elastography, contrast-enhanced ultrasound and parametric imaging. The guidelines presented above are consistent with the recommendations of the Polish Ultrasound Society. PMID:26807295

Regulation of ODC activity in the thymus and liver of rats by adrenal hormones.

PubMed

Zahner, S L; Prahlad, K V; Mitchell, J L

1986-01-01

The activity of L-ornithine decarboxylase (EC 4.1.1.17, ODC) has become a useful indicator of hormone responsiveness. Various regimens of dexamethasone, aldosterone and epinephrine, alone or in combination, were administered to adrenalectomized rats either in acute or chronic doses. In addition, adrenalectomized rats, which were chronically treated with aldosterone and epinephrine, were given a single injection of 50 micrograms dexamethasone and sacrificed at various time intervals after hormone treatment. Hepatic and thymic ODC activity was measured. The expected dexamethasone effect, an increase in hepatic and a decrease in thymic ODC, was observed. This study also revealed that aldosterone induced similar responses in these tissues. Epinephrine had the opposite effect since chronic administration of dexamethasone or aldosterone with epinephrine resulted in control levels of ODC. Furthermore, when aldosterone and epinephrine were chronically administered to adrenalectomized rats, to study the acute effects of dexamethasone on rat thymus and liver, the time course of the response in each tissue was found to be distinct. The influence of the adrenal gland on rat thymus and liver is not restricted only to glucocorticoids, but may also involve other hormones which it secretes.

Bilateral adrenal masses: a single-centre experience

PubMed Central

Bandgar, Tushar; Khare, Shruti; Jadhav, Swati; Lila, Anurag; Goroshi, Manjunath; Kasaliwal, Rajeev; Khadilkar, Kranti; Shah, Nalini S

2016-01-01

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. PMID:27037294

Renal denervation attenuates aldosterone expression and associated cardiovascular pathophysiology in angiotensin II-induced hypertension.

PubMed

Hong, Mo-Na; Li, Xiao-Dong; Chen, Dong-Rui; Ruan, Cheng-Chao; Xu, Jian-Zhong; Chen, Jing; Wu, Yong-Jie; Ma, Yu; Zhu, Ding-Liang; Gao, Ping-Jin

2016-10-18

The sympathetic nervous system interacts with the renin-angiotensin-aldosterone system (RAAS) contributing to cardiovascular diseases. In this study, we sought to determine if renal denervation (RDN) inhibits aldosterone expression and associated cardiovascular pathophysiological changes in angiotensin II (Ang II)-induced hypertension. Bilateral RDN or SHAM operation was performed before chronic 14-day Ang II subcutaneous infusion (200ng/kg/min) in male Sprague-Dawley rats. Bilateral RDN blunted Ang II-induced hypertension and ameliorated the mesenteric vascular dysfunction. Cardiovascular hypertrophy in response to Ang II was significantly attenuated by RDN as shown by histopathology and transthoracic echocardiography. Moreover, Ang II-induced vascular and myocardial inflammation and fibrosis were suppressed by RDN with concurrent decrease in fibronectin and collagen deposition, macrophage infiltration, and MCP-1 expression. Interestingly, RDN also inhibited Ang II-induced aldosterone expression in the plasma, kidney and heart. This was associated with the reduction of calcitonin gene-related peptide (CGRP) in the adrenal gland. Ang II promoted aldosterone secretion which was partly attenuated by CGRP in the adrenocortical cell line, suggesting a protective role of CGRP in this model. Activation of transforming growth factor-β (TGF-β)/Smad and mitogen-activated protein kinases (MAPKs) signaling pathway was both inhibited by RDN especially in the heart. These results suggest that the regulation of the renal sympathetic nerve in Ang II-induced hypertension and associated cardiovascular pathophysiological changes is likely mediated by aldosterone, with CGRP involvement.

Renal denervation attenuates aldosterone expression and associated cardiovascular pathophysiology in angiotensin II-induced hypertension

PubMed Central

Chen, Dong-Rui; Ruan, Cheng-Chao; Xu, Jian-Zhong; Chen, Jing; Wu, Yong-Jie; Ma, Yu; Zhu, Ding-Liang; Gao, Ping-Jin

2016-01-01

The sympathetic nervous system interacts with the renin-angiotensin-aldosterone system (RAAS) contributing to cardiovascular diseases. In this study, we sought to determine if renal denervation (RDN) inhibits aldosterone expression and associated cardiovascular pathophysiological changes in angiotensin II (Ang II)-induced hypertension. Bilateral RDN or SHAM operation was performed before chronic 14-day Ang II subcutaneous infusion (200ng/kg/min) in male Sprague-Dawley rats. Bilateral RDN blunted Ang II-induced hypertension and ameliorated the mesenteric vascular dysfunction. Cardiovascular hypertrophy in response to Ang II was significantly attenuated by RDN as shown by histopathology and transthoracic echocardiography. Moreover, Ang II-induced vascular and myocardial inflammation and fibrosis were suppressed by RDN with concurrent decrease in fibronectin and collagen deposition, macrophage infiltration, and MCP-1 expression. Interestingly, RDN also inhibited Ang II-induced aldosterone expression in the plasma, kidney and heart. This was associated with the reduction of calcitonin gene-related peptide (CGRP) in the adrenal gland. Ang II promoted aldosterone secretion which was partly attenuated by CGRP in the adrenocortical cell line, suggesting a protective role of CGRP in this model. Activation of transforming growth factor-β (TGF-β)/Smad and mitogen-activated protein kinases (MAPKs) signaling pathway was both inhibited by RDN especially in the heart. These results suggest that the regulation of the renal sympathetic nerve in Ang II-induced hypertension and associated cardiovascular pathophysiological changes is likely mediated by aldosterone, with CGRP involvement. PMID:27661131

Outcome of adrenal vein sampling performed during concurrent mineralocorticoid receptor antagonist therapy.

PubMed

Haase, Matthias; Riester, Anna; Kröpil, Patric; Hahner, Stefanie; Degenhart, Christoph; Willenberg, Holger S; Reincke, Martin

2014-12-01

Pharmacological inhibition of mineralocorticoid receptor (MR) signaling in patients with primary aldosteronism (PA) reestablishes aldosterone synthesis by nondiseased zona glomerulosa cells through activation of the renin-angiotensin-aldosterone system. In this context, current guidelines recommend discontinuing MR blockade for diagnostic procedures, including adrenal vein sampling (AVS). Discontinuation of MR blockade in high-risk patients may be harmful because of uncontrolled hypertension and severe hypokalemia. We hypothesize that MR antagonist therapy can be continued during AVS as long as renin levels remain suppressed. The objective of this study was to assess the validity of AVS results in the context of MR antagonistic therapy. We retrospectively analyzed all AVS studies in Munich (since 2008) and Düsseldorf (since 2011) and identified four of 237 (1.7%) patients with PA who underwent AVS while treated with an MR antagonist. Adrenalectomy was recommended based on the results of AVS in all four patients. After adrenalectomy, follow-up data were obtained to confirm improvement or remission of PA. Main outcome measures included blood pressure values, daily defined doses of antihypertensive medication, as well as levels of aldosterone, renin, and potassium, and the aldosterone/renin ratio. In all patients, renin remained low or suppressed during AVS despite MR antagonist treatment. AVS clearly demonstrated unilateral aldosterone excess in each case. After adrenalectomy, all patients showed remission of PA as demonstrated by blood pressure values, potassium levels, and the aldosterone/renin ratio. In selected cases of PA, MR antagonist therapy might be continued during AVS, provided that renin values remain low.

Aldosterone sensitizes connecting tubule glomerular feedback via the aldosterone receptor GPR30

PubMed Central

Ren, YiLin; D'Ambrosio, Martin A.; Garvin, Jeffrey L.; Leung, Pablo; Kutskill, Kristopher; Wang, Hong; Peterson, Edward L.

2014-01-01

Increasing Na delivery to epithelial Na channels (ENaC) in the connecting tubule (CNT) dilates the afferent arteriole (Af-Art), a process we call connecting tubule glomerular feedback (CTGF). We hypothesize that aldosterone sensitizes CTGF via a nongenomic mechanism that stimulates CNT ENaC via the aldosterone receptor GPR30. Rabbit Af-Arts and their adherent CNTs were microdissected and simultaneously perfused. Two consecutive CTGF curves were elicited by increasing luminal NaCl in the CNT. During the control period, the concentration of NaCl that elicited a half-maximal response (EC50) was 37.0 ± 2.0 mmol/l; addition of aldosterone 10−8 mol/l to the CNT lumen caused a left-shift (decrease) in EC50 to 19.3 ± 1.3 mmol/l (P = 0.001 vs. control; n = 6). Neither the transcription inhibitor actinomycin D nor the translation inhibitor cycloheximide prevented the effect of aldosterone (control EC50 = 34.7 ± 1.9 mmol/l; aldosterone+actinomycin D EC50 = 22.6 ± 1.6 mmol/l; P < 0.001 and control EC50 = 32.4 ± 4.3 mmol/l; aldosterone+cycloheximide EC50 = 17.4 ± 3.3 mmol/l; P < 0.001). The aldosterone antagonist eplerenone prevented the sensitization of CTGF by aldosterone (control EC50 = 33.2 ± 1.7 mmol/l; aldosterone+eplerenone EC50 = 33.5 ± 1.3 mmol/l; n = 7). The GPR30 receptor blocker G-36 blocked the sensitization of CTGF by aldosterone (aldosterone EC50 = 16.5 ± 1.9 mmol/l; aldosterone+G-36 EC50 = 29.0 ± 2.1 mmol/l; n = 7; P < 0.001). Finally, we found that the sensitization of CTGF by aldosterone was mediated, at least in part, by the sodium/hydrogen exchanger (NHE). We conclude that aldosterone in the CNT lumen sensitizes CTGF via a nongenomic effect involving GPR30 receptors and NHE. Sensitized CTGF induced by aldosterone may contribute to renal damage by increasing Af-Art dilation and glomerular capillary pressure (glomerular barotrauma). PMID:24966088

Renal and adrenal tumours in children

PubMed Central

2007-01-01

The differential diagnosis of renal and supra-renal masses firstly depends on the age of the child. Neuroblastoma (NBL) may be seen antenatally or in the newborn period; this tumour has a good prognosis unlike NBL seen in older children (particularly NBL in those aged 2–4 years). Benign renal masses predominate in early infancy but beyond the first year of life Wilms' tumour is the most common renal malignancy, until adolescence when renal cell carcinoma has similar or increased frequency as children get older. Adrenal adenomas and carcinomas also occur in childhood; these tumours are indistinguishable on imaging but criteria for the diagnosis of adrenal carcinoma include size larger than 5 cm, a tendency to invade the inferior vena cava and to metastasise. The most topical dilemmas in the radiological assessment of renal and adrenal tumours are presented. Topics covered include a proposed revision to the staging of NBL, the problems inherent in distinguishing nephrogenic rests from Wilms' tumour and the current recently altered approach regarding small lung nodules in children with Wilms' tumour. PMID:17339140

The Gene of the Ubiquitin-Specific Protease 8 Is Frequently Mutated in Adenomas Causing Cushing's Disease.

PubMed

Perez-Rivas, Luis G; Theodoropoulou, Marily; Ferraù, Francesco; Nusser, Clara; Kawaguchi, Kohei; Stratakis, Constantine A; Faucz, Fabio Rueda; Wildemberg, Luiz E; Assié, Guillaume; Beschorner, Rudi; Dimopoulou, Christina; Buchfelder, Michael; Popovic, Vera; Berr, Christina M; Tóth, Miklós; Ardisasmita, Arif Ibrahim; Honegger, Jürgen; Bertherat, Jerôme; Gadelha, Monica R; Beuschlein, Felix; Stalla, Günter; Komada, Masayuki; Korbonits, Márta; Reincke, Martin

2015-07-01

We have recently reported somatic mutations in the ubiquitin-specific protease USP8 gene in a small series of adenomas of patients with Cushing's disease. To determine the prevalence of USP8 mutations and the genotype-phenotype correlation in a large series of patients diagnosed with Cushing's disease. We performed a retrospective, multicentric, genetic analysis of 134 functioning and 11 silent corticotroph adenomas using Sanger sequencing. Biochemical and clinical features were collected and examined within the context of the mutational status of USP8, and new mutations were characterized by functional studies. A total of 145 patients who underwent surgery for an ACTH-producing pituitary adenoma. Mutational status of USP8. Biochemical and clinical features included sex, age at diagnosis, tumor size, preoperative and postoperative hormonal levels, and comorbidities. We found somatic mutations in USP8 in 48 (36%) pituitary adenomas from patients with Cushing's disease but in none of 11 silent corticotropinomas. The prevalence was higher in adults than in pediatric cases (41 vs 17%) and in females than in males (43 vs 17%). Adults having USP8-mutated adenomas were diagnosed at an earlier age than those with wild-type lesions (36 vs 44 y). Mutations were primarily found in adenomas of 10 ± 7 mm and were inversely associated with the development of postoperative adrenal insufficiency. All the mutations affected the residues Ser718 or Pro720, including five new identified alterations. Mutations reduced the interaction between USP8 and 14-3-3 and enhanced USP8 activity. USP8 mutants diminished epidermal growth factor receptor ubiquitination and induced Pomc promoter activity in immortalized AtT-20 corticotropinoma cells. USP8 is frequently mutated in adenomas causing Cushing's disease, especially in those from female adult patients diagnosed at a younger age.

The Gene of the Ubiquitin-Specific Protease 8 Is Frequently Mutated in Adenomas Causing Cushing's Disease

PubMed Central

Perez-Rivas, Luis G.; Theodoropoulou, Marily; Ferraù, Francesco; Nusser, Clara; Kawaguchi, Kohei; Stratakis, Constantine A.; Faucz, Fabio Rueda; Wildemberg, Luiz E.; Assié, Guillaume; Beschorner, Rudi; Dimopoulou, Christina; Buchfelder, Michael; Popovic, Vera; Berr, Christina M.; Tóth, Miklós; Ardisasmita, Arif Ibrahim; Honegger, Jürgen; Bertherat, Jerôme; Gadelha, Monica R.; Beuschlein, Felix; Stalla, Günter; Komada, Masayuki; Korbonits, Márta

2015-01-01

Context: We have recently reported somatic mutations in the ubiquitin-specific protease USP8 gene in a small series of adenomas of patients with Cushing's disease. Objective: To determine the prevalence of USP8 mutations and the genotype-phenotype correlation in a large series of patients diagnosed with Cushing's disease. Design: We performed a retrospective, multicentric, genetic analysis of 134 functioning and 11 silent corticotroph adenomas using Sanger sequencing. Biochemical and clinical features were collected and examined within the context of the mutational status of USP8, and new mutations were characterized by functional studies. Patients: A total of 145 patients who underwent surgery for an ACTH-producing pituitary adenoma. Main Outcomes Measures: Mutational status of USP8. Biochemical and clinical features included sex, age at diagnosis, tumor size, preoperative and postoperative hormonal levels, and comorbidities. Results: We found somatic mutations in USP8 in 48 (36%) pituitary adenomas from patients with Cushing's disease but in none of 11 silent corticotropinomas. The prevalence was higher in adults than in pediatric cases (41 vs 17%) and in females than in males (43 vs 17%). Adults having USP8-mutated adenomas were diagnosed at an earlier age than those with wild-type lesions (36 vs 44 y). Mutations were primarily found in adenomas of 10 ± 7 mm and were inversely associated with the development of postoperative adrenal insufficiency. All the mutations affected the residues Ser718 or Pro720, including five new identified alterations. Mutations reduced the interaction between USP8 and 14-3-3 and enhanced USP8 activity. USP8 mutants diminished epidermal growth factor receptor ubiquitination and induced Pomc promoter activity in immortalized AtT-20 corticotropinoma cells. Conclusions: USP8 is frequently mutated in adenomas causing Cushing's disease, especially in those from female adult patients diagnosed at a younger age. PMID:25942478

Adrenalectomy for adrenal-mediated hypertension: National Surgical Quality Improvement Program analysis of an institutional experience.

PubMed

Shada, Amber L; Stokes, Jayme B; Turrentine, Florence E; Simpson, Virginia B; Padia, Shetal H; Carey, Robert M; Hanks, John B; Smith, Philip W

2014-11-01

Adrenal-mediated hypertension (AMH) has been increasingly treated by laparoscopic adrenalectomy (LA). Metabolic derangements in patients with AMH could result in perioperative complications and mortality. Long-term operative and clinical outcomes after laparoscopic treatment of AMH have not been evaluated using large clinical databases. The institutional National Surgical Quality Improvement Program (NSQIP) data for patients undergoing adrenalectomy for AMH between 2002 and 2012 were reviewed. Patient demographics, perioperative variables, and outcomes were analyzed and compared with national NSQIP adrenalectomy data. Improvement in AMH was recorded when discontinuation or reduction of antihypertensive medication occurred or with a decrease of blood pressure on the preoperative antihypertensive regimen. Ninety-four patients underwent adrenalectomy. There were 48 patients with pheochromocytoma (PHE) and 46 patients with aldosterone-producing adenoma (APA). Eighty-five patients (90%) were taking antihypertensive medications preoperatively compared with 36 patients (38%) postoperatively (P < 0.0001). Patients with PHE were more likely to discontinue all medications compared with the patients with APA (80 vs 20%, respectively, P < 0.0001). Patients with PHE and APA, respectively, took an average of 2.0 and 3.2 antihypertensive medications preoperatively compared with 0.3 and 1.2 postoperatively. There were no conversions to open procedures or 30-day mortality. Our results were 0 per cent for cerebral vascular accident, 0 per cent for myocardial infarction, and 0.5 per cent for transfusions compared with the national NSQIP data of 0.2, 0, and 6.7 per cent, respectively. Patients presenting with significant AMH including PHE and APA can be effectively and safely treated with LA with minimal complications and with a significant number of patients eliminating or decreasing their need for antihypertensive medications.

Silent subtype 3 pituitary adenomas are not always silent and represent poorly differentiated monomorphous plurihormonal Pit-1 lineage adenomas.

PubMed

Mete, Ozgur; Gomez-Hernandez, Karen; Kucharczyk, Walter; Ridout, Rowena; Zadeh, Gelareh; Gentili, Fred; Ezzat, Shereen; Asa, Sylvia L

2016-02-01

Originally classified as a variant of silent corticotroph adenoma, silent subtype 3 adenomas are a distinct histologic variant of pituitary adenoma of unknown cytogenesis. We reviewed the clinical, biochemical, radiological, immunohistochemical and ultrastructural features of 31 silent subtype 3 adenomas to clarify their cellular origin. Among 25 with clinical and/or radiological data, all were macroadenomas; there was cavernous sinus invasion in 30% of cases and involvement of the clivus in 17% of cases. Almost 90% of patients were symptomatic; 67% had mass effect symptoms, 37% were hypogonadal and 8% had secondary adrenal insufficiency. Significant hormonal excess in 29% of cases included hyperthyroidism in 17%, acromegaly in 8% and hyperprolactinemia above 150 μg/l in 4%. Two individuals with hyperprolactinemia who were younger than 30 years had multiple endocrine neoplasia type 1. Immunohistochemically, all 31 tumors were diffusely positive for the pituitary lineage-specific transcription factor Pit-1. Although three only expressed Pit-1, others revealed variable positivity for one or more hormones of Pit-1 cell lineage (growth hormone, prolactin, thyroid-stimulating hormone), as well as alpha-subunit and estrogen receptor. Most tumors exhibited perinuclear reactivity for keratins with the CAM5.2 antibody; scattered fibrous bodies were noted in five (16%) tumors. The mean MIB-1 labeling index was 4% (range, 1-9%). Fourteen cases examined by electron microscopy were composed of a monomorphous population of large polygonal or elongated cells with nuclear spheridia. Sixty-five percent of patients had residual disease after surgery; after a mean follow-up of 48.4 months (median 41.5; range=2-171) disease progression was documented in 53% of those cases. These data identify silent subtype 3 adenomas as aggressive monomorphous plurihormonal adenomas of Pit-1 lineage that may be associated with hyperthyroidism, acromegaly or galactorrhea and amenorrhea. Our

Prospective validation of an automated chemiluminescence-based assay of renin and aldosterone for the work-up of arterial hypertension.

PubMed

Rossi, Gian Paolo; Ceolotto, Giulio; Rossitto, Giacomo; Seccia, Teresa Maria; Maiolino, Giuseppe; Berton, Chiara; Basso, Daniela; Plebani, Mario

2016-09-01

The availability of simple and accurate assays of plasma active renin (DRC) and aldosterone concentration (PAC) can improve the detection of secondary forms of arterial hypertension. Thus, we investigated the performance of an automated chemiluminescent assay for DRC and PAC in referred hypertensive patients. We prospectively recruited 260 consecutive hypertensive patients referred to an ESH Center for Hypertension. After exclusion of six protocol violations, 254 patients were analyzed: 67.3% had primary hypertension, 17.3% an aldosterone producing adenoma (APA), 11.4% idiopathic hyperaldosteronism (IHA), 2.4% renovascular hypertension (RVH), 0.8% familial hyperaldosteronism type 1 (FH-1), 0.4% apparent mineralocorticoid excess (AME), 0.4% a renin-producing tumor, and 3.9% were adrenalectomized APA patients. Bland-Altman plots and Deming regression were used to analyze results. The diagnostic accuracy (area under the curve, AUC of the ROC) of the DRC-based aldosterone-renin ratio (ARRCL) was compared with that of the PRA-based ARR (ARRRIA) using as reference the conclusive diagnosis of APA. At Bland-Altman plot, the DRC and PAC assay showed no bias as compared to the PRA and PAC assay. A tight relation was found between the DRC and the PRA values (concordance correlation coefficient=0.92, p<0.0001) and the PAC values measured with radioimmunoassay and chemiluminescence (concordance correlation coefficient=0.93, p<0.001). For APA identification the AUC of the ARRCL was higher than that of the ARRRIA [0.974 (95% CI 0.940-0.991) vs. 0.894 (95% CI 0.841-0.933), p=0.02]. This rapid automated chemiluminescent DRC/PAC assay performed better than validated PRA/PAC radioimmunoassays for the identification of APA in referred hypertensive patients.

Inappropriately low aldosterone concentrations in adults with AIDS-related diarrhoea in Zambia: a study of response to fluid challenge

PubMed Central

Kaile, Trevor; Zulu, Isaac; Lumayi, Ruth; Ashman, Neil; Kelly, Paul

2008-01-01

Background Chronic diarrhoea is one of the most debilitating consequences of HIV infection in sub-Saharan Africa and it carries a high mortality rate. We report unexpectedly low concentrations of circulating aldosterone in 12 patients (6 men, 6 women) in the University Teaching Hospital, Lusaka, who all had diarrhoea for over one month. Changes in serum electrolytes, blood pressure, Karnofsky score and serum aldosterone concentration were being monitored during a short study of responses to saline infusion (3 litres/24 h) over 72 hours. Findings At baseline, 9/12 (75%) of the patients were hyponatraemic, 10/11 (91%) were hypokalaemic, and 6/12 (50%) had undetectable aldosterone concentrations. Blood pressure and Karnofsky score rose and creatinine concentration fell in response to the infusion. Conclusion Circulating aldosterone concentrations were inappropriately low and complicate the profound electrolyte deficiencies resulting from chronic diarrhoea. Management of these deficiencies needs to be more aggressive than is currently practised and consideration should be given to a formal clinical trial of mineralocorticoid replacement in these severely ill patients. If the inappropriately low aldosterone reflects a general adrenal failure, it may explain a considerable proportion of the high mortality seen both before and after initiation of anti-retroviral therapy. PMID:18710534

Association between urine aldosterone and diastolic function in patients with primary aldosteronism and essential hypertension.

PubMed

Chang, Yi-Yao; Lee, Hsiu-Hao; Hung, Chi-Sheng; Wu, Xue-Ming; Lee, Jen-Kuang; Wang, Shuo-Meng; Liao, Min-Tsun; Chen, Ying-Hsien; Wu, Vin-Cent; Wu, Kwan-Dun; Lin, Yen-Hung

2014-09-01

To investigate the association between aldosterone and cardiac diastolic dysfunction. We prospectively enrolled 20 patients with primary aldosteronism (PA) and 22 patients with essential hypertension (EH). Plasma aldosterone concentration, plasma renin activity, and 24-h urine aldosterone level were measured. Echocardiography, including tissue Doppler image recordings, was performed. PA patients had a significantly higher left ventricular (LV) mass index and worse LV diastolic function than those in EH patients. Among various measures of aldosterone, log-transformed 24-h urine aldosterone level had the most consistent correlation with diastolic function. Aldosterone is strongly associated with LV diastolic dysfunction. Twenty-four hour urine aldosterone is a good indicator to evaluate the impact of aldosterone on LV diastolic function. Copyright © 2014. Published by Elsevier Inc.

Diagnosis and treatment of pituitary adenomas.

PubMed

Chanson, P; Salenave, S

2004-12-01

Pituitary tumors cause symptoms by secreting hormones (prolactin, PRL, responsible for amenorrhea-galactorrhea in women and decreased libido in men; growth hormone, GH, responsible for acromegaly; adrenocorticotropic hormone, ACTH, responsible for Cushing's syndrome; thyroid-stimulating hormone, TSH, responsible for hyperthyroidism), depressing the secretion of hormones (hypopituitarism), or by mass-related effects (headaches, visual field abnormalities...). All patients with pituitary tumors should be evaluated for gonadal, thyroid and adrenal function as well as PRL and GH secretion. Specific stimulation and suppression tests for pituitary hormones are performed in selected situations for detecting the type of hypersecretion or the response to treatment. Imaging procedures (mainly magnetic resonance imaging, MRI, nowadays) determine the presence, size and extent of the lesion. The classification of pituitary tumors is based on the staining properties of the cell cytoplasm viewed by light microscopy and immunocytochemistry revealing the secretory pattern of the adenoma. Treatment of pituitary adenomas consists of surgery (performed in more than 99% of cases via a transphenoidal route) and radiotherapy, generally fractionated or, in selected cases, using stereotactic techniques such as gamma-knife. The availability of medical treatment (dopamine, DA, agonists, somatostatin analogs, GH-receptor antagonists...) has profoundly modified the indications of radiotherapy, drugs being now generally used as a second-line treatment, after surgery (or even as first-line treatment). Based on the results of the different treatment modalities for each type of pituitary adenoma, recommendations will be proposed. They may be summarized as follows. For treatment of GH-secreting adenomas, trans-sphenoidal surgery is the first-line therapy except when the macroadenoma is giant or if surgery is contra-indicated; postoperative radiation therapy (fractionated, or by gamma-knife) is

Aldosterone increases cardiac vagal tone via G protein-coupled oestrogen receptor activation

PubMed Central

Brailoiu, G Cristina; Benamar, Khalid; Arterburn, Jeffrey B; Gao, Erhe; Rabinowitz, Joseph E; Koch, Walter J; Brailoiu, Eugen

2013-01-01

In addition to acting on mineralocorticoid receptors, aldosterone has been recently shown to activate the G protein-coupled oestrogen receptor (GPER) in vascular cells. In light of the newly identified role for GPER in vagal cardiac control, we examined whether or not aldosterone activates GPER in rat nucleus ambiguus. Aldosterone produced a dose-dependent increase in cytosolic Ca2+ concentration in retrogradely labelled cardiac vagal neurons of nucleus ambiguus; the response was abolished by pretreatment with the GPER antagonist G-36, but was not affected by the mineralocorticoid receptor antagonists, spironolactone and eplerenone. In Ca2+-free saline, the response to aldosterone was insensitive to blockade of the Ca2+ release from lysosomes, while it was reduced by blocking the Ca2+ release via ryanodine receptors and abolished by blocking the IP3 receptors. Aldosterone induced Ca2+ influx via P/Q-type Ca2+ channels, but not via L-type and N-type Ca2+ channels. Aldosterone induced depolarization of cardiac vagal neurons of nucleus ambiguus that was sensitive to antagonism of GPER but not of mineralocorticoid receptor. in vivo studies, using telemetric measurement of heart rate, indicate that microinjection of aldosterone into the nucleus ambiguus produced a dose-dependent bradycardia in conscious, freely moving rats. Aldosterone-induced bradycardia was blocked by the GPER antagonist, but not by the mineralocorticoid receptor antagonists. In summary, we report for the first time that aldosterone decreases heart rate by activating GPER in cardiac vagal neurons of nucleus ambiguus. PMID:23878371

Imaging of adrenal masses with emphasis on adrenocortical tumors.

PubMed

Sundin, Anders

2012-01-01

Because of the more widespread and frequent use of cross-sectional techniques, mainly computed tomography (CT), an increasing number of adrenal tumors are detected as incidental findings ("incidentalomas"). These incidentaloma patients are much more frequent than those undergoing imaging because of symptoms related to adrenal disease. CT and magnetic resonance imaging (MRI) are in most patients sufficient for characterization and follow-up of the incidentaloma. In a minor portion of patients, biochemical screening reveals a functional tumor and further diagnostic work-up and therapy need to be performed according to the type of hormonal overproduction. In oncological patients, especially when the morphological imaging criteria indicate an adrenal metastasis, biopsy of the lesion should be considered after pheochromocytoma is ruled out biochemically. In the minority of patients in whom CT and MRI fail to characterize the tumor and when time is of essence, functional imaging mainly by positron emission tomography (PET) is available using various tracers. The most used PET tracer, [(18)F]fluoro-deoxy-glucose ((18)FDG), is able to differentiate benign from malignant adrenal tumors in many patients. (11)C-metomidate ((11)C-MTO) is a more specialized PET tracer that binds to the 11-beta-hydroxylase enzyme in the adrenal cortex and thus makes it possible to differ adrenal tumors (benign adrenocortical adenoma and adrenocortical cancer) from those of non-adrenocortical origin.

Reversing the established order: Should adrenal venous sampling precede cross-sectional imaging in the evaluation of primary aldosteronism?

PubMed

Asmar, Melissa; Wachtel, Heather; Yan, Yan; Fraker, Douglas L; Cohen, Debbie; Trerotola, Scott O

2015-08-01

Adrenal venous sampling (AVS) is the definitive evaluation for primary aldosteronism (PA). Pre-AVS cross-sectional imaging does not reduce the need for AVS. The goal of this study was to examine whether performing AVS prior to imaging could decrease the use of imaging in the evaluation of PA at a high volume, experienced center. We performed a retrospective analysis of all AVS procedures (n = 337) done for PA from 2001-2013. Patients whose cross-sectional imaging reports were unavailable (n = 90) or AVS was non-diagnostic (n = 12) were excluded. AVS was performed using modified Mayo technique. Univariate analysis utilized the χ² test and fisher's exact test. Of the 235 patients analyzed, 63% (n = 148) were male. The mean age was 55 ± 11 years. AVS was non-lateralizing in 43% (n = 101); these patients might have avoided imaging with an AVS-first approach. Imaging and AVS were concordant in 52% (n = 123). In patients ≤40yo (n = 23), 35% (n = 8) had no lateralization on AVS, and might have avoided imaging in an AVS-first approach. Imaging and AVS were concordant in 52% (n = 12) of patients ≤ 40yo, versus 52% (n = 111) of patients > 40 yo (P = 0.987). An AVS-first, imaging-second approach could have avoided CT/MRI in 43% of patients. At a high volume, experienced center, performing AVS first on patients with PA may reduce unnecessary cross-sectional imaging studies. © 2015 Wiley Periodicals, Inc.

Central effects of ghrelin on the adrenal cortex: a morphological and hormonal study.

PubMed

Milosević, Verica Lj; Stevanović, Darko M; Nesić, Dejan M; Sosić-Jurjević, Branka T; Ajdzanović, Vladimir Z; Starcević, Vesna P; Severs, Walter B

2010-06-01

Ghrelin, a growth hormone secretagogue that exerts an important role in appetite and weight regulation, participates in the activation of the hypothalamo-pituitary-adrenal (HPA) axis. Male Wistar rats (5/group) received daily for 5 days, via an ICV (intracerebroventricular) cannula, 5 microl phosphate buffered saline with or without 1 microg of rat ghrelin. Two hours after the last injection, blood and adrenal glands were collected from decapitated rats for blood hormone analyses and histologic and morphometric processing. Ghrelin treatment resulted in increased (p<0.05) body weight (13%), absolute whole adrenal gland weight (18%) and whole adrenal gland volume (20%). The absolute volumes of the entire adrenal cortex, ZG, ZF, and ZR also increased (p<0.05) after ghrelin by 20%, 21%, 21% and 11%, respectively. Ghrelin-treated rats had elevated (p<0.05) blood concentrations of ACTH, aldosterone and corticosterone (68%, 32% and 67%, respectively). The data clearly provide both morphological and hormonal status that ghrelin acts centrally to exert a global stimulatory effect on the adrenal cortex. Clarifying of the ghrelin precise role in the multiple networks affecting the stress hormone release, besides its well known energy and metabolic unbalance effects, remains a very important research goal.

A Novel KCNJ5-insT149 Somatic Mutation Close to, but Outside, the Selectivity Filter Causes Resistant Hypertension by Loss of Selectivity for Potassium

PubMed Central

Kuppusamy, Maniselvan; Caroccia, Brasilina; Stindl, Julia; Bandulik, Sascha; Lenzini, Livia; Gioco, Francesca; Fishman, Veniamin; Zanotti, Giuseppe; Gomez-Sanchez, Celso; Bader, Michael; Warth, Richard

2014-01-01

Context: Understanding the function of the KCNJ5 potassium channel through characterization of naturally occurring novel mutations is key for dissecting the mechanism(s) of autonomous aldosterone secretion in primary aldosteronism. Objective: We sought for such novel KCNJ5 channel mutations in a large database of patients with aldosterone-producing adenomas (APAs). Methods: We discovered a novel somatic c.446insAAC insertion, resulting in the mutant protein KCNJ5-insT149, in a patient with severe drug-resistant hypertension among 195 consecutive patients with a conclusive diagnosis of APA, 24.6% of whom showed somatic KCNJ5 mutations. By site-directed mutagenesis, we created the mutated cDNA that was transfected, along with KCNJ3 cDNA, in mammalian cells. We also localized CYP11B2 in the excised adrenal gland with immunohistochemistry and immunofluorescence using an antibody specific to human CYP11B2. Whole-cell patch clamp recordings, CYP11B2 mRNA, aldosterone measurement, and molecular modeling were performed to characterize the novel KCNJ5-insT149 mutation. Results: Compared with wild-type and mock-transfected adrenocortical cells, HAC15 cells expressing the mutant KCNJ5 showed increased CYP11B2 expression and aldosterone secretion. Mammalian cells expressing the mutated KCNJ5-insT149 channel exhibited a strong Na+ inward current and, in parallel, a substantial rise in intracellular Ca2+, caused by activation of voltage-gated Ca2+ channels and reduced Ca2+ elimination by Na+/Ca2+ exchangers, as well as an increased production of aldosterone. Conclusions: This novel mutation shows pathological Na+ permeability, membrane depolarization, raised cytosolic Ca2+, and increased aldosterone synthesis. Hence, a novel KCNJ5 channelopathy located after the pore α-helix preceding the selectivity filter causes constitutive secretion of aldosterone with ensuing resistant hypertension in a patient with a small APA. PMID:25057880

Glucocorticoid-suppressible hyperaldosteronism and adrenal tumors occurring in a single French pedigree.

PubMed Central

Pascoe, L; Jeunemaitre, X; Lebrethon, M C; Curnow, K M; Gomez-Sanchez, C E; Gasc, J M; Saez, J M; Corvol, P

1995-01-01

Glucocorticoid-suppressible hyperaldosteronism is a dominantly inherited form of hypertension believed to be caused by the presence of a hybrid CYP11B1/CYP11B2 gene which has arisen from an unequal crossing over between the two CYP11B genes in a previous meiosis. We have studied a French pedigree with seven affected individuals in which two affected individuals also have adrenal tumors and two others have micronodular adrenal hyperplasia. One of the adrenal tumors and the surrounding adrenal tissue has been removed, giving a rare opportunity to study the regulation and action of the hybrid gene causing the disease. The hybrid CYP11B gene was demonstrated to be expressed at higher levels than either CYP11B1 or CYP11B2 in the cortex of the adrenal by RT-PCR and Northern blot analysis. In situ hybridization showed that both CYP11B1 and the hybrid gene were expressed in all three zones of the cortex. In cell culture experiments hybrid gene expression was stimulated by ACTH leading to increased production of aldosterone and the hybrid steroids characteristic of glucocorticoid-suppressible hyperaldosteronism. The genetic basis of the adrenal pathologies in this family is not known but may be related to the duplication causing the hyperaldosteronism. Images PMID:7593610

Angiotensin 1-7 Is a Negative Modulator of Aldosterone Secretion In Vitro and In Vivo.

PubMed

Shefer, Gabi; Marcus, Yonit; Knoll, Esther; Dolkart, Oleg; Foichtwanger, Shulamit; Nevo, Nava; Limor, Rona; Stern, Naftali

2016-08-01

Angiotensin (1-7) [Ang 1-7] is a 7 amino acid peptide generated predominantly from Ang II by the action of Ang-converting enzyme 2. We previously showed that Ang 1-7 reduced plasma aldosterone and plasma renin activity in high fructose-fed rats, and that the reduction in circulating aldosterone seemed to accord a parallel reduction in plasma renin activity. Here, we tested the possibility that Ang 1-7 affects aldosterone secretion acting directly in glomerulosa cells. First, as detected by immunofluorescence, the receptor for Ang 1-7, Mas1 is localized predominantly at the rat adrenal subcapsular region. Second, in isolated rat glomerulosa cells incubates, Ang 1-7 attenuated the aldosterone response to Ang II, with the strongest effect seen on Ang II (10(-9) M) (control 22±2.5 pg/10(5) cells; Ang II [10(-9) M] 189±11 pg/10(5) cells; Ang II [10(-9) M]+Ang 1-7 [10(-6) M] 33±3.6 pg/10(5) cells; P<0.001) and the largest effect on adrenocorticotropic hormone (10(-8) M) (control 30±3.4 pg/10(5) cells; ACTH [10(-8) M] 409±32.5 pg/10(5) cells; ACTH [10(-8) M]+Ang 1-7 [10(-6) M] 280±12.5 pg/10(5) cells; P<0.001). In contrast, Ang 1-7 did not affect the aldosterone response to potassium (K(+)). In rats subjected to a low-salt diet for 7 days, continuous infusion of Ang 1-7 (576 μg/kg per day) resulted in a lesser rise in aldosterone (salt deplete+Ang 1-7, 16.4±4.8 ng/dL) compared with rats receiving vehicle (salt deplete+vehicle, 27.6±5.3 ng/dL; P<0.01) but did not modify plasma renin activity. Taken together, these results indicate that Ang 1-7 can act as a negative modulator of aldosterone secretion in vitro and in vivo. © 2016 American Heart Association, Inc.

Successful Adrenal Venous Sampling by Non-experts with Reference to CT Images

DOE Office of Scientific and Technical Information (OSTI.GOV)

Morita, Satoru, E-mail: i@imodey.com; Yamazaki, Hiroshi; Sonoyama, Yasuyuki

PurposeTo establish technical success rates and safety of adrenal venous sampling (AVS) performed by non-experts with reference to CT images.Materials and Methods104 AVS procedures with adrenocorticotropic hormone stimulation were performed for patients with suspected primary aldosteronism. One of three radiology residents with 2nd, 5th, and 5th grade experience undertook the procedure under the guidance of an experienced, board-certified interventional radiologist with reference to contrast-enhanced CT images obtained in 102 cases. Successful catheterization of the adrenal veins was assessed using three criteria: an adrenal venous cortisol concentration of more than 200 μg/dL (criterion A); an adrenal vein/inferior vena cava cortisol ratio ofmore » more than 5:1 (criterion B); and an adrenal vein/inferior vena cava cortisol ratio of more than 10:1 (criterion C).ResultsThe operators were aware of the anatomy of the left adrenal veins in 102 cases (98 %) and of the right adrenal veins in 99 cases (95 %) prior to the procedure. CT identified the correct position of the right adrenal vein orifice in 82 of 99 cases (83 %). The overall technical success rates for AVS from the right adrenal vein according to criteria A, B, and C, were 96, 96, and 94 %, respectively. Those for the left adrenal vein were 97, 98, and 94 %, respectively. No significant differences in success rates were observed between the operators (p = 0.922–0.984). No major complications, including adrenal vein rupture, were observed.ConclusionsWhen CT images are used to guide AVS, the procedure can be performed successfully and safely even by non-experts.« less

Obstructive Sleep Apnea and Aldosterone

PubMed Central

Svatikova, Anna; Olson, Lyle J.; Wolk, Robert; Phillips, Bradley G.; Adachi, Taro; Schwartz, Gary L.; Somers, Virend K.

2009-01-01

Background: Obstructive sleep apnea (OSA) is a major risk factor for hypertension and has been associated with increased risk for cardiovascular morbidity. A dysregulated renin-angiotensin-aldosterone system may contribute to excess sodium retention and hypertension and may be activated in OSA. We tested the hypothesis that serum levels of aldosterone and plasma renin activity (PRA) are increased by apneic sleep in subjects without cardiovascular disease, compared to healthy control subjects. Methods and Results: Plasma aldosterone level was measured in 21 subjects with moderate to severe OSA and was compared to 19 closely matched healthy subjects. Plasma renin activity (PRA) was measured in 19 OSA patients and in 20 healthy controls. Aldosterone and PRA were measured before sleep (9pm), after 5 hrs of untreated OSA (2am) and in the morning after awakening (6am). There were no baseline (9pm) differences in serum aldosterone levels and PRA between the healthy controls and OSA patients (aldosterone: 55.2 ± 9 vs 56.0 ± 9 pg/mL; PRA: 0.99 ± 0.15 vs 1.15 ± 0.15 ng/mL/hr). Neither several hours of untreated severe OSA nor CPAP treatment affected aldosterone levels and PRA in OSA patients. Diurnal variation of both aldosterone and PRA was observed in both groups, in that morning renin and aldosterone levels were higher than those measured at night before sleep. Conclusions: Our study shows that patients with moderate to severe OSA without co-existing cardiovascular disease have plasma aldosterone and renin levels similar to healthy subjects. Neither untreated OSA nor CPAP treatment acutely affect plasma aldosterone or renin levels. Citation: Svatikova A; Olson LJ; Wolk R; Phillips BG; Adachi T; Schwartz GL; Somers VK. Obstructive sleep apnea and aldosterone. SLEEP 2009;32(12):1589-1592. PMID:20041594

A Novel Method of Adrenal Venous Sampling via an Antecubital Approach

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jiang, Xiongjing, E-mail: jxj103@hotmail.com; Dong, Hui; Peng, Meng

PurposeCurrently, almost all adrenal venous sampling (AVS) procedures are performed by femoral vein access. The purpose of this study was to establish the technique of AVS via an antecubital approach and evaluate its safety and feasibility.Materials and MethodsFrom January 2012 to June 2015, 194 consecutive patients diagnosed as primary aldosteronism underwent AVS via an antecubital approach without ACTH simulation. Catheters used for bilateral adrenal cannulations were recorded. The success rate of bilateral adrenal sampling, operation time, fluoroscopy time, dosage of contrast, and incidence of complications were calculated.ResultsA 5F MPA1 catheter was first used to attempt right adrenal cannulation in all patients.more » Cannulation of the right adrenal vein was successfully performed in 164 (84.5%) patients. The 5F JR5, Cobra2, and TIG catheters were the ultimate catheters for right adrenal cannulation in 16 (8.2%), 5 (2.6%), and 9 (4.6%) patients, respectively. For left adrenal cannulation, JR5 and Cobra2 catheters were used in 19 (9.8%) and 10 (5.2%) patients, respectively, while only TIG catheters were used in the remaining 165 (85.1%) patients. The rate of successful adrenal sampling on the right, left, and bilateral sides was 91.8%, 93.3%, and 87.6%, respectively. The mean time of operation was (16.3 ± 4.3) minutes, mean fluoroscopy time was (4.7 ± 1.3) minutes, and the mean use of contrast was (14.3 ± 4.7) ml. The incidence of adrenal hematoma was 1.0%.ConclusionsThis study showed that AVS via an antecubital approach was safe and feasible, with a high rate of successful sampling.« less

Adrenal venous sampling: the learning curve of a single interventionalist with 282 consecutive procedures.

PubMed

Jakobsson, Hugo; Farmaki, Katerina; Sakinis, Augustinas; Ehn, Olof; Johannsson, Gudmundur; Ragnarsson, Oskar

2018-01-01

Primary aldosteronism (PA) is a common cause of secondary hypertension. Adrenal venous sampling (AVS) is the gold standard for assessing laterality of PA, which is of paramount importance to decide adequate treatment. AVS is a technically complicated procedure with success rates ranging between 30% and 96%. The aim of this study was to investigate the success rate of AVS over time, performed by a single interventionalist. This was a retrospective study based on consecutive AVS procedures performed by a single operator between September 2005 and June 2016. Data on serum concentrations of aldosterone and cortisol from right and left adrenal vein, inferior vena cava, and peripheral vein were collected and selectivity index (SI) calculated. Successful AVS was defined as SI > 5. In total, 282 AVS procedures were performed on 269 patients, 168 men (62%) and 101 women (38%), with a mean age of 55±11 years (range, 26-78 years). Out of 282 AVS procedures, 259 were successful, giving an overall success rate of 92%. The most common reason for failure was inability to localize the right adrenal vein (n=16; 76%). The success rates were 63%, 82%, and 94% during the first, second, and third years, respectively. During the last 8 years the success rate was 95%, and on average 27 procedures were performed annually. Satisfactory AVS success rate was achieved after approximately 36 procedures and satisfactory success rate was maintained by performing approximately 27 procedures annually. AVS should be limited to few operators that perform sufficiently large number of procedures to achieve, and maintain, satisfactory AVS success rate.

Hypokalemia and Pendrin Induction by Aldosterone.

PubMed

Xu, Ning; Hirohama, Daigoro; Ishizawa, Kenichi; Chang, Wen Xiu; Shimosawa, Tatsuo; Fujita, Toshiro; Uchida, Shunya; Shibata, Shigeru

2017-05-01

Aldosterone plays an important role in regulating Na-Cl reabsorption and blood pressure. Epithelial Na + channel, Na + -Cl - cotransporter, and Cl - /HCO 3 - exchanger pendrin are the major mediators of Na-Cl transport in the aldosterone-sensitive distal nephron. Existing evidence also suggests that plasma K + concentration affects renal Na-Cl handling. In this study, we posited that hypokalemia modulates the effects of aldosterone on pendrin in hyperaldosteronism. Chronic aldosterone infusion in mice increased pendrin levels at the plasma membrane, and correcting hypokalemia in this model almost completely blocked pendrin upregulation. However, hypokalemia induced by a low-K + diet resulted in pendrin downregulation along with reduced plasma aldosterone levels, indicating that both hypokalemia and aldosterone excess are necessary for pendrin induction. In contrast, decreased plasma K + levels were sufficient to increase Na + -Cl - cotransporter levels. We found that phosphorylation of mineralocorticoid receptor that prevents aldosterone binding in intercalated cells was suppressed by hypokalemia, which resulted in enhanced pendrin response to aldosterone, explaining the coordinated action of aldosterone and hypokalemia in pendrin regulation. Finally, to address the physiological significance of our observations, we administered aldosterone to mice lacking pendrin. Notably, plasma K + levels were significantly lower in pendrin knockout mice (2.7±0.1 mmol/L) than in wild-type mice (3.0±0.1 mmol/L) after aldosterone infusion, demonstrating that pendrin alleviates hypokalemia in a state of aldosterone excess. These data indicate that the decreased plasma K + levels promote pendrin induction by aldosterone, which, in concert with Na + -Cl - cotransporter, counteracts the progression of hypokalemia but promotes hypertension in primary aldosterone excess. © 2017 American Heart Association, Inc.

Adrenocortical neoplasia: evolving concepts in tumorigenesis with an emphasis on adrenal cortical carcinoma variants.

PubMed

de Krijger, Ronald R; Papathomas, Thomas G

2012-01-01

Adrenocortical carcinoma (ACC) is a rare, heterogeneous malignancy with a poor prognosis. According to WHO classification 2004, ACC variants include oncocytic ACCs, myxoid ACCs and ACCs with sarcomatous areas. Herein, we provide a comprehensive review of these rare subtypes of adrenocortical malignancy and emphasize their clinicopathological features with the aim of elucidating aspects of diagnostic categorization, differential diagnostics and biological behavior. The issue of current terminology, applied to biphasic tumors with pleomorphic, sarcomatous or sarcomatoid elements arising in adrenal cortex, is also discussed. We additionally present emerging evidence concerning the adrenal cortical tumorigenesis and the putative adenoma-carcinoma sequence as well.

From Appearance of Adrenal Autoantibodies to Clinical Symptoms of Addison's Disease: Natural History.

PubMed

Betterle, Corrado; Garelli, Silvia; Presotto, Fabio; Furmaniak, Jadwiga

2016-01-01

Recent progress in the immunopathology field has greatly improved our understanding of the natural history of autoimmune diseases, particularly of Addison's disease. Addison's disease is known to be a chronic illness characterized by adrenocortical gland insufficiency that develops following a long and mainly asymptomatic period, characterized by the presence of circulating autoantibodies directed to adrenal cortex antigens. In this chapter we describe the groups of subjects at risk of developing Addison's disease, together with the diagnostic tests considered the most appropriate for evaluating adrenal function: determination of basal plasma adrenocorticotropic hormone (ACTH) levels, plasma renin activity, plasma aldosterone and cortisol levels, and cortisol levels after intravenous stimulation with ACTH (ACTH test). The employment of specific clinical, immunological and functional criteria in the subjects with autoantibodies to the adrenal cortex allows identifying those at risk of developing overt disease. The independent risk factors for the progression to adrenal failure have also been identified and they contribute to different risks of developing clinical Addison's disease. Based on the risk level, the subjects should be monitored over time to observe early signs of adrenal dysfunction, and start substitutive treatment as soon as possible. For patients presenting with high risk, prevention strategies and trials might be available. © 2016 S. Karger AG, Basel.

Vitamin D3 May Ameliorate the Ketoconazole Induced Adrenal Injury: Histological and Immunohistochemical Studies on Albino Rats

PubMed Central

Khalil, Mahmoud Salah

2015-01-01

Ketoconazole (KZ) is used widely for treating the superficial, systemic fungal activities and hyperandrogenemic states. Its uses are limited by its deleterious effect on histological structure and function of the adrenal cortex. This study investigates whether vitamin D3 supplement can ameliorate the morphological changes induced by KZ. Thirty four adult male albino rats were randomized into control group (Group I) which was subdivided into: control 1 (n=7) and control 2 (n=7): In control 1, rats were intraperitoneal (I.P) injected once with 1 ml of polyethylene glycol-400 for 15 consecutive days and control 2 rats were injected I.P with (1 μg/kg) of vitamin D3 for the same period. Group II (n=10): rats were I.P injected with KZ (10 mg/100 g of body weight) once daily for 15 days; Group III (n=10): rats were I.P concomitantly injected with KZ and vitamin D3 similar doses to animals in groups II and control 2 respectively. Blood samples were collected to determine plasma ACTH, corticosterone and aldosterone levels. The right adrenal specimens sections were stained with Haematoxylin & Eosin and Masson Trichrome for histological studies and treated with Bax, Ubiquitin and vitamin D receptors for immunohistochemical studies. KZ induced adrenal cortical morphological changes in forms of disturbed adrenocorticocyte cytological architecture, nuclear changes, and intracellular lipid accumulation. KZ also increased adrenal Bax and Ub but decreased the vitamin D receptors immunopositive staining expression, in addition to increased plasma ACTH as well as decreased corticosterone and aldosterone levels. These changes were ameliorated by supplementing with vitamin D3. PMID:26379312

Vitamin D3 May Ameliorate the Ketoconazole Induced Adrenal Injury: Histological and Immunohistochemical Studies on Albino Rats.

PubMed

Khalil, Mahmoud Salah

2015-08-27

Ketoconazole (KZ) is used widely for treating the superficial, systemic fungal activities and hyperandrogenemic states. Its uses are limited by its deleterious effect on histological structure and function of the adrenal cortex. This study investigates whether vitamin D3 supplement can ameliorate the morphological changes induced by KZ. Thirty four adult male albino rats were randomized into control group (Group I) which was subdivided into: control 1 (n=7) and control 2 (n=7): In control 1, rats were intraperitoneal (I.P) injected once with 1 ml of polyethylene glycol-400 for 15 consecutive days and control 2 rats were injected I.P with (1 μg/kg) of vitamin D3 for the same period. Group II (n=10): rats were I.P injected with KZ (10 mg/100 g of body weight) once daily for 15 days; Group III (n=10): rats were I.P concomitantly injected with KZ and vitamin D3 similar doses to animals in groups II and control 2 respectively. Blood samples were collected to determine plasma ACTH, corticosterone and aldosterone levels. The right adrenal specimens sections were stained with Haematoxylin & Eosin and Masson Trichrome for histological studies and treated with Bax, Ubiquitin and vitamin D receptors for immunohistochemical studies. KZ induced adrenal cortical morphological changes in forms of disturbed adrenocorticocyte cytological architecture, nuclear changes, and intracellular lipid accumulation. KZ also increased adrenal Bax and Ub but decreased the vitamin D receptors immunopositive staining expression, in addition to increased plasma ACTH as well as decreased corticosterone and aldosterone levels. These changes were ameliorated by supplementing with vitamin D3.

Aldosteronism and hypertension.

PubMed

Calhoun, David A

2006-09-01

A growing body of evidence suggests that hyperaldosteronism contributes significantly to the development and the severity of hypertension as well as to resistance to antihypertensive treatment. In cross-sectional analyses, plasma aldosterone levels have been shown to relate to BP levels, particularly in obese individuals. In these same individuals, BP was not related to plasma renin activity, suggesting an effect of aldosterone on BP independent of renin-angiotensin II. In a recent prospective analysis from the Framingham investigators, baseline serum aldosterone was strongly associated with development of hypertension during a 4-yr follow-up.

Abnormal gel flotation caused by contrast media during adrenal vein sampling.

PubMed

Lima-Oliveira, Gabriel; Lippi, Giuseppe; Salvagno, Gian Luca; Gelati, Matteo; Bassi, Antonella; Contro, Alberto; Pizzolo, Francesca; Guidi, Gian Cesare

2016-10-15

During adrenal venous sampling (AVS) procedure, radiologists administer a contrast agent via the catheter to visualize the proper catheter position. A patient with primary aldosteronism diagnostic-hypothesis was admitted for AVS. A venogram was performed to
confirm the catheter's position with 2mL of Iopamidol 300 mg/mL. Samples were collected with syringe connected to a hydrophilic coated catheter by low-pressure aspiration from each of the four collection sites: inferior vena cava in the suprarenal portion, inferior vena cava in the infrarenal portion, left adrenal vein, and right adrenal vein; then immediately transferred from syringe to tubes with gel separator. All tubes were centrifuged at 1200 x g for 10 minutes. At the end of centrifugation process, primary blood tubes containing blood from inferior vena cava and left adrenal vein exhibited the standard gel separator barrier, while tubes from right adrenal vein showed abnormal flotation of gel separator. The radiologist confirmed the usage of 2.6 mL instead of 2.0 mL of Iopamidol 300 mg/mL. This iodinated contrast media, with 1.33 g/cm 3 of density, was used close to the right adrenal vein due to some difficulty to access it. The abnormal flotation of gel separator in samples taken from right adrenal vein can be explained by the usage of the iodinated
contrast media. We suggest using plain-tubes (without gel separator) for AVS in order to avoid preanalytical nonconformities. Moreover, a blood volume equivalent to twice the catheter extension should be discarded to eliminate residual contrast media before collection of samples for laboratory assays.

Abnormal gel flotation caused by contrast media during adrenal vein sampling

PubMed Central

Lima-Oliveira, Gabriel; Lippi, Giuseppe; Salvagno, Gian Luca; Gelati, Matteo; Bassi, Antonella; Contro, Alberto; Pizzolo, Francesca; Guidi, Gian Cesare

2016-01-01

Introduction During adrenal venous sampling (AVS) procedure, radiologists administer a contrast agent via the catheter to visualize the proper catheter position. Materials and methods A patient with primary aldosteronism diagnostic-hypothesis was admitted for AVS. A venogram was performed to
confirm the catheter’s position with 2mL of Iopamidol 300 mg/mL. Samples were collected with syringe connected to a hydrophilic coated catheter by low-pressure aspiration from each of the four collection sites: inferior vena cava in the suprarenal portion, inferior vena cava in the infrarenal portion, left adrenal vein, and right adrenal vein; then immediately transferred from syringe to tubes with gel separator. All tubes were centrifuged at 1200 x g for 10 minutes. Results At the end of centrifugation process, primary blood tubes containing blood from inferior vena cava and left adrenal vein exhibited the standard gel separator barrier, while tubes from right adrenal vein showed abnormal flotation of gel separator. The radiologist confirmed the usage of 2.6 mL instead of 2.0 mL of Iopamidol 300 mg/mL. This iodinated contrast media, with 1.33 g/cm3 of density, was used close to the right adrenal vein due to some difficulty to access it. Conclusion The abnormal flotation of gel separator in samples taken from right adrenal vein can be explained by the usage of the iodinated
contrast media. We suggest using plain-tubes (without gel separator) for AVS in order to avoid preanalytical nonconformities. Moreover, a blood volume equivalent to twice the catheter extension should be discarded to eliminate residual contrast media before collection of samples for laboratory assays. PMID:27812311

G protein abnormalities in pituitary adenomas.

PubMed

Spada, A; Lania, A; Ballarè, E

1998-07-25

It has been demonstrated that the majority of secreting and nonsecreting adenomas is monoclonal in origin suggesting that these neoplasia arise from the replication of a single mutated cell, in which growth advantage results from either activation of protooncogenes or inactivation of antioncogenes. Although a large number of genes has been screened for mutations, only few genetic abnormalities have been found in pituitary tumors such as allelic deletion of chromosome 11q13 where the MEN-1 gene has been localised, and mutations in the gene encoding the alpha subunit of the stimulatory Gs and Gi2 protein. These mutations constitutively activate the alpha subunit of the Gs and Gi2 protein by inhibiting their intrinsic GTPase activity. Both Gs alpha and Gi2alpha can be considered products of protooncogenes (gsp and gip2, respectively) since gain of function mutations that activate mitogenic signals have been recognized in human tumors. Gsp oncogene is found in 30-40% of GH-secreting adenomas, in a low percentage of nonfunctioning and ACTH-secreting pituitary adenomas, in toxic thyroid adenomas and differentiated thyroid carcinomas. The same mutations, occurred early in embriogenesis, have been also identified in tissues from patients affected with the McCune Albright syndrome. These mutations result in an increased cAMP production and in the subsequent overactivation of specific pathways involved in both cell growth and specific programmes of cell differentiation. By consequence, the endocrine tumors expressing gsp oncogene retain differentiated functions. The gip2 oncogene has been identified in about 10% of nonfunctioning pituitary adenomas, in tumors of the ovary and the adrenal cortex. However, it remains to be established whether Gi proteins activate mitogenic signals in pituitary cells. Since Gi proteins are involved in mediating the effect of inhibitory neurohormones on intracellular effectors, it has been proposed that in pituitary tumors the low expression of

[Diffuse hypertrichosis revealing non-classical congenital adrenal hyperplasia].

PubMed

Berthin, C; Sibilia, P; Martins-Hericher, J; Donzeau, A; Martin, L

2018-04-01

Non-classical congenital adrenal hyperplasia (NC-CAH) is a recessive autosomal disease caused by a deficiency of adrenal steroidogenesis enzymes. It must be distinguished from classical CAH, either simple virilising or salt-wasting, diagnosed during the neonatal period and responsible for potentially lethal disorders of sexual differentiation. NC-CAH presents a simpler and less specific clinical picture. Herein, we present two cases comprising twin girls consulting for diffuse hypertrichosis. Two 5-year-old twin girls were seen at our consultation for increased pilosity on all four limbs, but with no facial pilosity or synophrys, as well as comedones on the chin. Their height and weight and psychomotor development was normal, with no signs of precocious puberty and no clitoral hypertrophy. Levels of 17OH-P and SDHA were high, while FSH and LH were low and IGF1 and TSH were normal. Analysis of gene CYP21 associated with NC-CAH showed mutations p.V281L and IVS2-13A/C>G. Mutation p.V281L was present in the heterozygous state in the older sister and the father, together with moderate hyperpilosity but without hirsutism or acne. No mutations were found in the mother, indicating either de novo appearance of mutation IVS2-13A/C>G in the twins or germline mosaicism in the mother. We diagnosed NC-CAH as the cause of diffuse hypertrichosis in these twins. This disease is not rare, with a prevalence of 1/1000 to 1500 among peoples of European descent. It is often diagnosed late since routine neonatal screening is not performed. In some cases, NC-CAH remains asymptomatic. The appearance of pubic hair at around 5 to 7 years is the initial reason for consultation, particularly with a dermatologist. Hyperandrogenism varies, involving hirsutism, acne, fertility disorders and premature ageing of bone. Cortisol and aldosterone levels are generally normal. The risk of acute adrenal insufficiency is extremely low. Differential diagnosis concerns ovarian or adrenal tumors and

Aldosterone antagonists in heart failure.

PubMed

Miller, Susan E; Alvarez, René J

2013-01-01

Chronic, systolic heart failure is an increasing and costly health problem, and treatments based on pathophysiology have evolved that include the use of aldosterone antagonists. Advances in the understanding of neurohormonal responses to heart failure have led to better pharmacologic treatments. The steroid hormone aldosterone has been associated with detrimental effects on the cardiovascular system, such as ventricular remodeling and endothelial dysfunction. This article will review the literature and guidelines that support the use of aldosterone antagonists in the treatment of chronic, systolic heart failure. Aldosterone antagonists are life-saving drugs that have been shown to decrease mortality in patients with New York Heart Association class III to IV heart failure and in patients with heart failure after an acute myocardial infarction. Additional studies are being conducted to determine if the role of aldosterone antagonists can be expanded to patients with less severe forms of heart failure. Aldosterone antagonists are an important pharmacologic therapy in the neurohormonal blockade necessary in the treatment of systolic heart failure. These drugs have been shown to decrease mortality and reduce hospital readmission rates. The major complication of aldosterone antagonists is hyperkalemia, which can be avoided with appropriate patient selection and diligent monitoring.

Adrenal venous sampling: the learning curve of a single interventionalist with 282 consecutive procedures

PubMed Central

Jakobsson, Hugo; Farmaki, Katerina; Sakinis, Augustinas; Ehn, Olof; Johannsson, Gudmundur; Ragnarsson, Oskar

2018-01-01

PURPOSE Primary aldosteronism (PA) is a common cause of secondary hypertension. Adrenal venous sampling (AVS) is the gold standard for assessing laterality of PA, which is of paramount importance to decide adequate treatment. AVS is a technically complicated procedure with success rates ranging between 30% and 96%. The aim of this study was to investigate the success rate of AVS over time, performed by a single interventionalist. METHODS This was a retrospective study based on consecutive AVS procedures performed by a single operator between September 2005 and June 2016. Data on serum concentrations of aldosterone and cortisol from right and left adrenal vein, inferior vena cava, and peripheral vein were collected and selectivity index (SI) calculated. Successful AVS was defined as SI >5. RESULTS In total, 282 AVS procedures were performed on 269 patients, 168 men (62%) and 101 women (38%), with a mean age of 55±11 years (range, 26–78 years). Out of 282 AVS procedures, 259 were successful, giving an overall success rate of 92%. The most common reason for failure was inability to localize the right adrenal vein (n=16; 76%). The success rates were 63%, 82%, and 94% during the first, second, and third years, respectively. During the last 8 years the success rate was 95%, and on average 27 procedures were performed annually. CONCLUSION Satisfactory AVS success rate was achieved after approximately 36 procedures and satisfactory success rate was maintained by performing approximately 27 procedures annually. AVS should be limited to few operators that perform sufficiently large number of procedures to achieve, and maintain, satisfactory AVS success rate. PMID:29467114

[Differences of blood plasma renin activity, angiotensin II and aldosterone levels in essential or secondary hypertension].

PubMed

Song, Ai-ling; Zeng, Zheng-pei; Tong, An-li; Lu, Lin; Chen, Shi; Li, Ming; Fu, Chun-li; Wang, Yong-hui; Sun, Mei-li

2012-04-01

To study on the difference of plasma renin activity (PRA), angiotensin II (Ang II), and aldosterone levels in patients with essential hypertension (EH) or primary aldosteronism (PA) or pheochromocytoma (PHEO), and to analyze the sensitivity and specificity on the diagnosis of PA among patients with hypertension with aldosterone/PRA ratio (ARR). The plasma aldosterone, Ang II and PRA concentrations in supine and upright positions were measured by radioimmunoassay from 413 patients including idiopathic hyperaldosteronism (IHA, n = 111), aldosterone-producing adenoma (APA, n = 118), PHEO (n = 98) and EH (n = 86). ARR was calculated. Plasma aldosterone concentrations in both of supine and upright positions in PHEO group [374 (294, 465) pmol/L and 629 (449, 997) pmol/L] and PA group [471 (346, 632) pmol/L and 673 (499, 825) pmol/L] were higher than those in EH group [277 (224, 332) pmol/L and 427 (341, 501) pmol/L] (P < 0.01). They were also higher in APA group [576 (416, 731) pmol/L and 726 (554, 906) pmol/L] than those in IHA group [399 (313, 504) pmol/L and 609 (485, 776) pmol/L] (P < 0.01). Ang II levels in both positions were lower in PA group [43.2 (26.4, 74.4) ng/L and 60.1 (38.5, 103.6) ng/L] than in EH group [56.7 (43.3, 78.9) ng/L and 84.3 (61.3, 108.4) ng/L] or PHEO group [54.3 (29.9, 101.5) ng/L and 102.8 (49.9, 167.0) ng/L] (all P values < 0.01), and there was no difference between IHA and APA group (P > 0.05). The PRA level in both positions of each group were PHEO group [0.3 (0.2, 1.0) µg · L(-1) · h(-1) and 1.4 (0.6, 3.4) µg · L(-1) · h(-1)] > EH group [0.2 (0.1, 0.4) µg · L(-1) · h(-1) and 0.6 (0.4, 1.0) µg · L(-1) · h(-1)] (P < 0.01) > PA group [0.1 (0.1, 0.1) µg · L(-1) · h(-1) and 0.2 (0.1, 0.3) µg · L(-1) · h(-1)] (P < 0.01), and APA group [0.1 (0.1, 0.1) µg · L(-1) · h(-1) and 0.1 (0.1, 0.3) µg · L(-1) · h(-1)] < IHA group [0.1 (0.1, 0.2) µg · L(-1) · h(-1) and 0.2 (0.1, 0.3) µg · L(-1) · h(-1)] (supine P < 0

Pituitary adenoma and unexpected sudden infant death: a case report.

PubMed

Matsuura, H; Kitazawa, Y; Tanaka, M; Morooka, K

1994-01-01

Pituitary adenomas can cause sudden death in adults, but they are quite rare during infancy. Herein we present an unusual case of sudden infant death associated with a pituitary adenoma. The clinical presentations were "quietness" complained of by the parents and probable gigantism with accelerated growth rate during the first 2 months of life. The female infants had been in good health until one day when, at the age of 3 months, she was found immobile in bed. Microscopic examination showed that the cells of the entire pituitary gland were replaced by bizarre undifferentiated tumor cells. There were no invasive lesions in the surrounding brain tissue. It was also found that the cortex of the adrenal glands was atrophic. No metastatic lesions were observed in any organ. While the mechanism leading our infant to death is both controversial and unknown, we speculated that insufficient secretion of steroid hormones might have caused cardiovascular collapse.

Role of adrenal vein sampling in primary aldosteronism: Impact of imaging, localization, and age.

PubMed

Wachtel, Heather; Zaheer, Salman; Shah, Parth K; Trerotola, Scott O; Karakousis, Giorgos C; Roses, Robert E; Cohen, Debbie L; Fraker, Douglas L

2016-04-01

The role of adrenal vein sampling (AVS) has been debated, with some authorities advocating selective use in younger patients (≤40 years), and those localized by preoperative imaging. We examined our experience to determine the impact of AVS in patients who routinely underwent AVS with a high success rate. A retrospective cohort study was performed using a prospectively maintained database of patients referred for evaluation of PA (1997-2013). Patients were classified as localized (L) if a unilateral mass was identified on imaging, and non-localized (NL) otherwise. Of 367 patients, 94% (n = 345) underwent successful AVS. Seventy-two percent (n = 265) were L; AVS was lateralizing 58% (n = 214). AVS changed management in 43% of patients (n = 158). In patients ≤40 years, AVS changed management in 30% (n = 15). In patients ≤40 years with a ≥1 cm adrenal mass, 12% (n = 3) would have undergone unnecessary surgery based on imaging results alone; in patients >40 years with a ≥1 cm adrenal mass, 3% (n = 5) would have undergone wrong-side surgery, and 30% (n = 50) would have undergone unnecessary surgery based on imaging. AVS changed management in a significant minority of patients regardless of age and imaging findings. AVS should be routinely recommended in all patients with PA, to direct operative therapy. J. Surg. Oncol. 2016;113:532-537. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Genetic Variations in the KCNJ5 Gene in Primary Aldosteronism Patients from Xinjiang, China

PubMed Central

Li, Nan-Fang; Li, Hong-Jian; Zhang, De-Lian; Zhang, Ju-Hong; Yao, Xiao-Guang; Wang, Hong-Mei; Abulikemu, Suofeiya; Zhou, Ke-Ming; Zhang, Xiang-Yang

2013-01-01

Background Primary aldosteronism (PA) is the most common endocrine form of secondary hypertension, and one of the most common subtypes of sporadic PA is aldosterone-producing adenoma (APA). Recently, two somatic mutations of the KCNJ5 gene were implicated in APA, and two germline mutations were associated with familial hyperaldosteronism III. Objectives This case-control study was designed to investigate the relationship between genetic variations in the KCNJ5 gene and sporadic PA patients in Xinjiang, China. Methods Five common single nucleotide polymorphisms (SNPs) of the KCNJ5 gene (rs6590357, rs4937391, rs3740835, rs2604204, and rs11221497) were detected in patients with sporadic PA (n = 235) and essential hypertension (EH; n = 913) by the TaqMan polymerase chain reaction method. Results The EH group and the PA group showed significant differences in the distributions of genotypes and alleles of rs4937391 and rs2604204 in total and male subjects (P<0.05), as well as rs3740835 in male subjects (P<0.05). However, only the association between the rs2604204 genotype and male sporadic PA remained significant after Bonferroni’s correction (P<0.01). Furthermore, logistic regression analysis demonstrated that the CC genotype of rs2604204 was a risk factor for male patients with sporadic PA, after adjusting for age and body mass index (odds ratio = 2.228, 95% CI: 1.300–3.819, P = 0.004). Conclusion The genetic variant rs2604204 of KCNJ5 is associated with sporadic PA in Chinese males, suggesting that KCNJ5 may be involved in the pathogenesis of sporadic PA in these particular patients. PMID:23382865

5-Bromo-2'-deoxyuridine stimulates the pituitary-adrenal axis in the rat: an effect blocked partially by endothelin-receptor antagonists.

PubMed

Malendowicz, L K; Nussdorfer, G G

1996-01-01

The bolus intraperitoneal administration of 5-bromo-2'-deoxyuridine (BrdU), at a dose in the range of those currently used for in vivo cell-kinetic studies, was found to provoke a marked rise in the plasma concentrations of adrenocorticotrophic hormone (ACTH), corticosterone and aldosterone in rats. This secretagogue effect of BrdU was annulled by the chronic pretreatment of animals with dexamethasone. The prolonged administration of endothelin-1 (ET-1) raised the blood level of aldosterone (but not of ACTH or corticosterone), and did not alter the response to BrdU. The pretreatment of rats with BQ-123 or BQ-788, two specific antagonists of ET-1 receptor subtypes A and B, did not affect the plasma concentrations of ACTH, corticosterone and aldosterone, but did partially reverse the effects of BrdU. In view of these findings we concluded that BrdU activates the pituitary-adrenal axis in rats, with its main mode of action being pituitary ACTH release; and the suppressive actions of BQ-123 and BQ-788 are independent of their antagonism on ET-1 receptors, and may be due to their interference with the intra-cellular mechanism(s) mediating the secretagogue action of BrdU. This effect of BrdU may have particular relevance to in vivo studies using BrdU labelling to assess cell kinetics of tissues (e.g. lymphatic tissue) affected profoundly by adrenal steroid hormones.

Differential effects of mineralocorticoid blockade on the hypothalamo-pituitary-adrenal axis in pregnant and nonpregnant ewes

PubMed Central

Lingis, Melissa; Richards, Elaine M.

2011-01-01

During pregnancy, plasma ACTH and cortisol are chronically increased; this appears to occur through a reset of hypothalamo-pituitary-adrenal (HPA) activity. We have hypothesized that differences in mineralocorticoid receptor activity in pregnancy may alter feedback inhibition of the HPA axis. We tested the effect of MR antagonism in pregnant and nonpregnant ewes infused for 4 h with saline or the MR antagonist canrenoate. Pregnancy significantly increased plasma ACTH, cortisol, angiotensin II, and aldosterone. Infusion of canrenoate increased plasma ACTH, cortisol, and aldosterone in both pregnant and nonpregnant ewes; however, the temporal pattern of these responses differed between these two reproductive states. In nonpregnant ewes, plasma ACTH and cortisol transiently increased at 1 h of infusion, whereas in pregnant ewes the levels gradually increased and were significantly elevated from 2 to 4 h of infusion. MR blockade increased plasma aldosterone from 2 to 4 h in the pregnant ewes but only at 4 h in the nonpregnant ewes. In both pregnant and nonpregnant ewes, the increase in plasma aldosterone was significantly related to the timing and magnitude of the increase in plasma potassium. The results indicate a differential effect of MR activity in pregnant and nonpregnant ewes and suggest that the slow changes in ACTH, cortisol, and aldosterone are likely to be related to blockade of MR effects in the kidney rather than to effects of MR blockade in hippocampus or hypothalamus. PMID:21205934

Improved technical success and radiation safety of adrenal vein sampling using rapid, semi-quantitative point-of-care cortisol measurement.

PubMed

Page, Michael M; Taranto, Mario; Ramsay, Duncan; van Schie, Greg; Glendenning, Paul; Gillett, Melissa J; Vasikaran, Samuel D

2018-01-01

Objective Primary aldosteronism is a curable cause of hypertension which can be treated surgically or medically depending on the findings of adrenal vein sampling studies. Adrenal vein sampling studies are technically demanding with a high failure rate in many centres. The use of intraprocedural cortisol measurement could improve the success rates of adrenal vein sampling but may be impracticable due to cost and effects on procedural duration. Design Retrospective review of the results of adrenal vein sampling procedures since commencement of point-of-care cortisol measurement using a novel single-use semi-quantitative measuring device for cortisol, the adrenal vein sampling Accuracy Kit. Success rate and complications of adrenal vein sampling procedures before and after use of the adrenal vein sampling Accuracy Kit. Routine use of the adrenal vein sampling Accuracy Kit device for intraprocedural measurement of cortisol commenced in 2016. Results Technical success rate of adrenal vein sampling increased from 63% of 99 procedures to 90% of 48 procedures ( P = 0.0007) after implementation of the adrenal vein sampling Accuracy Kit. Failure of right adrenal vein cannulation was the main reason for an unsuccessful study. Radiation dose decreased from 34.2 Gy.cm 2 (interquartile range, 15.8-85.9) to 15.7 Gy.cm 2 (6.9-47.3) ( P = 0.009). No complications were noted, and implementation costs were minimal. Conclusions Point-of-care cortisol measurement during adrenal vein sampling improved cannulation success rates and reduced radiation exposure. The use of the adrenal vein sampling Accuracy Kit is now standard practice at our centre.

24-hour urinary aldosterone excretion test

MedlinePlus

Aldosterone - urine; Addison disease - urine aldosterone; Cirrhosis - serum aldosterone ... A 24-hour urine sample is needed. You will need to collect your urine over 24 hours . Your health care provider will tell ...

Bimodal Aldosterone Distribution in Low-Renin Hypertension

PubMed Central

2013-01-01

BACKGROUND In low-renin hypertension (LRH), serum aldosterone levels are higher in those subjects with primary aldosteronism and may be lower in those with non-aldosterone mineralocorticoid excess or primary renal sodium retention. We investigated the hypothesis that the frequency distribution of aldosterone in LRH is bimodal. METHODS Of the 3,532 attendees at the sixth examination cycle of the Framingham Offspring Study, 1,831 were included in this cross-sectional analysis after we excluded those with conditions or taking medications such as antihypertensive drugs that might affect renin or aldosterone. RESULTS Three hundred three subjects (17%) had untreated hypertension (SBP ≥140mm Hg or DBP ≥90mm Hg). LRH, defined as plasma renin ≤5 mU/L, was present in 93 of those 303 hypertensive subjects (31%). Aldosterone values were adjusted statistically for age, sex, and the urinary sodium/creatinine ratio. In the subjects with LRH, the adjusted aldosterone distribution was bimodal (dip test for unimodality, P = 0.008). The adjusted aldosterone distribution was unimodal in the normal subjects (P = 0.98) and in the hypertensive subjects with normal plasma renin (P = 0.94). CONCLUSIONS In this community-based sample of white subjects, those with low-renin hypertension had a bimodal adjusted aldosterone distribution. Subjects with normal-renin hypertension and subjects with normal blood pressure had unimodal adjusted aldosterone distributions. These findings suggest 2 pathophysiological variants of LRH, one that is aldosterone-dependent and one that is non-aldosterone-dependent. PMID:23757402

Aldosterone to Renin Ratio as a Screening Instrument for Primary Aldosteronism in a Middle-Aged Population with Atrial Fibrillation.

PubMed

Mourtzinis, Georgios; Ebrahimi, Ahmad; Gustafsson, Helena; Johannsson, Gudmundur; Manhem, Karin

2017-11-01

Atrial fibrillation seems to be overrepresented among patients with primary aldosteronism. The aim of this study was to determine the usefulness of aldosterone to renin ratio as a screening instrument for primary aldosteronism in an atrial fibrillation population with relatively low cardiovascular risk profile. A total of 149 patients <65 years and with history of AF were screened for primary aldosteronism using aldosterone to renin ratio. Pathologically increased aldosterone to renin ratio (>65 pmol/mIU) was found in 15 participants (10.1%). Further investigation of the positive screened participants and confirmatory saline infusion test resulted in a diagnosis of primary aldosteronism in four individuals out of 149 (2.6%). Three out of the four individuals with primary aldosteronism had previously been diagnosed with hypertension, but only one out of the four had uncontrolled blood pressure, that is, >140/90 mmHg. All participants had normal potassium levels. Individuals with increased aldosterone to renin ratio had significantly higher mean systolic and diastolic blood pressure in comparison to participants with normal aldosterone to renin ratio (136 vs. 126 mmHg, p=0.02 and 84 vs. 78 mmHg, p=0.02). These findings suggest that assessment of aldosterone to renin ratio can be useful for identification of underlying primary aldosteronism in patients with diagnosed atrial fibrillation and hypertension in spite of well controlled blood pressure and normokalemia. © Georg Thieme Verlag KG Stuttgart · New York.

Conn syndrome and Crohn disease in a pediatric case: an interesting parallel.

PubMed

Rodriguez, Manuel A; Alkhoury, Fuad; Malvezzi, Leopoldo; Diaz, Alejandro

2013-01-01

Conn syndrome is characterized by surreptitious secretion of aldosterone in which patients are found to have hypertension, hypokalemia, and metabolic alkalosis. Although rare, the most common presentation in the pediatric population is bilateral hyperplasia of the adrenal glands as opposed to an adenoma. Crohn disease is part of the spectrum of inflammatory bowel disease, which manifests in children as flare-ups of bloody diarrhea and abdominal pain. The association of concurrent Conn syndrome and Crohn disease has been previously presented in two cases in adults. This is the first pediatric case to be reported in the literature.

[Recommendations for the diagnosis and treatment of classic forms of 21-hydroxylase-deficient congenital adrenal hyperplasia].

PubMed

Rodríguez, Amparo; Ezquieta, Begoña; Labarta, José Igancio; Clemente, María; Espino, Rafael; Rodriguez, Amaia; Escribano, Aranzazu

2017-08-01

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is an autosomal recessive disorder caused by mutations in the CYP21A2 gene. Cortisol and aldosterone synthesis are impaired in the classic forms (adrenal insufficiency and salt-wasting crisis). Females affected are virilised at birth, and are at risk for genital ambiguity. In this article we give recommendations for an early as possible diagnosis and an appropriate and individualised treatment. A patient and family genetic study is essential for the diagnosis of the patient, and allows genetic counselling, as well as a prenatal diagnosis and treatment for future pregnancy. Copyright © 2016 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

Comparison of aldosterone synthesis in adrenal cells, effect of various AT1 receptor blockers with or without atrial natriuretic peptide.

PubMed

Miura, Shin-Ichiro; Nakayama, Asuka; Tomita, Sayo; Matsuo, Yoshino; Suematsu, Yasunori; Saku, Keijiro

2015-01-01

Bifunctional angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) that can block the activation of not only AT1 receptor, but also neprilysin, which metabolizes vasoactive peptides including atrial natriuretic peptide (ANP), are currently being developed. However, the usefulness of the inactivation of ANP in addition to the AT1 receptor with regard to aldosterone (Ald) synthesis is not yet clear. We evaluated the inhibitory effects of various ARBs combined with or without ANP on Ang II-induced adrenal Ald synthesis using a human adrenocortical cell line (NCI-H295R). Ang II increased Ald synthesis in a dose- and time-dependent manner. Ald synthesis induced by Ang II was completely blocked by azilsartan, but not PD123319 (AT2 receptor antagonist). CGP42112 AT2 receptor agonist did not affect Ald synthesis. While most ARBs block Ang II-induced Ald synthesis to different extents, azilsartan and olmesartan have similar blocking effects on Ald synthesis. The different effects of ARBs were particularly observed at 10(-7) and 10(-8 )M. ANP attenuated Ang II-induced Ald synthesis, and ANP-mediated attenuation of Ang II-induced Ald synthesis were blocked by inhibitors of G-protein signaling subtype 4 and protein kinase G. ANP (10(-8) and 10(-7 )M) without ARBs inhibited Ald synthesis, and the combination of ANP (10(-7 )M) and ARB (10(-8 )M) had an additive effect with respect to the inhibition of Ald synthesis. In conclusions, ARBs had differential effects on Ang II-induced Ald synthesis, and ANP may help to block Ald synthesis when the dose of ARB is not sufficient to block its secretion.

Acute adrenal crisis

MedlinePlus

... condition that occurs when there is not enough cortisol. This is a hormone produced by the adrenal ... parts. The outer portion, called the cortex, produces cortisol. This is an important hormone for controlling blood ...

Natriuretic Peptide Receptor Guanylyl Cyclase-A Protects Podocytes from Aldosterone-Induced Glomerular Injury

PubMed Central

Ogawa, Yoshihisa; Yokoi, Hideki; Kasahara, Masato; Mori, Kiyoshi; Kato, Yukiko; Kuwabara, Takashige; Imamaki, Hirotaka; Kawanishi, Tomoko; Koga, Kenichi; Ishii, Akira; Tokudome, Takeshi; Kishimoto, Ichiro; Sugawara, Akira; Nakao, Kazuwa

2012-01-01

Natriuretic peptides produced by the heart in response to cardiac overload exert cardioprotective and renoprotective effects by eliciting natriuresis, reducing BP, and inhibiting cell proliferation and fibrosis. These peptides also antagonize the renin-angiotensin-aldosterone system, but whether this mechanism contributes to their renoprotective effect is unknown. Here, we examined the kidneys of mice lacking the guanylyl cyclase-A (GC-A) receptor for natriuretic peptides under conditions of high aldosterone and high dietary salt. After 4 weeks of administering aldosterone and a high-salt diet, GC-A knockout mice, but not wild-type mice, exhibited accelerated hypertension with massive proteinuria. Aldosterone-infused GC-A knockout mice had marked mesangial expansion, segmental sclerosis, severe podocyte injury, and increased oxidative stress. Reducing the BP with hydralazine failed to lessen such changes; in contrast, blockade of the renin-angiotensin-aldosterone system markedly reduced albuminuria, ameliorated podocyte injury, and reduced oxidative stress. Furthermore, treatment with the antioxidant tempol significantly reduced albuminuria and abrogated the histologic changes. In cultured podocytes, natriuretic peptides inhibited aldosterone-induced mitogen-activated protein kinase phosphorylation. Taken together, these results suggest that renoprotective properties of the endogenous natriuretic peptide/GC-A system may result from the local inhibition of the renin-angiotensin-aldosterone system and oxidative stress in podocytes. PMID:22652704

Screening for primary aldosteronism--normal ranges for aldosterone and renin in three South African population groups.

PubMed

Rayner, B L; Myers, J E; Opie, L H; Trinder, Y A; Davidson, J S

2001-07-01

To establish normal ranges for plasma aldosterone, renin and aldosterone/renin (A/R) ratio in South African normotensives under typical outpatient conditions, and to estimate the prevalence of primary aldosteronism (PA) among hypertensives in primary care settings. One hundred and thirty-six normotensive subjects and 154 sex- and age-matched hypertensives at three primary care clinics had measurements of blood pressure, plasma creatinine, K+, aldosterone, plasma renin activity, and spot urine for urinary Na+/creatinine ratio. Medication was not withdrawn before testing. Mean plasma renin activity in black normotensive subjects (0.95 +/- 1.25 ng/ml/h, mean +/- standard deviation (SD)) was significantly lower than in white (2.09 +/- 1.12 ng/ml/h; P < 0.0001) and coloured (1.81 +/- 1.86 ng/ml/h, P = 0.013) normotensives. Mean plasma aldosterone in black normotensives (306 +/- 147 pmol/l) was also significantly lower than in white (506 +/- 324 pmol/l, P = 0.0002) and coloured (418 +/- 304 pmol/l, P = 0.0148) normotensives. In hypertensives, there were no significant differences in renin or aldosterone levels between the three population groups. Urinary Na+/creatinine ratios, an index of Na+ intake, were not significantly different in the three population groups. None of the normotensives had an A/R ratio > or = 1,000 plus aldosterone > or = 750, while 7.1% of hypertensives exceeded these levels, suggesting that they are appropriate criteria for screening for PA. A large fraction of black normotensive subjects had low renin and aldosterone levels compared with whites, suggesting a salt-retaining tendency in black subjects. These results have important implications for the interpretation of plasma renin and aldosterone levels in hypertensive patients. In primary care settings, 7.1% of hypertensives had biochemical results indicating the need for investigation of PA.

Adrenal incidentaloma in adults - management recommendations by the Polish Society of Endocrinology.

PubMed

Bednarczuk, Tomasz; Bolanowski, Marek; Sworczak, Krzysztof; Górnicka, Barbara; Cieszanowski, Andrzej; Otto, Maciej; Ambroziak, Urszula; Pachucki, Janusz; Kubicka, Eliza; Babińska, Anna; Koperski, Łukasz; Januszewicz, Andrzej; Prejbisz, Aleksander; Górska, Maria; Jarząb, Barbara; Hubalewska-Dydejczyk, Alicja; Glinicki, Piotr; Ruchała, Marek; Kasperlik-Załuska, Anna

2016-01-01

A wide use of imaging techniques results in more frequent diagnosis of adrenal incidenataloma. To analyse the current state of knowledge on adrenal incidentaloma in adults in order to prepare practical management recommendations. Following a discussion, the Polish Society of Endocrinology expert working group have analysed the available data and summarised the analysis results in the form of recommendations. Unenhanced adrenal computed tomography (CT) may be recommended as an initial assessment examination helpful in the differentiation between adenomas and "non-adenomatous" lesions. In the case of density > 10 Hounsfield units, CT with contrast medium washout assessment or MRI are recommended. However, in all patients with adrenal incidentaloma, hormonal assessment is recommended in order to exclude pheochromocytoma and hypercortisolism, notwithstanding the clinical picture or concomitant diseases. In addition, examination to exclude primary hyperaldosteronism is suggested in patients with diagnosed hypertension or hypokalaemia. Surgical treatment should be recommended in patients with adrenal incidentaloma, where imaging examinations suggest a malignant lesion (oncological indication) or with confirmed hormonal activity (endocrinological indication). The basis of the surgical treatment is laparoscopic adrenalectomy. Patients with suspected pheochromocytoma must be pharmacologically prepared prior to surgery. In patients not qualified for surgery, control examinations (imaging and laboratory tests) should be established individually, taking into consideration such features as the size, image, and growth dynamics of the tumour, clinical symptoms, hormonal tests results, and concomitant diseases.

Impact of aldosterone antagonists on the substrate for atrial fibrillation: Aldosterone promotes oxidative stress and atrial structural/electrical remodeling

PubMed Central

Mayyas, Fadia; Alzoubi, Karem H.; Van Wagoner, David R.

2014-01-01

Atrial fibrillation (AF), the most common cardiac arrhythmia, is an electrocardiographic description of a condition with multiple and complex underlying mechanisms. Oxidative stress is an important driver of structural remodeling that creates a substrate for AF. Oxidant radicals may promote increase of atrial oxidative damage, electrical and structural remodeling, and atrial inflammation. AF and other cardiovascular morbidities activate angiotensin (Ang-II)-dependent and independent cascades. A key component of the renin–angiotensin-aldosterone system (RAAS) is the mineralocorticoid aldosterone. Recent studies provide evidence of myocardial aldosterone synthesis. Aldosterone promotes cardiac oxidative stress, inflammation and structural/electrical remodeling via multiple mechanisms. In HF patients, aldosterone production is enhanced. In patients and in experimental HF and AF models, aldosterone receptor antagonists have favorable influences on cardiac remodeling and oxidative stress. Therapeutic approaches that seek to reduce AF burden by modulating the aldosterone system are likely beneficial but underutilized. PMID:23993726

Rare case of Cushing's disease due to double ACTH-producing adenomas, one located in the pituitary gland and one into the stalk.

PubMed

Mendola, Marco; Dolci, Alessia; Piscopello, Lanfranco; Tomei, Giustino; Bauer, Dario; Corbetta, Sabrina; Ambrosi, Bruno

2014-01-01

We describe a patient affected by Cushing's disease due to the presence of double pituitary adenomas, one located within the anterior pituitary and the other in the infundibulum associated with a remnant of Rakthe's pouch. Cure was achieved only after the infundibulum lesion was surgically removed. A 38-year-old female presented with unexplained weight gain, hirsutism, amenorrhea, asthenia, recurrent cutaneous micotic infections and alopecia. Hormonal studies indicated Cushing's disease and MRI showed an enlarged pituitary gland with a marked and homogeneous enhancement after injection of gadolinium and an enlarged infundibulum with a maximum diameter of 8 mm. As a venous sampling of the inferior petrosal sinus after 10 μg iv desmopressin stimulation revealed a central to peripheral ACTH ratio consistent with a pituitary ACTH-secreting tumor, transphenoidal explorative surgery was performed and a 4-mm pituitary adenoma immunopositive for ACTH was disclosed and removed. Since postoperative hormonal evaluation showed persistent hypercortisolism, confirmed by dynamic tests, the patient again underwent surgery by transcranial access and the infundibulum mass was removed. Histology and immunochemistry were consistent with an ACTH-secreting adenoma. A few months after the second operation, cushingoid features were significantly reverted and symptoms improved. Although Cushing's patients bearing multiple adenomas have already been documented, the presence of two adenomas both immunohistochemically positive for ACTH is a very rare cause of Cushing's disease and this is the first report of a case of double ACTH-producing adenomas, one located in the pituitary gland and one attached to the stalk.

A Continuum of Renin-Independent Aldosteronism in Normotension

PubMed Central

Baudrand, Rene; Guarda, Francisco J.; Fardella, Carlos; Hundemer, Gregory; Brown, Jenifer; Williams, Gordon; Vaidya, Anand

2017-01-01

Primary aldosteronism (PA) is a severe form of autonomous aldosteronism. Milder forms of autonomous and renin-independent aldosteronism may be common, even in normotension. We characterized aldosterone secretion in 210 normotensives who had suppressed plasma renin activity (PRA<1.0 ng/mL/h), completed an oral sodium suppression test, received an infusion of angiotensin II (AngII), and had measurements of blood pressure (BP) and renal plasma flow (RPF). Continuous associations between urinary aldosterone excretion rate (AER), renin, and potassium handling were investigated. Severe autonomous aldosterone secretion that was consistent with confirmed PA was defined based on accepted criteria of an AER >12 mcg/24h with urinary sodium excretion >200 mmol/24h. Across the population, there were strong and significant associations between higher AER and higher urinary potassium excretion, higher AngII-stimulated aldosterone, and lower PRA, suggesting a continuum of renin-independent aldosteronism and mineralocorticoid receptor activity. Autonomous aldosterone secretion that fulfilled confirmatory criteria for PA was detected in 29 participants (14%). Normotensives with evidence suggestive of confirmed PA had higher 24h urinary AER (20.2±12.2 vs. 6.2±2.9 mcg/24h, P<0.001) as expected, but also higher AngII-stimulated aldosterone (12.4±8.6 vs. 6.6±4.3 ng/dL, P<0.001) and lower 24h urinary sodium-to-potassium excretion (2.69±0.65 vs. 3.69±1.50 mmol/mmol, P=0.001); however, there were no differences in age, aldosterone-to-renin ratio, BP, or RPF between the two groups. These findings indicate a continuum of renin-independent aldosteronism and mineralocorticoid receptor activity in normotension that ranges from subtle to overtly dysregulated and autonomous. Longitudinal studies are needed to determine whether this spectrum of autonomous aldosterone secretion contributes to hypertension and cardiovascular disease. PMID:28289182

Myeloid cells are capable of synthesizing aldosterone to exacerbate damage in muscular dystrophy.

PubMed

Chadwick, Jessica A; Swager, Sarah A; Lowe, Jeovanna; Welc, Steven S; Tidball, James G; Gomez-Sanchez, Celso E; Gomez-Sanchez, Elise P; Rafael-Fortney, Jill A

2016-12-01

FDA-approved mineralocorticoid receptor (MR) antagonists are used to treat heart failure. We have recently demonstrated efficacy of MR antagonists for skeletal muscles in addition to heart in Duchenne muscular dystrophy mouse models and that mineralocorticoid receptors are present and functional in skeletal muscles. The goal of this study was to elucidate the underlying mechanisms of MR antagonist efficacy on dystrophic skeletal muscles. We demonstrate for the first time that infiltrating myeloid cells clustered in damaged areas of dystrophic skeletal muscles have the capacity to produce the natural ligand of MR, aldosterone, which in excess is known to exacerbate tissue damage. Aldosterone synthase protein levels are increased in leukocytes isolated from dystrophic muscles compared with controls and local aldosterone levels in dystrophic skeletal muscles are increased, despite normal circulating levels. All genes encoding enzymes in the pathway for aldosterone synthesis are expressed in muscle-derived leukocytes. 11β-HSD2, the enzyme that inactivates glucocorticoids to increase MR selectivity for aldosterone, is also increased in dystrophic muscle tissues. These results, together with the demonstrated preclinical efficacy of antagonists, suggest MR activation is in excess of physiological need and likely contributes to the pathology of muscular dystrophy. This study provides new mechanistic insight into the known contribution of myeloid cells to muscular dystrophy pathology. This first report of myeloid cells having the capacity to produce aldosterone may have implications for a wide variety of acute injuries and chronic diseases with inflammation where MR antagonists may be therapeutic. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Influence of diagnostic criteria on the interpretation of adrenal vein sampling.

PubMed

Lethielleux, Gaëlle; Amar, Laurence; Raynaud, Alain; Plouin, Pierre-François; Steichen, Olivier

2015-04-01

Guidelines promote the use of adrenal vein sampling (AVS) to document lateralized aldosterone hypersecretion in primary aldosteronism. However, there are large discrepancies between institutions in the criteria used to interpret its results. This study evaluates the consequences of these differences on the classification and management of patients. The results of all 537 AVS procedures performed between January 2001 and July 2010 in our institution were interpreted with 4 diagnostic criteria used in experienced institutions where AVS is performed without cosyntropin (Brisbane, Padua, Paris, and Turin) and with criteria proposed by a recent consensus statement. AVS procedures were classified as unsuccessful, lateralized, or not lateralized according to each set of criteria. Almost 5× more AVS procedures were classified as unsuccessful with the strictest criteria than with the least strict criteria (18% versus 4%, respectively). Similarly, over 2× more AVS procedures were classified as lateralized with the least stringent criteria than with the most stringent criteria (60% versus 26%, respectively). Multiple samples were available from ≥1 side for 155 AVS procedures. These procedures were classified differently by ≥2 right-left sample pairs in 12% to 20% of cases. Thus, different sets of criteria used to interpret AVS in experienced institutions translate into heterogeneous classifications and hence management decisions, for patients with primary aldosteronism. Defining the most appropriate procedures and diagnostic criteria is needed for AVS to achieve optimal performance and fully justify its status as a gold standard. © 2015 American Heart Association, Inc.

Adrenal malignant melanoma masquerading as a pheochromocytoma in a patient with a history of a multifocal papillary and medullary thyroid carcinoma.

PubMed

Barmpari, Maria E; Savvidis, Christos; Dede, Anastasia D; Markogiannakis, Haridimos; Dikoglou, Christina; Xekouki, Paraskevi; Stratakis, Constantine A; Manouras, Andreas; Malaktari-Skarantavou, Sofia

2016-04-01

Adrenal masses usually represent benign and nonfunctional adrenal adenomas; however, primary or metastatic malignancy should also be considered. Discovery of an adrenal mass needs further evaluation in order to exclude malignancy and hormonal secretion. We present a rare case of a possibly primary adrenal malignant melanoma with imaging and biochemical features of a pheochromocytoma. A 61-year-old male farmer was referred for evaluation of a mass in the right supraclavicular region and a left adrenal lesion. The patient had a history of a multifocal papillary and medullary thyroid carcinoma. Laboratory tests revealed increased 24hour urinary dopamine and also increased serum calcitonin and neuron specific enolase. A pathology report of the resected right supraclavicular mass and left adrenal showed a malignant melanoma. This is a case of a possibly primary adrenal malignant melanoma with imaging and biochemical features of a pheochromocytoma. Although this case is very rare and there are rigid diagnostic criteria for the diagnosis of primary adrenal melanoma, it underlines the fact that the differential diagnosis of a dopamine secreting adrenal mass should include primary or metastatic malignant melanoma in order to determine the best diagnostic approach for the patient and select the most appropriate surgical management.

Outcome of endoscopic transsphenoidal surgery in combination with somatostatin analogues in patients with growth hormone producing pituitary adenoma.

PubMed

Zhou, Tao; Wang, Fuyu; Meng, Xianghui; Ba, Jianmin; Wei, Shaobo; Xu, Bainan

2014-11-01

To determine the efficacy of endoscopic surgery in combination with long-acting somatostatin analogues (SSAs) in treating patients with growth hormone (GH)-secreting pituitary tumor. We performed retrospective analysis of 133 patients with GH producing pituitary adenoma who underwent pure endoscopic transsphenoidal surgery in our center from January 2007 to July 2012. Patients were followed up for a range of 3-48 months. The radiological remission, biochemical remission and complication were evaluated. A total of 110 (82.7%) patients achieved radiological complete resection, 11 (8.2%) subtotal resection, and 12 (9.0%) partial resection. Eighty-eight (66.2%) patients showed nadir GH level less than 1 ng/mL after oral glucose administration. No mortality or severe disability was observed during follow up. Preoperative long-acting SSA successfully improved left ventricle ejection fraction (LVEF) and blood glucose in three patients who subsequently underwent success operation. Long-acting SSA (20 mg every 30 days) achieved biochemical remission in 19 out 23 (82.6%) patients who showed persistent high GH level after surgery. Endoscopic transsphenoidal surgery can biochemically cure the majority of GH producing pituitary adenoma. Post-operative use of SSA can improve biochemical remission.

Outcome of Endoscopic Transsphenoidal Surgery in Combination with Somatostatin Analogues in Patients with Growth Hormone Producing Pituitary Adenoma

PubMed Central

Zhou, Tao; Wang, Fuyu; Meng, Xianghui; Ba, Jianmin; Wei, Shaobo

2014-01-01

Objective To determine the efficacy of endoscopic surgery in combination with long-acting somatostatin analogues (SSAs) in treating patients with growth hormone (GH)-secreting pituitary tumor. Methods We performed retrospective analysis of 133 patients with GH producing pituitary adenoma who underwent pure endoscopic transsphenoidal surgery in our center from January 2007 to July 2012. Patients were followed up for a range of 3-48 months. The radiological remission, biochemical remission and complication were evaluated. Results A total of 110 (82.7%) patients achieved radiological complete resection, 11 (8.2%) subtotal resection, and 12 (9.0%) partial resection. Eighty-eight (66.2%) patients showed nadir GH level less than 1 ng/mL after oral glucose administration. No mortality or severe disability was observed during follow up. Preoperative long-acting SSA successfully improved left ventricle ejection fraction (LVEF) and blood glucose in three patients who subsequently underwent success operation. Long-acting SSA (20 mg every 30 days) achieved biochemical remission in 19 out 23 (82.6%) patients who showed persistent high GH level after surgery. Conclusion Endoscopic transsphenoidal surgery can biochemically cure the majority of GH producing pituitary adenoma. Post-operative use of SSA can improve biochemical remission. PMID:25535518

Is Preoperative Biochemical Testing for Pheochromocytoma Necessary for All Adrenal Incidentalomas?

PubMed Central

Jun, Joo Hyun; Ahn, Hyun Joo; Lee, Sangmin M.; Kim, Jie Ae; Park, Byung Kwan; Kim, Jee Soo; Kim, Jung Han

2015-01-01

Abstract This study examined whether imaging phenotypes obtained from computed tomography (CT) can replace biochemical tests to exclude pheochromocytoma among adrenal incidentalomas (AIs) in the preoperative setting. We retrospectively reviewed the medical records of all patients (n = 251) who were admitted for operations and underwent adrenal-protocol CT for an incidentally discovered adrenal mass from January 2011 to December 2012. Various imaging phenotypes were assessed for their screening power for pheochromocytoma. Final diagnosis was confirmed by biopsy, biochemical tests, and follow-up CT. Pheochromocytomas showed similar imaging phenotypes as malignancies, but were significantly different from adenomas. Unenhanced attenuation values ≤10 Hounsfield units (HU) showed the highest specificity (97%) for excluding pheochromocytoma as a single phenotype. A combination of size ≤3 cm, unenhanced attenuation values ≤ 10 HU, and absence of suspicious morphology showed 100% specificity for excluding pheochromocytoma. Routine noncontrast CT can be used as a screening tool for pheochromocytoma by combining 3 imaging phenotypes: size ≤3 cm, unenhanced attenuation values ≤10 HU, and absence of suspicious morphology, and may substitute for biochemical testing in the preoperative setting. PMID:26559265

Intracellular calcium: a prerequisite for aldosterone action.

PubMed

Schäfer, C; Shahin, V; Albermann, L; Schillers, H; Hug, M J; Oberleithner, H

2003-12-01

Transport of salt and water in various tissues is under control of the mineralocorticoid hormone aldosterone. As a liphophilic hormone, aldosterone diffuses through the plasma membrane and, then, binds to cytosolic mineralocorticoid receptors in the target cells. After binding to nuclear pore complexes, the activated receptor is translocated to the nucleus where transcription processes are initiated. After a lag period of about 20 minutes hormone-specific early mRNA transcripts leave the nucleus through nuclear pores. Some of the steps in this cascade can be followed by electrophysiology in Xenopus laevis oocyte nuclei. In addition to the genomic pathway, aldosterone exerts a rapid pre-genomic response that involves an increase in intracellular calcium. In this study, we tested for the potential role of Ca(2+) in the genomic response of the hormone. We measured the electrical resistance across the nuclear envelope in response to aldosterone, in presence and absence of intracellular Ca(2+). Nuclear envelope electrical resistance reflects receptor binding to the nuclear pore complexes ("early" resistance peak, 2 minutes after aldosterone), ongoing transcription ("transient" resistance drop, 5-15 minutes after aldosterone) and mRNA export ("late" resistance peak, 20 minutes after aldosterone). Pre-injection of the Ca(2+) chelator EGTA eliminated all electrical responses evoked by aldosterone. The transient resistance drop and the late resistance peak, induced by the hormone, were prevented by the transcription inhibitor actinomycin D, coinjected with aldosterone, while the early resistance peak remained unaffected. We conclude that (i). the presence of intracellular Ca(2+) is a prerequisite for the genomic action of aldosterone. (ii). Intracellular calcium plays a role early in the signaling cascade, either in agonist-receptor interaction, or receptor transport/docking to the nuclear pore complexes.

NLRP3 Inflammasome Mediates Aldosterone-Induced Vascular Damage.

PubMed

Bruder-Nascimento, Thiago; Ferreira, Nathanne S; Zanotto, Camila Z; Ramalho, Fernanda; Pequeno, Isabela O; Olivon, Vania C; Neves, Karla B; Alves-Lopes, Rheure; Campos, Eduardo; Silva, Carlos Alberto A; Fazan, Rubens; Carlos, Daniela; Mestriner, Fabiola L; Prado, Douglas; Pereira, Felipe V; Braga, Tarcio; Luiz, Joao Paulo M; Cau, Stefany B; Elias, Paula C; Moreira, Ayrton C; Câmara, Niels O; Zamboni, Dario S; Alves-Filho, Jose Carlos; Tostes, Rita C

2016-12-06

Inflammation is a key feature of aldosterone-induced vascular damage and dysfunction, but molecular mechanisms by which aldosterone triggers inflammation remain unclear. The NLRP3 inflammasome is a pivotal immune sensor that recognizes endogenous danger signals triggering sterile inflammation. We analyzed vascular function and inflammatory profile of wild-type (WT), NLRP3 knockout (NLRP3 -/- ), caspase-1 knockout (Casp-1 -/- ), and interleukin-1 receptor knockout (IL-1R -/- ) mice treated with vehicle or aldosterone (600 µg·kg -1 ·d -1 for 14 days through osmotic mini-pump) while receiving 1% saline to drink. Here, we show that NLRP3 inflammasome plays a central role in aldosterone-induced vascular dysfunction. Long-term infusion of aldosterone in mice resulted in elevation of plasma interleukin-1β levels and vascular abnormalities. Mice lacking the IL-1R or the inflammasome components NLRP3 and caspase-1 were protected from aldosterone-induced vascular damage. In vitro, aldosterone stimulated NLRP3-dependent interleukin-1β secretion by bone marrow-derived macrophages by activating nuclear factor-κB signaling and reactive oxygen species generation. Moreover, chimeric mice reconstituted with NLRP3-deficient hematopoietic cells showed that NLRP3 in immune cells mediates aldosterone-induced vascular damage. In addition, aldosterone increased the expression of NLRP3, active caspase-1, and mature interleukin-1β in human peripheral blood mononuclear cells. Hypertensive patients with hyperaldosteronism or normal levels of aldosterone exhibited increased activity of NLRP3 inflammasome, suggesting that the effect of hyperaldosteronism on the inflammasome may be mediated through high blood pressure. Together, these data demonstrate that NLRP3 inflammasome, through activation of IL-1R, is critically involved in the deleterious vascular effects of aldosterone, placing NLRP3 as a potential target for therapeutic interventions in conditions with high aldosterone levels. �

Pertussis toxin treatment does not block inhibition by atrial natriuretic factor of aldosterone secretion in cultured bovine zona glomerulosa cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

De Lean, A.; Cantin, M.

1986-03-05

The authors have previously reported that atrial natriuretic factor (ANF) potently inhibits PGE or forskolin-stimulation aldosterone secretion in bovine zona glomerulosa (ZG) by acting through specific high affinity receptors. In order to evaluate the functional role of the regulatory protein N/sub i/ and the inhibition of adenylate cyclase activity (AC) in ZG, the authors have studied the effect of treatment with PT on inhibition by ANF of aldosterone production. Primary cultures of ZG were treated for 18 hours in serum-free F12 medium with (0-100 ng/ml PT). No effect of PT pretreatment was observed either on basal, PGE-stimulated or ANF-inhibited levelsmore » of steroidogenesis. When membranes prepared from control ZG were ADP-ribosylated with (/sup 32/P) NAD in the presence of PT, two toxin-specific bands with 39 Kd and 41 Kd were documented on SDS gel. Cell pretreatment with as low as 1 ng/ml drastically reduced further labelling of these two bands while higher doses completely abolished them. Since PT treatment covalently modifies completely the toxin substrate without altering ANF inhibition of adrenal steroidogenesis, the authors conclude that N/sub i/ is not involved in the mode of action of ANF on aldosterone production.« less

Activation of the Endogenous Renin-Angiotensin-Aldosterone System or Aldosterone Administration Increases Urinary Exosomal Sodium Channel Excretion.

PubMed

Qi, Ying; Wang, Xiaojing; Rose, Kristie L; MacDonald, W Hayes; Zhang, Bing; Schey, Kevin L; Luther, James M

2016-02-01

Urinary exosomes secreted by multiple cell types in the kidney may participate in intercellular signaling and provide an enriched source of kidney-specific proteins for biomarker discovery. Factors that alter the exosomal protein content remain unknown. To determine whether endogenous and exogenous hormones modify urinary exosomal protein content, we analyzed samples from 14 mildly hypertensive patients in a crossover study during a high-sodium (HS, 160 mmol/d) diet and low-sodium (LS, 20 mmol/d) diet to activate the endogenous renin-angiotensin-aldosterone system. We further analyzed selected exosomal protein content in a separate cohort of healthy persons receiving intravenous aldosterone (0.7 μg/kg per hour for 10 hours) versus vehicle infusion. The LS diet increased plasma renin activity and aldosterone concentration, whereas aldosterone infusion increased only aldosterone concentration. Protein analysis of paired urine exosome samples by liquid chromatography-tandem mass spectrometry-based multidimensional protein identification technology detected 2775 unique proteins, of which 316 exhibited significantly altered abundance during LS diet. Sodium chloride cotransporter (NCC) and α- and γ-epithelial sodium channel (ENaC) subunits from the discovery set were verified using targeted multiple reaction monitoring mass spectrometry quantified with isotope-labeled peptide standards. Dietary sodium restriction or acute aldosterone infusion similarly increased urine exosomal γENaC[112-122] peptide concentrations nearly 20-fold, which correlated with plasma aldosterone concentration and urinary Na/K ratio. Urine exosomal NCC and αENaC concentrations were relatively unchanged during these interventions. We conclude that urinary exosome content is altered by renin-angiotensin-aldosterone system activation. Urinary measurement of exosomal γENaC[112-122] concentration may provide a useful biomarker of ENaC activation in future clinical studies. Copyright © 2016 by

Activation of the Endogenous Renin-Angiotensin-Aldosterone System or Aldosterone Administration Increases Urinary Exosomal Sodium Channel Excretion

PubMed Central

Qi, Ying; Wang, Xiaojing; Rose, Kristie L.; MacDonald, W. Hayes; Zhang, Bing; Schey, Kevin L.

2016-01-01

Urinary exosomes secreted by multiple cell types in the kidney may participate in intercellular signaling and provide an enriched source of kidney-specific proteins for biomarker discovery. Factors that alter the exosomal protein content remain unknown. To determine whether endogenous and exogenous hormones modify urinary exosomal protein content, we analyzed samples from 14 mildly hypertensive patients in a crossover study during a high-sodium (HS, 160 mmol/d) diet and low-sodium (LS, 20 mmol/d) diet to activate the endogenous renin-angiotensin-aldosterone system. We further analyzed selected exosomal protein content in a separate cohort of healthy persons receiving intravenous aldosterone (0.7 μg/kg per hour for 10 hours) versus vehicle infusion. The LS diet increased plasma renin activity and aldosterone concentration, whereas aldosterone infusion increased only aldosterone concentration. Protein analysis of paired urine exosome samples by liquid chromatography-tandem mass spectrometry–based multidimensional protein identification technology detected 2775 unique proteins, of which 316 exhibited significantly altered abundance during LS diet. Sodium chloride cotransporter (NCC) and α- and γ-epithelial sodium channel (ENaC) subunits from the discovery set were verified using targeted multiple reaction monitoring mass spectrometry quantified with isotope-labeled peptide standards. Dietary sodium restriction or acute aldosterone infusion similarly increased urine exosomal γENaC[112–122] peptide concentrations nearly 20-fold, which correlated with plasma aldosterone concentration and urinary Na/K ratio. Urine exosomal NCC and αENaC concentrations were relatively unchanged during these interventions. We conclude that urinary exosome content is altered by renin-angiotensin-aldosterone system activation. Urinary measurement of exosomal γENaC[112–122] concentration may provide a useful biomarker of ENaC activation in future clinical studies. PMID:26113616

Expression and biochemical characteristics of two different aldosterone receptors in both healthy and dilated cardiomyopathy dog heart tissue.

PubMed

Reynoso Palomar, Alejandro R; Rodriguez Bravo, Moncerrat; Villa Mancera, Abel E; Mucha, Carlos J

2017-03-01

Recently, replicates of the aldosterone receptor expression have been done in healthy heart dog tissues through immunohistochemistry, showing an apparent heterogeneous distribution in the four chambers. Recent studies have also identified immediate effects of aldosterone, suggesting aldosterone also produces non-genomic effects caused by an unidentified receptor. In order to study the molecular and quantitative expression characteristics of aldosterone binding receptors in the canine heart, we conducted studies, using Western Blot, in the heart from both healthy animals and animals with dilated cardiomyopathy. The results show the presence and distribution of two aldosterone receptors; one of 110/120 kDa molecular weight, suggested as cytosolic/nuclear and the other of undetermined location with a 250 kDa molecular weight.

Aldosterone and cardiovascular disease: the heart of the matter

PubMed Central

He, B. Julie; Anderson, Mark E.

2012-01-01

Aldosterone contributes to the endocrine basis of heart failure and studies on cardiac aldosterone signaling have reinforced its value as a therapeutic target. Recent focus has shifted to new roles of aldosterone that appear to depend on co-existing pathologic stimuli, cell type, and disease etiology. This review evaluates recent advances in mechanisms underlying aldosterone-induced cardiac disease and highlights the interplay between aldosterone and Ca2+ and calmodulin dependent protein kinase II, whose hyperactivity during heart failure contributes to disease progression. Increasing evidence implicates aldosterone in diastolic dysfunction, and there is need to develop more targeted therapeutics such as aldosterone synthase inhibitors and molecularly specific anti-oxidants. Despite accumulating knowledge, many questions still persist and will likely dictate areas of future research. PMID:23040074

Colorectal adenoma stem-like cell populations: associations with adenoma characteristics and metachronous colorectal neoplasia.

PubMed

Bartley, Angela N; Parikh, Nila; Hsu, Chiu-Hsieh; Roe, Denise J; Buckmeier, Julie A; Corley, Lynda; Phipps, Ron A; Gallick, Gary; Lance, Peter; Thompson, Patricia A; Hamilton, Stanley R

2013-11-01

Cancer stem cells have tumor-initiation and tumor-maintenance capabilities. Stem-like cells are present in colorectal adenomas, but their relationship to adenoma pathology and patient characteristics, including metachronous development of an additional adenoma ("recurrence"), has not been studied extensively. We evaluated the expression of aldehyde dehydrogenase isoform 1A1 (ALDH1A1), a putative stem cell marker, in baseline adenomas from the placebo arm of chemoprevention trial participants with colonoscopic follow-up. An exploratory set of 20 baseline adenomas was analyzed by ALDH1A1 immunohistochemistry with morphometry, and a replication set of 89 adenomas from 76 high-risk participants was evaluated by computerized image analysis. ALDH1A1-labeling indices (ALI) were similar across patient characteristics and in advanced and nonadvanced adenomas. There was a trend toward higher ALIs in adenomas occurring in the right than left colon (P = 0.09). ALIs of synchronous adenomas were correlated (intraclass correlation coefficient 0.67). Participants in both sample sets who developed a metachronous adenoma had significantly higher ALIs in their baseline adenoma than participants who remained adenoma free. In the replication set, the adjusted odds for metachronous adenoma increased 1.46 for each 10% increase in ALIs (P = 0.03). A best-fit algorithm-based cutoff point of 22.4% had specificity of 75.0% and positive predictive value of 70.0% for metachronous adenoma development. A larger population of ALDH1A1-expressing cells in an adenoma is associated with a higher risk for metachronous adenoma, independent of adenoma size or histopathology. If confirmed, ALDH1A1 has potential as a novel biomarker in risk assessment and as a potential stem cell target for chemoprevention. ©2013 AACR

Colorectal adenoma stem-like cell populations: Associations with adenoma characteristics and metachronous colorectal neoplasia

PubMed Central

Bartley, Angela N.; Parikh, Nila; Hsu, Chiu-Hsieh; Roe, Denise J.; Buckmeier, Julie A.; Corley, Lynda; Phipps, Ron A.; Gallick, Gary; Lance, Peter; Thompson, Patricia A.; Hamilton, Stanley R.

2014-01-01

Cancer stem cells have tumor-initiation and tumor-maintenance capabilities. Stem-like cells are present in colorectal adenomas, but their relationship to adenoma pathology and patient characteristics, including metachronous development of an additional adenoma (“recurrence”), have not been studied extensively. We evaluated the expression of aldehyde dehydrogenase isoform 1A1 (ALDH1A1), a putative stem cell marker, in baseline adenomas from the placebo arm of chemoprevention trial participants with colonoscopic follow-up. An exploratory set of 20 baseline adenomas was analyzed by ALDH1A1 immunohistochemistry with morphometry, and a replication set of 89 adenomas from 76 high-risk participants was evaluated by computerized image analysis. ALDH1A1 labeling indices (ALIs) were similar across patient characteristics and in advanced and non-advanced adenomas. There was a trend toward higher ALIs in adenomas occurring in the right than left colon (p=0.09). ALIs of synchronous adenomas were correlated (intraclass correlation coefficient 0.67). Participants in both sample sets who developed a metachronous adenoma had significantly higher ALIs in their baseline adenoma than participants who remained adenoma-free. In the replication set, the adjusted odds for metachronous adenoma increased 1.46 for each 10% increase in ALIs (p=0.03). A best-fit algorithm-based cut-point of 22.4% had specificity of 75.0% and positive predictive value of 70.0% for metachronous adenoma development. A larger population of ALDH1A1-expressing cells in an adenoma is associated with a higher risk for metachronous adenoma, independent of adenoma size or histopathology. If confirmed, ALDH1A1 has potential as a novel biomarker in risk assessment and as a potential stem-cell target for chemoprevention. PMID:24008128

A Retroperitoneal Leiomyosarcoma Presenting as an Adrenal Incidentaloma in a Subject on Warfarin

PubMed Central

Khan, Ishrat N.; Adlan, Mohamed A.; Stechman, Michael J.; Premawardhana, Lakdasa D.

2015-01-01

Adrenal incidentalomas (AIs) are mostly benign and nonsecretory. Management algorithms lack sensitivity when assessing malignant potential, although functional status is easier to assess. We present a subject whose AI was a retroperitoneal leiomyosarcoma (RL). Case Presentation. A woman on warfarin with SLE and the antiphospholipid syndrome, presented with left loin pain. She was normotensive and clinically normal. Ultrasound scans demonstrated left kidney scarring, but CT scans revealed an AI. MRI scans later confirmed the AI without significant fat and no interval growth. Cortisol after 1 mg dexamethasone, urinary free cortisol and catecholamines, plasma aldosterone renin ratio, and 17-hydroxyprogesterone were within the reference range. Initially, adrenal haemorrhage was diagnosed because of warfarin therapy and the acute presentation. However, she underwent adrenalectomy because of interval growth of the AI. Histology confirmed an RL. The patient received adjuvant radiotherapy. Discussion. Our subject presented with an NSAI. However, we highlight the following: (a) the diagnosis of adrenal haemorrhage in this anticoagulated woman was revised because of interval growth; (b) the tumour, an RL, was relatively small at diagnosis; (c) this subject has survived well over 60 months despite an RL perhaps because of her acute presentation and early diagnosis of a small localised tumour. PMID:26064705

A Retroperitoneal Leiomyosarcoma Presenting as an Adrenal Incidentaloma in a Subject on Warfarin.

PubMed

Khan, Ishrat N; Adlan, Mohamed A; Stechman, Michael J; Premawardhana, Lakdasa D

2015-01-01

Adrenal incidentalomas (AIs) are mostly benign and nonsecretory. Management algorithms lack sensitivity when assessing malignant potential, although functional status is easier to assess. We present a subject whose AI was a retroperitoneal leiomyosarcoma (RL). Case Presentation. A woman on warfarin with SLE and the antiphospholipid syndrome, presented with left loin pain. She was normotensive and clinically normal. Ultrasound scans demonstrated left kidney scarring, but CT scans revealed an AI. MRI scans later confirmed the AI without significant fat and no interval growth. Cortisol after 1 mg dexamethasone, urinary free cortisol and catecholamines, plasma aldosterone renin ratio, and 17-hydroxyprogesterone were within the reference range. Initially, adrenal haemorrhage was diagnosed because of warfarin therapy and the acute presentation. However, she underwent adrenalectomy because of interval growth of the AI. Histology confirmed an RL. The patient received adjuvant radiotherapy. Discussion. Our subject presented with an NSAI. However, we highlight the following: (a) the diagnosis of adrenal haemorrhage in this anticoagulated woman was revised because of interval growth; (b) the tumour, an RL, was relatively small at diagnosis; (c) this subject has survived well over 60 months despite an RL perhaps because of her acute presentation and early diagnosis of a small localised tumour.

Efficacy of adrenal venous sampling is increased by point of care cortisol analysis

PubMed Central

Viste, Kristin; Grytaas, Marianne A; Jørstad, Melissa D; Jøssang, Dag E; Høyden, Eivind N; Fotland, Solveig S; Jensen, Dag K; Løvås, Kristian; Thordarson, Hrafnkell; Almås, Bjørg; Mellgren, Gunnar

2013-01-01

Primary aldosteronism (PA) is a common cause of secondary hypertension and is caused by unilateral or bilateral adrenal disease. Treatment options depend on whether the disease is lateralized or not, which is preferably evaluated with selective adrenal venous sampling (AVS). This procedure is technically challenging, and obtaining representative samples from the adrenal veins can prove difficult. Unsuccessful AVS procedures often require reexamination. Analysis of cortisol during the procedure may enhance the success rate. We invited 21 consecutive patients to participate in a study with intra-procedural point of care cortisol analysis. When this assay showed nonrepresentative sampling, new samples were drawn after redirection of the catheter. The study patients were compared using the 21 previous procedures. The intra-procedural cortisol assay increased the success rate from 10/21 patients in the historical cohort to 17/21 patients in the study group. In four of the 17 successful procedures, repeated samples needed to be drawn. Successful sampling at first attempt improved from the first seven to the last seven study patients. Point of care cortisol analysis during AVS improves success rate and reduces the need for reexaminations, in accordance with previous studies. Successful AVS is crucial when deciding which patients with PA will benefit from surgical treatment. PMID:24169597

Aldosterone, Parathyroid Hormone, and the Use of Renin-Angiotensin-Aldosterone System Inhibitors: The Multi-Ethnic Study of Atherosclerosis

PubMed Central

Brown, Jenifer; de Boer, Ian H.; Robinson-Cohen, Cassianne; Siscovick, David S.; Kestenbaum, Bryan; Allison, Matthew

2015-01-01

Context: Aldosterone and PTH are implicated in the pathogenesis of cardiovascular and skeletal diseases. An expanding body of evidence supports a bidirectional and positive physiologic relationship between aldosterone and PTH. Large population-based studies confirming this relationship, and whether it may be targeted as a potential method to mitigate the clinical consequences associated with excess aldosterone and PTH, are needed. Objective: We hypothesized that higher aldosterone levels would associate with higher PTH, and that the use of renin-angiotensin-aldosterone system (RAAS) inhibitors would predict lower PTH in a large, multi-ethnic, community-based cohort. Design, Setting, Participants: We conducted cross-sectional analyses of participants in the Multi-Ethnic Study of Atherosclerosis without apparent primary hyperparathyroidism or chronic kidney disease (n = 5668). We evaluated associations of RAAS inhibitor use with PTH concentration among 1888 treated hypertensive participants. We also tested associations of serum aldosterone concentration with PTH concentration among 1547 participants with these measurements. Outcome: Serum PTH concentration. Results: Higher aldosterone associated with higher PTH (β = 0.19 pg/ml per 1 ng/dl of aldosterone, P < .0001), and this finding was most pronounced among those with a primary hyperaldosteronism-like phenotype. There was a stepwise increment in PTH when comparing untreated normotensives, hypertensives using RAAS inhibitors, untreated hypertensives, and treated hypertensives using non-RAAS inhibitors (40.8, 45.0, 46.2, 47.1 pg/ml, respectively). The use of any RAAS inhibitor independently associated with lower PTH (β = −2.327 pg/ml per use of RAAS inhibitor, P = .006), when compared with the use of any non-RAAS inhibitor medication. Conclusions: Higher serum aldosterone concentration is associated with higher serum PTH concentration, and the use of RAAS inhibitors is associated with lower PTH concentration

Expression of leukemia inhibitory factor and leukemia inhibitory factor receptor in the canine pituitary gland and corticotrope adenomas.

PubMed

Hanson, J M; Mol, J A; Meij, B P

2010-05-01

Leukemia inhibitory factor (LIF) is a pleiotropic cytokine of the IL-6 family that activates the hypothalamic-pituitary-adrenal axis and promotes corticotrope cell differentiation during development. The aim of this study was to investigate the expression of LIF and its receptor (LIFR) in the canine pituitary gland and in corticotrope adenomas, and to perform a mutation analysis of LIFR. Using immunohistochemistry, immunofluorescence, and quantitative expression analysis, LIF and LIFR expression were studied in pituitary glands of control dogs and in specimens of corticotrope adenoma tissue collected through hypophysectomy in dogs with pituitary-dependent hypercortisolism (PDH, Cushing's disease). Using sequence analysis, cDNA was screened for mutations in the LIFR. In the control pituitary tissues and corticotrope adenomas, there was a low magnitude of LIF expression. The LIFR, however, was highly expressed and co-localized with ACTH(1-24) expression. Cytoplasmatic immunoreactivity of LIFR was preserved in corticotrope adenomas and adjacent nontumorous cells of pars intermedia. No mutation was found on mutation analysis of the complete LIFR cDNA. Surprisingly, nuclear to perinuclear immunoreactivity for LIFR was present in nontumorous pituitary cells of the pars distalis in 10 of 12 tissue specimens from PDH dogs. These data show that LIFR is highly co-expressed with adrenocorticotropic hormone (ACTH) and alpha-melanocyte-stimulating hormone (alpha-MSH) in the canine pituitary gland and in corticotrope adenomas. Nuclear immunoreactivity for LIFR in nontumorous cells of the pars distalis may indicate the presence of a corticotrope adenoma. Copyright (c) 2009 Elsevier Inc. All rights reserved.

Vegetarianism as a protective factor for colorectal adenoma and advanced adenoma in Asians.

PubMed

Lee, Chang Geun; Hahn, Suk Jae; Song, Min Keun; Lee, Jun Kyu; Kim, Jae Hak; Lim, Yun Jeong; Koh, Moon-Soo; Lee, Jin Ho; Kang, Hyoun Woo

2014-05-01

Although epidemiologic and animal studies suggest a vegetarian diet protects against the development of colorectal cancer, the relationship between vegetarian diet and incidence of colorectal adenoma is not yet conclusive, especially for Asians. The purpose of this study was to examine the protective effect of a vegetarian diet against colorectal adenoma and advanced adenoma. This cross-sectional study compared the prevalence of colorectal adenoma among Buddhist priests, who are obligatory vegetarians, with that among age and sex-matched controls. All the subjects underwent health checkups in a health-promotion center in Korea. Colorectal adenoma and advanced adenoma were both more prevalent in the general population group than in the Buddhist priest group (25.2 vs. 17.9 %, 6.7 vs. 2.0 %). However, the prevalence of metabolic syndrome, high body mass index, and waist circumference were higher in the Buddhist priest group. According to univariate analysis, non-vegetarian diet (general population) significantly increased the prevalence of colorectal adenoma and advanced adenoma compared with a vegetarian diet (Buddhist priests) (OR 1.54, 95 % CI 1.08-2.21, P = 0.018; OR 3.60, 95 % CI 1.53-8.48, P = 0.003). In a conditional regression analysis model, non-vegetarian diet was also a significant risk factor for colorectal adenoma and advanced adenoma (OR 1.52, 95 % CI 0.75-2.07, P = 0.043; OR 2.94, CI 0.97-7.18, P = 0.036). Vegetarianism may be effective in preventing both colorectal adenoma and advanced adenoma in Asians.

Congenital adrenal hyperplasia

MedlinePlus

... body produces more androgen, a type of male sex hormone. This causes male characteristics to appear early (or inappropriately). Congenital adrenal hyperplasia can affect both boys and girls. About 1 in 10,000 to ...

Obesity, hypertension and aldosterone: is leptin the link?

PubMed

Xie, Ding; Bollag, Wendy B

2016-07-01

Obesity is a serious health hazard with rapidly increasing prevalence in the United States. In 2014, the World Health Organization estimated that nearly 2 billion people worldwide were overweight with an estimated 600 million of these obese. Obesity is associated with many chronic diseases, including cardiovascular disease and hypertension. Data from the Framingham Heart study suggest that approximately 78% of the risk for hypertension in men and 65% in women is related to excess body weight, a relationship that is further supported by studies showing increases in blood pressure with weight gain and decreases with weight loss. However, the exact mechanism by which excess body fat induces hypertension remains poorly understood. Several clinical studies have demonstrated elevated plasma aldosterone levels in obese individuals, especially those with visceral adiposity, with decreased aldosterone levels measured in concert with reduced blood pressure following weight loss. Since aldosterone is a mineralocorticoid hormone that regulates blood volume and pressure, serum aldosterone levels may link obesity and hypertension. Nevertheless, the mechanism by which obesity induces aldosterone production is unclear. A recent study by Belin de Chantemele and coworkers suggests that one adipose-released factor, leptin, is a direct agonist for aldosterone secretion; other adipose-related factors may also contribute to elevated aldosterone levels in obesity, such as very low-density lipoprotein (VLDL), the levels of which are elevated in obesity and which also directly stimulates aldosterone biosynthesis. This focused review explores the possible roles of leptin and VLDL in modulating aldosterone secretion to underlie obesity-associated hypertension. © 2016 Society for Endocrinology.

The Aldosterone Synthase Inhibitor FAD286 is Suitable for Lowering Aldosterone Levels in ZDF Rats but not in db/db Mice.

PubMed

Hofmann, Anja; Brunssen, Coy; Peitzsch, Mirko; Balyura, Mariya; Mittag, Jennifer; Frenzel, Annika; Jannasch, Anett; Brown, Nicholas F; Weldon, Steven M; Gueneva-Boucheva, Kristina K; Eisenhofer, Graeme; Bornstein, Stefan R; Morawietz, Henning

2017-06-01

Inhibition of aldosterone synthase is an alternative treatment option to mineralocorticoid receptor antagonism to prevent harmful aldosterone actions. FAD286 is one of the best characterized aldosterone synthase inhibitors to date. FAD286 improves glucose tolerance and increases glucose-stimulated insulin secretion in obese and diabetic ZDF rats. However, there is limited knowledge about the dose-dependent effects of FAD286 on plasma aldosterone, corticosterone, and 11-deoxycorticosterone in ZDF rats and in db / db mice, a second important rodent model of obesity and type 2 diabetes. In addition, effects of FAD286 on plasma steroids in mice and rats are controversial. Therefore, obese Zucker diabetic fatty (ZDF) rats and db / db mice were treated with FAD286 for up to 15 weeks and plasma steroids were evaluated using highly sensitive liquid chromatography-tandem mass spectrometry. In ZDF rats, FAD286 (10 mg/kg/d) treatment resulted in nearly complete disappearance of plasma aldosterone while corticosterone levels remained unaffected and those of 11-deoxycorticosterone were increased ~4-fold compared to vehicle control. A lower dose of FAD286 (3 mg/kg / d) showed no effect on plasma aldosterone or corticosterone, but 11-deoxycorticosterone was again increased ~4-fold compared to control. In contrast to ZDF rats, a high dose of FAD286 (40 mg/kg/d) did not affect plasma aldosterone levels in db / db mice although 11-deoxycorticosterone increased ~2.5-fold. A low dose of FAD286 (10 mg/kg/d) increased plasma aldosterone without affecting corticosterone or 11-deoxycorticosterone. In conclusion, the aldosterone synthase inhibitor, FAD286, lowers plasma aldosterone in obese ZDF rats, but not in obese db / db mice. © Georg Thieme Verlag KG Stuttgart · New York.

[Clinical study on the postburn change in the hypothalamus-pituitary-adrenal hormones in severely burned patients].

PubMed

Li, Hong-mian; Liang, Zi-qian; Luo, Zuo-jie

2003-06-01

To investigate the postburn dynamic changes in the hypothalamus-pituitary-adrenal hormones in severely burned patients. Fifty burn patients were enrolled in the study. The plasma contents of total GC (cortisol), ACTH and aldosterone (ALDO) and urinary contents of 17-OHO and 17-KS were determined with radio-immunological assay (RIA) method after burn injury to compare with the normal values which were well established clinically. The postburn plasma and urinary contents of the above indices were increased evidently with two peak values in shock and infectious stages, whilst the majority of he indices were lower than the normal values after 6 postburn weeks (PBWs). The values of these hormones were the lowest in dying patients. On the other hand, the values approached normal levels in those patients whose burn wounds were healing. Increases of the plasma and urinary levels of hypothalamus-pituitary -adrenal hormones in severely burned patients were constantly seen. Burn shock and infection seemed to be the two major factors in inducing postburn stress reaction in burn victims. Abrupt decrease of the hormone levels in plasma and or urine indicated adrenal failure predicting a poor prognosis of the burn patients.

Adrenal gland involvement in the regulation of renal 11beta-hydroxysteroid dehydrogenase 2.

PubMed

Zallocchi, Marisa Laura; Matkovic, Laura; Calvo, Juan Carlos; Damasco, María Cristina

2004-06-01

Renal 11beta-hydroxysteroid dehydrogenase 2 (HSD2) catalyzes the conversion of active glucocorticoids to inert 11beta-keto compounds, thereby preventing the illicit binding of these hormones to mineralocorticoid receptors (MRs) and, thus, conferring aldosterone specificity. Absence or inhibition of HSD2 activity, originates a hypertensive syndrome with sodium retention and increased potassium elimination. Recent studies from our laboratory reported an increment of HSD2 activity in intact-stressed rats. To evaluate the adrenal involvement in this increase, we analyzed HSD2 activity and protein abundance in Intact, Sham-operated, and adrenalectomized rats under stress situations (gavage with an overload of 200 mM HCl (10 ml) and simulated gavage) or with corticosterone replacement. HSD2 activity was assessed in renal microsomal preparations obtained from different groups of animals. HSD2 protein abundance was measured by Western-blot. Circulating corticosterone was determined by radioimmunoassay. Sham-operated animals showed an increase in HSD2 activity and abundance compared to Intact and adrenalectomized rats suggesting the involvement of stress-related adrenal factors in HSD2 regulation. In the case of acidotic adrenalectomized animals, there was an increase in renal HSD2 activity when, along with the HCl overload, the rats were injected with corticosterone. This increment occurred without an increase in enzyme abundance. These results suggest the importance of circulating levels of glucocorticoids to respond to a metabolic acidosis, through regulation of HSD2 stimulation. The group subjected to a simulated gavage showed an increase in enzyme activity and protein abundance, thus demonstrating the need for both adrenal and extra-factors in the modulation of renal HSD2. The adrenalectomized animals injected with different doses of corticosterone, produced a progressive increase in enzyme activity and abundance, being significant for the dose of 68 microg

Novel somatic mutations in the catalytic subunit of the protein kinase A as a cause of adrenal Cushing's syndrome: a European multicentric study.

PubMed

Di Dalmazi, Guido; Kisker, Caroline; Calebiro, Davide; Mannelli, Massimo; Canu, Letizia; Arnaldi, Giorgio; Quinkler, Marcus; Rayes, Nada; Tabarin, Antoine; Laure Jullié, Marie; Mantero, Franco; Rubin, Beatrice; Waldmann, Jens; Bartsch, Detlef K; Pasquali, Renato; Lohse, Martin; Allolio, Bruno; Fassnacht, Martin; Beuschlein, Felix; Reincke, Martin

2014-10-01

Somatic mutations in PRKACA gene, encoding the catalytic subunit of protein kinase A (PKA), have been recently found in a high proportion of sporadic adenomas associated with Cushing's syndrome. The aim was to analyze the PRKACA mutation in a large cohort of patients with adrenocortical masses. Samples from nine European centers were included (Germany, n = 4; Italy, n = 4; France, n = 1). Samples were drawn from 149 patients with nonsecreting adenomas (n = 32 + 2 peritumoral), subclinical hypercortisolism (n = 36), Cushing's syndrome (n = 64 + 2 peritumoral), androgen-producing tumors (n = 4), adrenocortical carcinomas (n = 5 + 2 peritumoral), and primary bilateral macronodular adrenal hyperplasias (n = 8). Blood samples were available from patients with nonsecreting adenomas (n = 15), subclinical hypercortisolism (n = 10), and Cushing's syndrome (n = 35). Clinical and hormonal data were collected. DNA amplification by PCR of exons 6 and 7 of the PRKACA gene and direct sequencing were performed. PRKACA heterozygous mutations were found in 22/64 samples of Cushing's syndrome patients (34%). No mutations were found in peritumoral tissue and blood samples or in other tumors examined. The c.617A>C (p.Leu206Arg) occurred in 18/22 patients. Furthermore, two novel mutations were identified: c.600_601insGTG/p.Cys200_Gly201insVal in three patients and c.639C>G+c.638_640insATTATCCTGAGG/p.Ser213Arg+p.Leu212_Lys214insIle-Ile-Leu-Arg) in one. All the mutations involved a region implicated in interaction between PKA regulatory and catalytic subunits. Patients with somatic PRKACA mutations showed higher levels of cortisol after dexamethasone test and a smaller adenoma size, compared with nonmutated subjects. These data confirm and extend previous observations that somatic PRKACA mutations are specific for adrenocortical adenomas causing Cushing's syndrome.

Aldosterone induces rapid sodium intake by a nongenomic mechanism in the nucleus tractus solitarius.

PubMed

Qiao, Hu; Hu, Bo; Zhou, Hong; Yan, Jianqun; Jia, Ru; Lu, Bo; Sun, Bo; Luo, Xiao; Fan, Yuanyuan; Wang, Nan

2016-12-09

The purpose of this study was to determine whether aldosterone has a rapid action in the nucleus tractus solitarius (NTS) that increases sodium intake, and to examine whether this effect of aldosterone, if present, is mediated by G protein-coupled estrogen receptor (GPER). Adult male Sprague-Dawley rats with a stainless-steel cannula in the NTS were used. Aldosterone was injected into the NTS at the doses of 1, 5, 10 and 20 ng 0.1 μl -1 . A rapid dose-related increase of 0.3 M NaCl intake was induced within 30 min and this increase was not suppressed by the mineralocorticoid receptor (MR) antagonist spironolactone (10 ng 0.1 μl -1 ). Water intake was not affected by aldosterone. The GPER agonist G-1 produced a parallel and significant increase in sodium intake, while pre-treatment with GPER antagonist G15 (10 ng 0.1 μl -1 ) blocked the G-1 or aldosterone-induced rapid sodium intake. In addition, sodium intake induced by sodium depletion or low-sodium diet fell within 30 min after injection into the NTS of the MR antagonist spironolactone, while G15 had no effect. Our results confirm previous reports, and support the hypothesis that aldosterone evokes rapid sodium intake through a non-genomic mechanism involving GPER in NTS.

Aldosterone induces clonal β-cell failure through glucocorticoid receptor

PubMed Central

Chen, Fang; Liu, Jia; Wang, Yanyang; Wu, Tijun; Shan, Wei; Zhu, Yunxia; Han, Xiao

2015-01-01

Aldosterone excess causes insulin resistance in peripheral tissues and directly impairs the function of clonal β-cell. The aim of this study was to investigate the molecular mechanisms involved in the aldosterone-induced impairment of clonal β-cells. As expected, aldosterone induced apoptosis and β-cell dysfunction, including impairment of insulin synthesis and secretion, which were reversed by Glucocorticoid receptor (GR) antagonists or GR-specific siRNA. However, mineralocorticoid receptor (MR) antagonists or MR-specific siRNA had no effect on impairment of clonal β-cells induced by aldosterone. Besides, aldosterone significantly decreased expression and activity of MafA, while activated JNK and p38 MAPK in a GR-dependent manner. In addition, JNK inhibitors (SP600125) and/or p38 inhibitors (SB203580) could abolish the effect of aldosterone on MafA expression and activity. Importantly, overexpression of JNK1 or p38 reversed the protective effect of a GR antagonist on the decrease of MafA expression and activity. Furthermore, aldosterone inhibits MafA expression at the transcriptional and post-transcriptional level through activation of JNK and p38, respectively. Consequently, overexpression of MafA increased synthesis and secretion of insulin, and decreased apoptosis in clonal β-cells exposed to aldosterone. These findings identified aldosterone as an inducer of clonal β-cell failure that operates through the GR-MAPK-MafA signaling pathway. PMID:26287126

Functioning adrenal tumours in children and adolescents: an institutional experience.

PubMed

Mishra, A; Agarwal, G; Misra, A K; Agarwal, A; Mishra, S K

2001-02-01

The purpose of the present paper was to carry out an audit of clinicopathological profile and treatment outcome in 13 children with functioning adrenal tumours. The medical records of 13 children with functioning adrenal tumours who were managed between June 1990 and January 1999 were reviewed. Demographic data, clinical features, biochemical and localization studies, operative details and follow-up records were studied. Children with neuroblastoma were excluded. The mean age was 7.4 +/- 5.3 years. Seven patients had Cushing's syndrome (CS), two patients had virilizing tumours, three patients had phaeochromocytoma (PCC) and one patient had Conn's syndrome. All patients (except one child with CS) were treated surgically. Two children with adrenocortical carcinoma (ACCa) died during the perioperative period. Histopathological diagnosis was adrenal cortical adenoma (ACAd) in four patients, ACCa in five patients and PCC in three patients. Two ACCa patients died of metastases at 12 and 14 months, respectively, while the third is alive and well at 30 months. Children with ACAd are alive and well at 91, 56, 32 and 27 months postoperatively. Children with PCC are free of disease (normal urinary metanephrines) at 63, 18 and 8 months after surgery but require antihypertensive drugs in low doses. The outcome of surgery is good in cases of ACAd and PCC. Although outcome is poor in ACCa, surgery remains the mainstay of treatment and offers good palliation.

STAR splicing mutations cause the severe phenotype of lipoid congenital adrenal hyperplasia: insights from a novel splice mutation and review of reported cases.

PubMed

Camats, Núria; Pandey, Amit V; Fernández-Cancio, Mónica; Fernández, Juan M; Ortega, Ana M; Udhane, Sameer; Andaluz, Pilar; Audí, Laura; Flück, Christa E

2014-02-01

The steroidogenic acute regulatory protein (StAR) transports cholesterol to the mitochondria for steroidogenesis. Loss of StAR function causes lipoid congenital adrenal hyperplasia (LCAH) which is characterized by impaired synthesis of adrenal and gonadal steroids causing adrenal insufficiency, 46,XY disorder of sex development (DSD) and failure of pubertal development. Partial loss of StAR activity may cause adrenal insufficiency only. A newborn girl was admitted for mild dehydration, hyponatremia, hyperkalemia and hypoglycaemia and had normal external female genitalia without hyperpigmentation. Plasma cortisol, 17OH-progesterone, DHEA-S, androstendione and aldosterone were low, while ACTH and plasma renin activity were elevated, consistent with the diagnosis of primary adrenal insufficiency. Imaging showed normal adrenals, and cytogenetics revealed a 46,XX karyotype. She was treated with fluids, hydrocortisone and fludrocortisone. Genetic studies revealed a novel homozygous STAR mutation in the 3' acceptor splice site of intron 4, c.466-1G>A (IVS4-1G>A). To test whether this mutation would affect splicing, we performed a minigene experiment with a plasmid construct containing wild-type or mutant StAR gDNA of exons-introns 4-6 in COS-1 cells. The splicing was assessed on total RNA using RT-PCR for STAR cDNAs. The mutant STAR minigene skipped exon 5 completely and changed the reading frame. Thus, it is predicted to produce an aberrant and shorter protein (p.V156GfsX19). Computational analysis revealed that this mutant protein lacks wild-type exons 5-7 which are essential for StAR-cholesterol interaction. STAR c.466-1A skips exon 5 and causes a dramatic change in the C-terminal sequence of the protein, which is essential for StAR-cholesterol interaction. This splicing mutation is a loss-of-function mutation explaining the severe phenotype of our patient. Thus far, all reported splicing mutations of STAR cause a severe impairment of protein function and phenotype. �

Parathyroid Gland Function in Primary Aldosteronism.

PubMed

Asbach, E; Bekeran, M; Reincke, M

2015-12-01

Primary aldosteronism (PA) is the most frequent cause of secondary arterial hypertension. Beyond its effects on intravascular volume and blood pressure, PA causes metabolic alterations and a higher cardiovascular morbidity, which is reduced by PA-directed therapy. Experimental studies demonstrated that mineralocorticoid excess may also influence mineral homeostasis. A role in cardiovascular disease has also been attributed to parathyroid hormone (PTH). Increasing evidence supports a bidirectional interaction between aldosterone and PTH.Primary hyperparathyroidism is associated with arterial hypertension and an increased cardiovascular morbidity and mortality, which might be associated to higher aldosterone values; parathyreoidectomy results in lowered aldosterone and blood pressure levels. PA leads to secondary hyperparathyroidism, which is reversible by PA-directed therapy. A lower bone mineral density and a higher fracture rate were also shown to be reversible by PA-directed therapy. There is a suspicion of a bidirectional interaction between aldosterone and PTH, which might lead to a higher cardiovascular risk. There are more and more reports about coincident PA and primary hyperparathyroidism. From a pathophysiologic point of view this constellation is best characterized as tertiary hyperparathyroidism. Future aspects should further clarify the extent of these endocrine interactions and analyze the influence of this interplay on cardiovascular morbidity and mortality and bone health. © Georg Thieme Verlag KG Stuttgart · New York.

Effects of high-dose ketoconazole treatment on adrenal mineralocorticoid biosynthesis in dogs and rats.

PubMed

De Coster, R; Coene, M C; Haelterman, C; Beerens, D; Goeminne, N

1987-07-01

At high doses, ketoconazole blocks both testicular and adrenal androgen biosyntheses and partially inhibits the glucocorticoid production. To investigate the effects of this imidazole derivative on the mineralocorticoid biosynthesis, 7 male mongrel dogs received a single oral dose of 15 mg/kg of ketoconazole or placebo, in a cross-over way. From 2 to 4 h after treatment, an iv infusion of angiotensin II (10 ng/kg per min) was performed. Ketoconazole treatment significantly blunted the aldosterone and cortisol increment, whereas 18-hydroxycorticosterone, corticosterone, 11-deoxycorticosterone (DOC), progesterone, and 17 alpha-hydroxyprogesterone rose to peak concentrations, respectively 2.5-, 6-, 8-, 2.5- and 1.5-fold higher than those observed after placebo administration. Plasma 11-deoxycortisol and renin activity levels remained similar in both groups. On the other hand, 2 X 2 groups of 10 male adult rats each were fed with a normal or a sodium-depleted diet. Of the two sets of groups, one was treated ip with ketoconazole (20 mg/kg twice a day), the other with vehicle solution. In animals on either diet, ketoconazole lowered 18-hydroxycorticosterone and aldosterone concentrations. Plasma DOC rose up to 25-fold in the salt-deprived animals. Serum Na+, Cl-, corticosterone and plasma renin activity remained unaffected by the treatment. These results show that high-dose ketoconazole treatment partially inhibits the biosynthesis of aldosterone by affecting the cytochrome P-45011 beta.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of infusions of ring-A-reduced derivatives of aldosterone on the antinatriuretic and kaliuretic actions of aldosterone.

PubMed

Morris, D J; Souness, G W; Saccoccio, N A; Harnik, M

1989-01-01

Infusion of Ring-A-reduced metabolites of aldosterone in adrenalectomized male rats for 4 days revealed that 5 alpha-Ring-A-reduced derivatives, 5 alpha-dihydroaldosterone (5 alpha-DHAldo; 2.5-5.0 micrograms/day), 3 alpha,5 alpha-tetrahydroaldosterone (3 alpha,5 alpha-THAldo; 5-25 micrograms/day), and 3 beta,5 alpha-THAldo (50-175 micrograms/day) possessed intrinsic Na+-retaining activity. The same infusions of 5 alpha-DHAldo, 3 alpha,5 alpha-THAldo, and 3 beta,5 alpha-THAldo, also lowered the urinary excretion of potassium. The 5 beta-Ring-A-reduced derivative 3 alpha,5 beta-THAldo did not demonstrate either of these biological properties. In another set of experiments, on the fourth day of infusion, aldosterone (0.1 microgram/rat) was administered acutely subcutaneously; none of the Ring-A-reduced derivatives altered the Na+-retaining activity of aldosterone. However, in a dose-dependent manner, both 3 alpha,5 alpha-THAldo and 3 beta,5 alpha-THAldo blunted the urinary K+-secretory effect of aldosterone; low dosages of 5 alpha-DHAldo and larger dosages of 3 alpha,5 beta-THAldo did not. Thus, the 5 alpha-reduced derivatives of aldosterone not only lowered urinary Na+ and K+ excretion in their own right, but two of them blunted the kaliuretic response of the parent mineralocorticoid, aldosterone. Further experiments will be required to determine whether these aldosterone metabolites are further metabolized or interconverted during the expression of the regulatory properties described here and whether these properties are physiologically relevant.

Urinary renin, but not angiotensinogen or aldosterone, reflects the renal renin-angiotensin-aldosterone system activity and the efficacy of renin-angiotensin-aldosterone system blockade in the kidney.

PubMed

van den Heuvel, Mieke; Batenburg, Wendy W; Jainandunsing, Sjaam; Garrelds, Ingrid M; van Gool, Jeanette M G; Feelders, Richard A; van den Meiracker, Anton H; Danser, A H Jan

2011-11-01

To study which renin-angiotensin-aldosterone system (RAAS) component best reflects renal RAAS activity. We measured urinary and plasma renin, prorenin, angiotensinogen, aldosterone, albumin and creatinine in 101 diabetic and nondiabetic patients with or without hypertension. Plasma prorenin was elevated in diabetic patients. Urinary prorenin was undetectable. Urinary albumin and renin were higher in diabetic patients. Men had higher plasma renin/prorenin levels, and lower plasma angiotensinogen levels than women. Plasma creatinine and albumin were also higher in men. Urinary RAAS components showed no sexual dimorphism, whereas urinary creatinine and albumin were higher in men. Angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers increased plasma renin and decreased plasma angiotensinogen, without altering plasma aldosterone. In contrast, in urine, these drugs decreased renin and aldosterone without affecting angiotensinogen. When analyzing all patients together, urinary angiotensinogen excretion closely mimicked that of albumin, whereas urinary angiotensinogen and albumin levels both were 0.05% or less of their concomitant plasma levels. This may reflect the identical glomerular filtration and tubular handling of both proteins, which have a comparable molecular weight. In contrast, urinary renin excretion did not correlate with urinary albumin excretion, and the urinary/plasma concentration ratio of renin was more than 200 times the ratio of albumin, despite its comparable molecular weight. Urinary aldosterone excretion closely followed urinary creatinine excretion. The increased urinary renin levels in diabetes and the decreased urinary renin levels following RAAS blockade, occurring independently of changes in plasma renin, reflect the activated renal RAAS in diabetes and the success of RAAS blockade in the kidney, respectively. Urinary renin, therefore, more closely reflects renal RAAS activity than urinary angiotensinogen or

Intraadrenal corticotropin in bilateral macronodular adrenal hyperplasia.

PubMed

Louiset, Estelle; Duparc, Céline; Young, Jacques; Renouf, Sylvie; Tetsi Nomigni, Milène; Boutelet, Isabelle; Libé, Rossella; Bram, Zakariae; Groussin, Lionel; Caron, Philippe; Tabarin, Antoine; Grunenberger, Fabienne; Christin-Maitre, Sophie; Bertagna, Xavier; Kuhn, Jean-Marc; Anouar, Youssef; Bertherat, Jérôme; Lefebvre, Hervé

2013-11-28

Bilateral macronodular adrenal hyperplasia is a rare cause of primary adrenal Cushing's syndrome. In this form of hyperplasia, hypersecretion of cortisol suppresses the release of corticotropin by pituitary corticotrophs, which results in low plasma corticotropin levels. Thus, the disease has been termed corticotropin-independent macronodular adrenal hyperplasia. We examined the abnormal production of corticotropin in these hyperplastic adrenal glands. We obtained specimens of hyperplastic macronodular adrenal tissue from 30 patients with primary adrenal disease. The corticotropin precursor proopiomelanocortin and corticotropin expression were assessed by means of a polymerase-chain-reaction assay and immunohistochemical analysis. The production of corticotropin and cortisol was assessed in 11 specimens with the use of incubated explants and cell cultures coupled with hormone assays. Corticotropin levels were measured in adrenal and peripheral venous blood samples from 2 patients. The expression of proopiomelanocortin messenger RNA (mRNA) was detected in all samples of hyperplastic adrenal tissue. Corticotropin was detected in steroidogenic cells arranged in clusters that were disseminated throughout the adrenal specimens. Adrenal corticotropin levels were higher in adrenal venous blood samples than in peripheral venous samples, a finding that was consistent with local production of the peptide within the hyperplastic adrenals. The release of adrenal corticotropin was stimulated by ligands of aberrant membrane receptors but not by corticotropin-releasing hormone or dexamethasone. A semiquantitative score for corticotropin immunostaining in the samples correlated with basal plasma cortisol levels. Corticotropin-receptor antagonists significantly inhibited in vitro cortisol secretion. Cortisol secretion by the adrenals in patients with macronodular hyperplasia and Cushing's syndrome appears to be regulated by corticotropin, which is produced by a subpopulation of

Aldosterone response to angiotensin II during hypoxemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Colice, G.L.; Ramirez, G.

1986-07-01

Exercise stimulates the renin-angiotensin-aldosterone system (RAAS). However, increases in plasma aldosterone concentrations (PAC) are suppressed when exercise is performed at high altitude or under hypoxemic conditions. As the angiotensin-II response to high-altitude exercise is normal, it is speculated that an inhibitor, discharged during hypoxemia, acted to suppress angiotensin-II-mediated aldosterone release. A study was conducted to test this hypothesis, taking into account the measurement of the aldosterone response to exogenous angiotensin II during normoxemia and hypoxemia. It was found that the dose-response curve of PAC to angiotensin II was not significantly inhibited by the considered model of hypoxemia. The hypoxemia-mediated releasemore » of an angiotensin II inhibitor does, therefore, not explain the previous observations of PAC suppression during hypoxemic exercise. 28 references.« less

Aldosterone is associated with left ventricular hypertrophy in hemodialysis patients.

PubMed

Feniman De Stefano, Greicy Mara Mengue; Zanati-Basan, Silméia Garcia; De Stefano, Laercio Martins; Silva, Viviana Rugolo Oliveira E; Xavier, Patrícia Santi; Barretti, Pasqual; da Silva Franco, Roberto Jorge; Caramori, Jacqueline Costa Teixeira; Martin, Luis Cuadrado

2016-10-01

Patients with chronic kidney disease present a higher degree of left ventricular hypertrophy than expected for hypertension levels. In chronic kidney disease the plot between the quotient extracellular water/total body water and aldosterone is shifted up and to the right. There are few studies that verified the role of aldosterone in cardiac remodeling in this set of patients. The aim of this study was to evaluate the relationship between serum aldosterone and left ventricular mass index in patients with chronic kidney disease on hemodialysis. The patients were submitted to clinical and laboratory evaluation, bioelectrical impedance, echocardiography and ambulatory blood pressure monitoring. The 27 patients included were divided into two groups according to aldosterone level and compared with each other. The group of patients with higher aldosterone levels had higher left ventricular mass index. These groups were heterogeneous with regard to ambulatory systolic blood pressure, body mass index, and aldosterone levels and homogeneous with regard to the quotient extracellular water/total body water, renin-angiotensin-aldosterone system blockers, beta blocker use and other clinical characteristics. The association between aldosterone levels and left ventricular mass index was adjusted to confounding variables by a multiple linear regression analysis in which aldosterone was independently associated with left ventricular mass index. The data presented are consistent with a pathogenic role of aldosterone in left ventricular hypertrophy in patients with chronic kidney dialysis in dialysis patients. ClinicalTrials.gov identifier: NCT01128101. © The Author(s), 2016.

Immune-endocrine interactions in the mammalian adrenal gland: facts and hypotheses.

PubMed

Nussdorfer, G G; Mazzocchi, G

1998-01-01

Several cytokines, which are the major mediators of the inflammatory responses, are well-known to stimulate the hypothalamopituitary corticotropin-releasing hormone (CRH)/adrenocorticotropic hormone (ACTH) system, thereby evoking secretory responses by the adrenal cortex. Many of these cytokines, including interleukin-1 (IL-1), IL-2, IL-6, tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (INF-gamma) are synthesized in the adrenal gland by both parenchymal cells and resident macrophages, and the release of some of them (e.g., IL-6 and TNF-alpha) is regulated by the main agonists of steroid hormone secretion (e.g., ACTH and angiotensin-II) and bacterial endotoxins. Adrenocortical and adrenomedullary cells are provided with specific receptors for IL-1, IL-2, and IL-6. IL-1 and TNF-alpha directly inhibit aldosterone secretion of zona glomerulosa cells, whereas IL-6 enhances it. IL-2, IL-3, IL-6, and INF-alpha are able to directly stimulate glucocorticoid production by zona fasciculata and zona reticularis cells, whereas IL-1 exerts an analogous effect through an indirect mechanism involving the stimulation of catecholamine release by chromaffin cells and/or the activation of the intramedullary CRH/ACTH system; again, TNF-alpha depresses glucocorticoid synthesis. IL-6 raises androgen secretion by inner adrenocortical layers. IL-1 enhances the proliferation of adrenocortical cells, and findings suggest that cytokines may control the apoptotic deletion of senescent zona reticularis cells. The relevance of the intraadrenal cytokine system in the fine-tuning of the secretion and growth of the adrenal cortex under normal conditions remains to be explored. However, indirect proof is available that local immune-endocrine interactions may play an important role in modulating adrenal responses to inflammatory and immune challenges and stresses.

Adrenal Vein Sampling for Conn's Syndrome: Diagnosis and Clinical Outcomes.

PubMed

Deipolyi, Amy R; Bailin, Alexander; Wicky, Stephan; Alansari, Shehab; Oklu, Rahmi

2015-06-19

Adrenal vein sampling (AVS) is the gold standard test to determine unilateral causes of primary aldosteronism (PA). We have retrospectively characterized our experience with AVS including concordance of AVS results and imaging, and describe the approach for the PA patient in whom bilateral AVS is unsuccessful. We reviewed the medical records of 85 patients with PA and compared patients who were treated medically and surgically on pre-procedure presentation and post-treatment outcomes, and evaluated how technically unsuccessful AVS results were used in further patient management. Out of the 92 AVS performed in 85 patients, AVS was technically successful bilaterally in 58 (63%) of cases. Either unsuccessful AVS prompted a repeat AVS, or results from the contralateral side and from CT imaging were used to guide further therapy. Patients who were managed surgically with adrenalectomy had higher initial blood pressure and lower potassium levels compared with patients who were managed medically. Adrenalectomy results in significantly decreased blood pressure and normalization of potassium levels. AVS can identify surgically curable causes of PA, but can be technically challenging. When one adrenal vein fails to be cannulated, results from the contralateral vein can be useful in conjunction with imaging and clinical findings to suggest further management.

Collecting Duct Nitric Oxide Synthase 1ß Activation Maintains Sodium Homeostasis During High Sodium Intake Through Suppression of Aldosterone and Renal Angiotensin II Pathways.

PubMed

Hyndman, Kelly A; Mironova, Elena V; Giani, Jorge F; Dugas, Courtney; Collins, Jessika; McDonough, Alicia A; Stockand, James D; Pollock, Jennifer S

2017-10-24

During high sodium intake, the renin-angiotensin-aldosterone system is downregulated and nitric oxide signaling is upregulated in order to remain in sodium balance. Recently, we showed that collecting duct nitric oxide synthase 1β is critical for fluid-electrolyte balance and subsequently blood pressure regulation during high sodium feeding. The current study tested the hypothesis that high sodium activation of the collecting duct nitric oxide synthase 1β pathway is critical for maintaining sodium homeostasis and for the downregulation of the renin-angiotensin-aldosterone system-epithelial sodium channel axis. Male control and collecting duct nitric oxide synthase 1β knockout (CDNOS1KO) mice were placed on low, normal, and high sodium diets for 1 week. In response to the high sodium diet, plasma sodium was significantly increased in control mice and to a significantly greater level in CDNOS1KO mice. CDNOS1KO mice did not suppress plasma aldosterone in response to the high sodium diet, which may be partially explained by increased adrenal AT1R expression. Plasma renin concentration was appropriately suppressed in both genotypes. Furthermore, CDNOS1KO mice had significantly higher intrarenal angiotensin II with high sodium diet, although intrarenal angiotensinogen levels and angiotensin-converting enzyme activity were similar between knockout mice and controls. In agreement with inappropriate renin-angiotensin-aldosterone system activation in the CDNOS1KO mice on a high sodium diet, epithelial sodium channel activity and sodium transporter abundance were significantly higher compared with controls. These data demonstrate that high sodium activation of collecting duct nitric oxide synthase 1β signaling induces suppression of systemic and intrarenal renin-angiotensin-aldosterone system, thereby modulating epithelial sodium channel and other sodium transporter abundance and activity to maintain sodium homeostasis. © 2017 The Authors. Published on behalf of the

Aldosterone stimulates superoxide production in macula densa cells.

PubMed

Zhu, Xiaolong; Manning, R Davis; Lu, Deyin; Gomez-Sanchez, Celso E; Fu, Yiling; Juncos, Luis A; Liu, Ruisheng

2011-09-01

Two major factors which regulate tubuloglomerular feedback (TGF)-mediated constriction of the afferent arteriole are release of superoxide (O(2)(-)) and nitric oxide (NO) by macula densa (MD) cells. MD O(2)(-) inactivates NO; however, among the factors that increase MD O(2)(-) release, the role of aldosterone is unclear. We hypothesize that aldosterone activates the mineralocorticoid receptor (MR) on MD cells, resulting in increased O(2)(-) production due to upregulation of cyclooxygenase-1 (COX-2) and NOX-2, and NOX-4, isoforms of NAD(P)H oxidase. Studies were performed on MMDD1 cells, a renal epithelial cell line with properties of MD cells. RT-PCR and Western blotting confirmed the expression of MR. Aldosterone (10(-8) mol/l for 30 min) doubled MMDD1 cell O(2)(-) production, and this was completely blocked by MR inhibition with 10(-5) mol/l eplerenone. RT-PCR, real-time PCR, and Western blotting demonstrated aldosterone-induced increases in COX-2, NOX-2, and NOX-4 expression. Inhibition of COX-2 (NS398), NADPH oxidase (apocynin), or a combination blocked aldosterone-induced O(2)(-) production to the same degree. These data suggest that aldosterone-stimulated MD O(2)(-) production is mediated by COX-2 and NADPH oxidase. Next, COX-2 small-interfering RNA (siRNA) specifically decreased COX-2 mRNA without affecting NOX-2 or NOX-4 mRNAs. In the presence of the COX-2 siRNA, the aldosterone-induced increases in COX-2, NOX-2, and NOX-4 mRNAs and O(2)(-) production were completely blocked, suggesting that COX-2 causes increased expression of NOX-2 and NOX-4. In conclusion 1) MD cells express MR; 2) aldosterone increases O(2)(-) production by activating MR; and 3) aldosterone stimulates COX-2, which further activates NOX-2 and NOX-4 and generates O(2)(-). The resulting balance between O(2)(-) and NO in the MD is important in modulating TGF.

Changes in Body Mass Index in Pheochromocytoma Patients Following Adrenalectomy.

PubMed

Spyroglou, Ariadni; Adolf, Christian; Hahner, Stefanie; Quinkler, Marcus; Ladurner, Roland; Reincke, Martin; Beuschlein, Felix

2017-03-01

Catecholamine excess from pheochromocytoma results in cardiovascular symptoms such as arterial hypertension and tachycardia and induces metabolic alterations including glucose intolerance and increase in resting metabolic rate. The objective of our study was to investigate the effect of surgical cure of pheochromocytoma on body-mass-index and the correlation of body-mass-index changes to preoperative endocrine parameters. Pheochromocytoma patients from the Munich ENSAT Registry were matched (1:2) for age and gender to patients from the German Conn's Registry, who had undergone surgery for aldosterone-producing-adenomas. Thereby, 43 pheochromocytoma patients (17 males/26 females) and 86 aldosterone-producing-adenoma patients were analyzed for body-mass-index, blood pressure, and catecholamine levels before and one year after adrenalectomy. Seventy-four percent of pheochromocytoma patients were hypertensive preoperatively and 48% one year postoperatively. Systolic blood pressure did not differ significantly in pre- and postoperative measurements whereas diastolic blood pressure was significantly reduced over time. Moreover, pheochromocytoma patients gained body weight (p<0.001) one year following adrenalectomy accompanied by significant increases in body-mass-index, whereas aldosterone-producing adenoma patients displayed a slight weight loss. Despite weight gain, diagnosis of diabetes mellitus dropped from 9 of 43 investigated pheochromocytoma patients at baseline to 4 at follow-up. A significant correlation between body-mass-index changes to the preoperative catecholamine levels was found only for urinary normetanephrines. These data suggest that normalization of chronic catecholamine excess by adrenalectomy is associated with an increase in body-mass-index, which is more pronounced in patients with high preoperative levels of urinary normetanephrines. © Georg Thieme Verlag KG Stuttgart · New York.

Adrenocortical carcinoma

MedlinePlus

... develop this tumor. ACC can produce the hormones cortisol, aldosterone, estrogen, or testosterone, as well as other ... Symptoms of increased cortisol or other adrenal gland hormones may include: Fatty, rounded hump high on the back just below the neck ( buffalo ...

Effects of long-term pravastatin treatment on spermatogenesis and on adrenal and testicular steroidogenesis in male hypercholesterolemic patients.

PubMed

Bernini, G P; Brogi, G; Argenio, G F; Moretti, A; Salvetti, A

1998-05-01

To evaluate the influence of an hydrophilic statin, pravastatin, on adrenal and testicular steroidogenesis and spermatogenesis, eight male hypercholesterolemic patients were studied. All patients observed a hypocholesterolemic diet and received placebo for 4 weeks followed by pravastatin (20 mg/die) for 6 months. Before, during (4th-5th week) and at the end (23th-24th week) of active treatment, CRH (1 microgram i.v.), ACTH (Synacthen 250 micrograms i.v.) and human CG (HCG 3000 IU i.m.) tests were performed in addition to semen analysis. Pravastatin significantly reduced total cholesterol (20.3%), calculated LDL-cholesterol (24.6%) and apolipoprotein B (10.5%, increased apolipoprotein A1 (16.1%) and did not influence plasma HDL-cholesterol and triglycerides. Basal plasma cortisol, aldosterone, androstenedione, testosterone and oestradiol did not change under active treatment. Pravastatin administration affected neither adrenal hormone responses to CRH and ACTH or testicular response to HCG nor spermatogenesis in respect of motility, morphology and sperm count. In conclusion, long-term pravastatin treatment, at doses effective in improving lipid profile, did not influence testicular reproductive and endocrine function and did not interfere with basal and stimulated adrenal activity of male hypercholesterolemic patients.

Diagnostic performance of multidetector computed tomography in distinguishing unilateral from bilateral abnormalities in primary hyperaldosteronism: comparison of multidetector computed tomography with adrenal vein sampling.

PubMed

Raman, Siva P; Lessne, Mark; Kawamoto, Satomi; Chen, Yifei; Salvatori, Roberto; Prescott, Jason D; Fishman, Elliot K

2015-01-01

The management of patients with primary hyperaldosteronism (PH) varies depending on whether the unregulated aldosterone secretion localizes to a single unilateral adrenal gland, traditionally determined using adrenal vein sampling (AVS). This study seeks to determine if the performance of multidetector computed tomography (MDCT) examinations performed using the latest scanner technology can reasonably match the results of AVS, and potentially avoid AVS in some patients. Computed tomographic scans in 56 patients with PH were independently reviewed by 2 radiologists for the presence of adrenal nodules and qualitative adrenal thickening. Results were correlated with AVS results. Of 35 patients with MDCT evidence of unilateral nodules, the imaging findings correctly predicted AVS localization in only 23 (65.7%) cases. When stratified by size, MDCT was accurate in only 71.4% of cases for nodules measuring 10 mm or less, and only 55.0% of cases for nodules measuring 11 to 20 mm. Of the 12 cases where MDCT did not correctly localize, AVS localized to the contralateral adrenal gland in 4 cases, whereas AVS suggested no lateralization in 8 cases. In patients with normal bilateral adrenal glands on MDCT, 2/7 (28.6%) of cases demonstrated unilateral localization on AVS, and in patients with bilateral adrenal nodules, only 3/14 (21.4%) did not demonstrate lateralization on AVS. Multidetector computed tomography, even when performed with the latest generation of MDCT scanners, does not offer sufficient diagnostic accuracy to replace AVS in patients with PH.

Investigation of aldosterone-synthase inhibition in rats.

PubMed

Ménard, Joël; Gonzalez, Marie-Françoise; Guyene, Thanh-Tam; Bissery, Alvine

2006-06-01

In-vivo investigation of aldosterone-synthase inhibitors requires experimental models to characterize the biological effects of these compounds. Seven successive experiments were performed in groups of 2-month-old male spontaneously hypertensive rats. Urinary free aldosterone was the main end-point measured during two contrasted diets: low sodium-high potassium (LS), inducing high urinary aldosterone (839 pmol/24 h, 95% confidence interval 654-1077), and high sodium-normal potassium (HS), inducing low urinary aldosterone (38.1 pmol/24 h; 95% confidence interval, 32.4-44.9). FAD 286 A (10 and 30 mg/kg) decreased urinary free aldosterone by 53 and 87% on the LS diet, and 50 and 75% on the HS. Plasma renin concentration increased three-fold after a 4-week treatment of 30 mg/kg FAD 286 A on the LS diet and did not change on the HS. The combination of FAD 286 A (30 mg/kg) and spironolactone (30 mg/kg) on the LS diet induced a biological picture of severe hypoaldosteronism and was not tolerated, whereas the HS diet prevented these abnormalities. The combination of FAD 286 A (30 mg/kg) and furosemide (30 mg/kg) on the HS diet corrected the diuretic-induced hypokalemia (4.1 +/- 0.2 versus 3.7 +/- 2.2 mEq/l, P < 0.033). This experimental model will be useful to screen future aldosterone-synthase inhibitors and study their biological effects in various experimental conditions.

Latest aspects of aldosterone actions on the heart muscle.

PubMed

Kritis, A A; Gouta, C P; Liaretidou, E I; Kallaras, K I

2016-02-01

The genomic action of aldosterone has already been known to the scientific community and is well-documented to a satisfactory degree. However, the existence of rapid, non-genomic aldosterone actions has repeatedly been proven. These actions are apparent to a lot of tissues, among which the cardiac tissue, with the cardiac cells being responsible for the secretion of endogenous aldosterone. In the genomic pathway, the connection between the hormone and its receptor results increased reabsorption of sodium and water and excretion of potassium. Thus, the genomic procedure reacts indirectly on cardiovascular system by altering the blood pressure. New studies have shed light on unknown aspects of the non-genomic mechanism, which is sometimes performed by means of mineralocorticoid receptor (MR), while others through an MR-independent pathway. It is believed that aldosterone exerts its non-genomic action with the help of a different receptor, probably a G protein coupled receptor. A possible target is protein kinase C (PKC), and PKCε is postulated increase the permeability of the membrane of the cardiac cells to sodium, resulting in delayed repolarization and prolongation of action potential. These findings totally agree with and account for the serendipitous finding of our laboratory, that there is a positive correlation between plasma aldosterone levels and left ventricle (LV) contraction duration. Also, aldosterone has been proven to exacerbate the oxidative stress and induce vasoconstriction by acting on the vascular resistance and the cardiac output. Finally, this article deals with the role of aldosterone in cardiac fibrosis and the latest aspects of aldosterone actions on the heart muscle as well as providing a historical overview of the landmarks pertaining aldosterone's research.

Aldosterone acutely stimulates NCC activity via a SPAK-mediated pathway.

PubMed

Ko, Benjamin; Mistry, Abinash C; Hanson, Lauren; Mallick, Rickta; Wynne, Brandi M; Thai, Tiffany L; Bailey, James L; Klein, Janet D; Hoover, Robert S

2013-09-01

Hypertension is a leading cause of morbidity and mortality worldwide, and disordered sodium balance has long been implicated in its pathogenesis. Aldosterone is perhaps the key regulator of sodium balance and thus blood pressure. The sodium chloride cotransporter (NCC) in the distal convoluted tubule of the kidney is a major site of sodium reabsorption and plays a key role in blood pressure regulation. Chronic exposure to aldosterone increases NCC protein expression and function. However, more acute effects of aldosterone on NCC are unknown. In our salt-abundant modern society where chronic salt deprivation is rare, understanding the acute effects of aldosterone is critical. Here, we examined the acute effects (12-36 h) of aldosterone on NCC in the rodent kidney and in a mouse distal convoluted tubule cell line. Studies demonstrated that aldosterone acutely stimulated NCC activity and phosphorylation without affecting total NCC abundance or surface expression. This effect was dependent upon the presence of the mineralocorticoid receptor and serum- and glucocorticoid-regulated kinase 1 (SGK1). Furthermore, STE20/SPS-1-related proline/alanine-rich kinase (SPAK) phosphorylation also increased, and gene silencing of SPAK eliminated the effect of aldosterone on NCC activity. Aldosterone administration via a minipump in adrenalectomized rodents confirmed an increase in NCC phosphorylation without a change in NCC total protein. These data indicate that acute aldosterone-induced SPAK-dependent phosphorylation of NCC increases individual transporter activity.

Prenatal diagnosis of Bartter syndrome: amniotic fluid aldosterone.

PubMed

Rachid, Myriam; Dreux, Sophie; Pean de Ponfilly, Gauthier; Vargas-Poussou, Rosa; Czerkiewicz, Isabelle; Chevenne, Didier; Oury, Jean-François; Deschênes, Georges; Muller, Françoise

2017-04-01

Bartter syndrome is a severe inherited tubulopathy characterized at birth by salt wasting, severe polyuria, dehydration, growth retardation and secondary hyperaldosteronism. Prenatally, the disease is usually discovered following onset of severe polyhydramnios. We studied amniotic fluid aldosterone concentration in cases of Bartter syndrome and in control groups. Amniotic fluid aldosterone was assayed by radioimmunoassay. We undertook a retrospective case-control study based on 36 cases of postnatally diagnosed Bartter syndrome and 144 controls matched for gestational age. Two controls groups were defined: controls with polyhydramnios (n=72) and control without polyhydramnios (n=72). Amniotic fluid aldosterone was compared between the three groups. The median amniotic fluid aldosterone concentration in the Bartter syndrome group (90 pg/mL) did not differ significantly from that in the controls with polyhydramnios (90 pg/mL, p=0.33) or the controls without polyhydramnios (87 pg/mL, p=0.41). In conclusion, amniotic fluid aldosterone assay cannot be used for prenatal diagnosis of Bartter syndrome.

Global- and renal-specific sympathoinhibition in aldosterone hypertension.

PubMed

Lohmeier, Thomas E; Liu, Boshen; Hildebrandt, Drew A; Cates, Adam W; Georgakopoulos, Dimitrios; Irwin, Eric D

2015-06-01

Recent technology for chronic electric activation of the carotid baroreflex and renal nerve ablation provide global and renal-specific suppression of sympathetic activity, respectively, but the conditions for favorable antihypertensive responses in resistant hypertension are unclear. Because inappropriately high plasma levels of aldosterone are prevalent in these patients, we investigated the effects of baroreflex activation and surgical renal denervation in dogs with hypertension induced by chronic infusion of aldosterone (12 μg/kg per day). Under control conditions, basal values for mean arterial pressure and plasma norepinephrine concentration were 100±3 mm Hg and 134±26 pg/mL, respectively. By day 7 of baroreflex activation, plasma norepinephrine was reduced by ≈40% and arterial pressure by 16±2 mm Hg. All values returned to control levels during the recovery period. Arterial pressure increased to 122±5 mm Hg concomitant with a rise in plasma aldosterone concentration from 4.3±0.4 to 70.0±6.4 ng/dL after 14 days of aldosterone infusion, with no significant effect on plasma norepinephrine. After 7 days of baroreflex activation at control stimulation parameters, the reduction in plasma norepinephrine was similar but the fall in arterial pressure (7±1 mm Hg) was diminished (≈55%) during aldosterone hypertension when compared with control conditions. Despite sustained suppression of sympathetic activity, baroreflex activation did not have central actions to inhibit either the stimulation of vasopressin secretion or drinking induced by increased plasma osmolality during chronic aldosterone infusion. Finally, renal denervation did not attenuate aldosterone hypertension. These findings suggest that aldosterone excess may portend diminished blood pressure lowering to global and especially renal-specific sympathoinhibition during device-based therapy. © 2015 American Heart Association, Inc.

Global and Renal-Specific Sympathoinhibition in Aldosterone Hypertension

PubMed Central

Lohmeier, Thomas E.; Liu, Boshen; Hildebrandt, Drew A.; Cates, Adam W.; Georgakopoulos, Dimitrios; Irwin, Eric D.

2015-01-01

Recent technology for chronic electrical activation of the carotid baroreflex and renal nerve ablation provide global and renal-specific suppression of sympathetic activity, respectively, but the conditions for favorable antihypertensive responses in resistant hypertension are unclear. Because inappropriately high plasma levels of aldosterone are prevalent in these patients, we investigated the effects of baroreflex activation and surgical renal denervation in dogs with hypertension induced by chronic infusion of aldosterone (12µg/kg/day). Under control conditions, basal values for mean arterial pressure and plasma norepinephrine concentration were 100±3 mm Hg and 134±26 pg/mL, respectively. By day 7 of baroreflex activation, plasma norepinephrine was reduced by ~ 40% and arterial pressure by 16±2 mmHg. All values returned to control levels during the recovery period. Arterial pressure increased to 122±5 mm Hg concomitant with a rise in plasma aldosterone concentration from 4.3±0.4 to 70.0±6.4 ng/dL after 14 days of aldosterone infusion, with no significant effect on plasma norepinephrine. After 7 days of baroreflex activation at control stimulation parameters, the reduction in plasma norepinephrine was similar but the fall in arterial pressure (7±1 mmHg) was diminished (~ 55%) during aldosterone hypertension as compared to control conditions. Despite sustained suppression of sympathetic activity, baroreflex activation did not have central actions to inhibit either the stimulation of vasopressin secretion or drinking induced by increased plasma osmolality during chronic aldosterone infusion. Finally, renal denervation did not attenuate aldosterone hypertension. These findings suggest that aldosterone excess may portend diminished blood pressure lowering to global and especially renal-specific sympathoinhibition during device-based therapy. PMID:25895584

Rapid stimulation of sodium intake combining aldosterone into the 4th ventricle and the blockade of the lateral parabrachial nucleus.

PubMed

Gasparini, S; Melo, M R; Leite, G F; Nascimento, P A; Andrade-Franzé, G M F; Menani, J V; Colombari, E

2017-03-27

Chronic infusion of aldosterone into the 4th ventricle (4th V) induces robust daily sodium intake, whereas acute injection of aldosterone into the 4th V produces no sodium intake. The inhibitory mechanism of the lateral parabrachial nucleus (LPBN) restrains sodium intake induced by different natriorexigenic stimuli and might affect the acute response to aldosterone into the 4th V. In the present study, 1.8% NaCl and water intake was tested in rats treated with acute injections of aldosterone into the 4th V combined with the blockade of the inhibitory mechanisms with injections of moxonidine (α 2 adrenergic/imidazoline agonist) or methysergide (a serotonergic antagonist) into the LPBN. Male Holtzman rats with stainless steel cannulas implanted in the 4th V and bilaterally in the LPBN were used. Aldosterone (250 or 500ng) into the 4th V combined with vehicle into the LPBN induced no 1.8% NaClintake compared to control (1.5±1.1 and 1.1±0.4, respectively, vs. vehicle into 4th V: 1.0±0.5ml/2h). However, aldosterone (250 or 500ng) into the 4th V combined with moxonidine (0.5nmol) into the LPBN induced strong ingestion of 1.8% NaCl (12.7±4.6 and 17.6±3.7ml/2h, respectively). Aldosterone (250ng) into the 4th V combined with methysergide (4μg) into the LPBN also induced 1.8% NaCl intake (17.6±5.4ml/2h). These data suggest that the inhibitory mechanisms of the LPBN counteract the facilitation of sodium intake produced by aldosterone injected into the 4th, restraining sodium intake in this condition. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

The Role of Aldosteronism in Causing Obesity-Related Cardiovascular Risk

PubMed Central

Calhoun, David A.; Sharma, Kumar

2010-01-01

Synopsis A large body of evidence strongly links aldosterone to development and progression of cardiovacscular disease, including vascular stiffness, left ventricular hypertrophy, congestive heart failure, chronic kidney disease, and especially, hypertension. Emerging data suggests that adipocytes may serve as a source of aldosterone, either directly, or indirectly, through release of aldosterone-stimulating factors. If adipocytes are confirmed to contribute importantly to hyperaldosteronism, it would have significant clinical implications in linking aldosterone to obesity-related increases in cardiovascular risk. Such a cause-and-effect would then provide the opportunity to reverse that risk with preferential use of aldosterone antagonists in obese patients. PMID:20621254

Asian women have attenuated sympathetic activation but enhanced renal–adrenal responses during pregnancy compared to Caucasian women

PubMed Central

Okada, Yoshiyuki; Best, Stuart A; Jarvis, Sara S; Shibata, Shigeki; Parker, Rosemary S; Casey, Brian M; Levine, Benjamin D; Fu, Qi

2015-01-01

Abstract Asians have a lower prevalence of hypertensive disorders of pregnancy than Caucasians. Since sympathetic overactivity and dysregulation of the renal–adrenal system (e.g. low aldosterone levels) have been found in preeclamptic women, we hypothesized that Asians have lower muscle sympathetic nerve activity (MSNA) and greater aldosterone concentrations during normal pregnancy than Caucasians. In a prospective study, blood pressure (BP), heart rate (HR), and MSNA were measured during supine and upright tilt (30 deg and 60 deg for 5 min each) in 9 Asians (32 ± 1 years (mean ± SEM)) and 12 Caucasians (29 ± 1 years) during pre-, early (≤8 weeks of gestation) and late (32–36 weeks) pregnancy, and post-partum (6–10 weeks after delivery). Supine MSNA increased with pregnancy in both groups (P < 0.001); it was significantly lower in Asians than Caucasians (14 ± 3 vs. 23 ± 3 bursts min−1 and 16 ± 5 vs. 30 ± 3 bursts min−1 in early and late pregnancy, respectively; P = 0.023). BP decreased during early pregnancy (P < 0.001), but was restored during late pregnancy. HR increased during pregnancy (P < 0.001) with no racial difference (P = 0.758). MSNA increased during tilting and it was markedly lower in Asians than Caucasians in late pregnancy (31 ± 6 vs. 49 ± 3 bursts min−1 at 60 deg tilt; P = 0.003). Upright BP was lower in Asians, even in pre-pregnancy (P = 0.006), and this racial difference persisted during pregnancy. Direct renin and aldosterone increased during pregnancy (both P < 0.001); these hormones were greater in Asians (P = 0.086 and P = 0.014). Thus, Asians have less sympathetic activation but more upregulated renal–adrenal responses than Caucasians during pregnancy. These results may explain, at least in part, why Asian women are at low risk of hypertensive disorders in pregnancy. Key points Asian women have a lower prevalence of hypertensive disorders of pregnancy than Caucasian

Sodium interference in the determination of urinary aldosterone.

PubMed

Aldea, Marta Lucía; Barallat, Jaume; Martín, María Amparo; Rosas, Irene; Pastor, María Cruz; Granada, María Luisa

2016-02-01

Primary hyperaldosteronism (PHA) is one of the most common endocrine forms of secondary hypertension. Among the most used confirmatory tests for PHA is urinary aldosterone determination after oral sodium loading test. The primary aim of our study was to investigate if sodium concentrations interfere with urinary aldosterone in an automated competitive immunoassay (Liaison®) as well as to verify the manufacturer's specifications. 24-hr urine samples were collected and stored frozen until assayed. Two pools at low and high aldosterone concentrations were prepared. Verification of performance for precision was tested according to Clinical and Laboratory Standards Institute (CLSI) document EP15-A2 and interference with increasing concentrations of NaCl according to CLSI EP7-A2. The assay met the quality specifications according to optimal biological variation. Our results show that sodium concentrations up to 200mmol/L do not interfere on urinary aldosterone quantification, but sodium concentrations above 486mmol/L negatively interfere with the test. The Liaison® automated method is useful for aldosterone determination in the PHA confirmatory test, but interferences with NaCl may occur. It is therefore recommended to determine urinary NaCl before measuring urinary aldosterone to avoid falsely low results. Copyright © 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Aldosterone Promotes Cardiac Endothelial Cell Proliferation In Vivo

PubMed Central

Gravez, Basile; Tarjus, Antoine; Pelloux, Véronique; Ouvrard‐Pascaud, Antoine; Delcayre, Claude; Samuel, Janelise; Clément, Karine; Farman, Nicolette; Jaisser, Fréderic; Messaoudi, Smail

2015-01-01

Background Experimentally, aldosterone in association with NaCl induces cardiac fibrosis, oxidative stress, and inflammation through mineralocorticoid receptor activation; however, the biological processes regulated by aldosterone alone in the heart remain to be identified. Methods and Results Mice were treated for 7 days with aldosterone, and then cardiac transcriptome was analyzed. Aldosterone regulated 60 transcripts (51 upregulated and 9 downregulated) in the heart (fold change ≥1.5, false discovery rate <0.01). To identify the biological processes modulated by aldosterone, a gene ontology analysis was performed. The majority of aldosterone‐regulated genes were involved in cell division. The cardiac Ki‐67 index (an index of proliferation) of aldosterone‐treated mice was higher than that of nontreated mice, confirming microarray predictions. Costaining of Ki‐67 with vinculin, CD68, α‐smooth muscle actin, CD31, or caveolin 1 revealed that the cycling cells were essentially endothelial cells. Aldosterone‐induced mineralocorticoid receptor–dependent proliferation was confirmed ex vivo in human endothelial cells. Moreover, pharmacological‐specific blockade of mineralocorticoid receptor by eplerenone inhibited endothelial cell proliferation in a preclinical model of heart failure (transverse aortic constriction). Conclusions Aldosterone modulates cardiac gene expression and induces the proliferation of cardiac endothelial cells in vivo. PMID:25564371

Giant pituitary adenoma: histological types, clinical features and therapeutic approaches.

PubMed

Iglesias, Pedro; Rodríguez Berrocal, Víctor; Díez, Juan José

2018-06-16

Giant pituitary adenomas comprise about 6-10% of all pituitary tumors. They are mostly clinically non-functioning adenomas and occur predominantly in males. The presenting symptoms are usually secondary to compression of neighboring structures, but also due to partial or total hypopituitarism. Functioning adenomas give rise to specific symptoms of hormonal hypersecretion. The use of dopamine agonists is considered a first-line treatment in patients with giant macroprolactinomas. Somatostatin analogs can also be used as primary treatment in cases of growth hormone and thyrotropin producing giant adenomas, although remission of the disease is not achieved in the vast majority of these patients. Neurosurgical treatment, either through transsphenoidal or transcranial surgery, continues to be the treatment of choice in the majority of patients with giant pituitary adenomas. The intrinsic complexity of these tumors requires the use of different therapies in a combined or sequential way. A multimodal approach and a therapeutic strategy involving a multidisciplinary team of expert professionals form the basis of the therapeutic success in these patients.

Aldosterone acutely stimulates NCC activity via a SPAK-mediated pathway

PubMed Central

Mistry, Abinash C.; Hanson, Lauren; Mallick, Rickta; Wynne, Brandi M.; Thai, Tiffany L.; Bailey, James L.; Klein, Janet D.; Hoover, Robert S.

2013-01-01

Hypertension is a leading cause of morbidity and mortality worldwide, and disordered sodium balance has long been implicated in its pathogenesis. Aldosterone is perhaps the key regulator of sodium balance and thus blood pressure. The sodium chloride cotransporter (NCC) in the distal convoluted tubule of the kidney is a major site of sodium reabsorption and plays a key role in blood pressure regulation. Chronic exposure to aldosterone increases NCC protein expression and function. However, more acute effects of aldosterone on NCC are unknown. In our salt-abundant modern society where chronic salt deprivation is rare, understanding the acute effects of aldosterone is critical. Here, we examined the acute effects (12–36 h) of aldosterone on NCC in the rodent kidney and in a mouse distal convoluted tubule cell line. Studies demonstrated that aldosterone acutely stimulated NCC activity and phosphorylation without affecting total NCC abundance or surface expression. This effect was dependent upon the presence of the mineralocorticoid receptor and serum- and glucocorticoid-regulated kinase 1 (SGK1). Furthermore, STE20/SPS-1-related proline/alanine-rich kinase (SPAK) phosphorylation also increased, and gene silencing of SPAK eliminated the effect of aldosterone on NCC activity. Aldosterone administration via a minipump in adrenalectomized rodents confirmed an increase in NCC phosphorylation without a change in NCC total protein. These data indicate that acute aldosterone-induced SPAK-dependent phosphorylation of NCC increases individual transporter activity. PMID:23739593

Contribution of aldosterone to cardiovascular and renal inflammation and fibrosis

PubMed Central

Brown, Nancy J.

2014-01-01

The steroid hormone aldosterone regulates sodium and potassium homeostasis. Aldosterone and activation of the mineralocorticoid receptor also causes inflammation and fibrosis of the heart, fibrosis and remodelling of blood vessels and tubulointerstitial fibrosis and glomerular injury in the kidney. Aldosterone and mineralocorticoid-receptor activation initiate an inflammatory response by increasing the generation of reactive oxygen species by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and mitochondria. High salt intake potentiates these effects, in part by activating the Rho family member Rac1, a regulatory subunit of reduced NADPH oxidase that activates the mineralocorticoid receptor. Studies in mice in which the mineralocorticoid receptor has been deleted from specific cell types suggest a key role for macrophages in promoting inflammation and fibrosis. Aldosterone can exert mineralocorticoid-receptor-independent effects via the angiotensin II receptor and via G-protein-coupled receptor 30. Mineralocorticoid-receptor antagonists are associated with decreased mortality in patients with heart disease and show promise in patients with kidney injury, but can elevate serum potassium concentration. Studies in rodents genetically deficient in aldosterone synthase or treated with a pharmacological aldosterone-synthase inhibitor are providing insight into the relative contribution of aldosterone compared with the contribution of mineralocorticoid-receptor activation in inflammation, fibrosis, and injury. Aldosterone-synthase inhibitors are under development in humans. PMID:23774812

The effect of metformin on the recurrence of colorectal adenoma in diabetic patients with previous colorectal adenoma.

PubMed

Han, Min Seok; Lee, Hyun Jung; Park, Soo Jung; Hong, Sung Pil; Cheon, Jae Hee; Kim, Won Ho; Kim, Tae Il

2017-08-01

Existing studies suggest that metformin lowers the risk and mortality of colorectal cancer. However, the effect of metformin on the suppression and prevention of colorectal adenomas is not clear. The aim of this study was to evaluate the effect of metformin on the recurrence of colorectal adenoma in diabetic patients with previous colorectal adenoma. Among 423 diabetic patients who underwent surveillance colonoscopy after resection of colorectal adenoma between 2005 and 2011, 257 patients were retrospectively reviewed. The patients were divided into two groups: one group comprising 106 patients who took metformin and another group comprising 151 patients who did not take metformin. The clinical characteristics, colorectal adenoma recurrence, and valuable factors for adenoma recurrence were analyzed. At surveillance colonoscopy after colonoscopic polypectomy for adenoma, 38 patients (35.8%) exhibited colorectal adenoma among 106 patients who took metformin, compared with 85 patients (56.3%) with colorectal adenoma among 151 patients who did not take metformin (odds ratio 0.434, 95% confidence interval 0.260-0.723, P = 0.001). Multivariate Cox analysis showed that metformin was associated with decreased recurrence of colorectal adenoma (hazard ratio 0.572, 95% confidence interval 0.385-0.852, P = 0.006) in diabetic patients with previous colorectal adenoma. The cumulative probability of colorectal adenoma recurrence was significantly lower in the metformin group than in the non-metformin group (P = 0.001). Metformin use in diabetic patients with previous colorectal adenoma is associated with a lower risk of colorectal adenoma recurrence.

Aldosterone Upregulates Transient Receptor Potential Melastatin 7 (TRPM7)*

PubMed Central

Valinsky, William C.; Jolly, Anna; Miquel, Perrine

2016-01-01

Transient receptor potential melastatin 7 (TRPM7) is a ubiquitously expressed Mg2+-permeable ion channel fused to a C-terminal α-kinase domain. Recently, aldosterone was shown to increase intracellular Mg2+ levels and alter inflammatory signaling in TRPM7-expressing HEK293 cells. This study was undertaken to assess whether these effects were related to an aldosterone-mediated increase of TRPM7 current and/or plasma membrane localization. Using HEK293 cells stably expressing WT-TRPM7, we found that 18-h application of aldosterone significantly increased TRPM7 current and TRPM7 plasma membrane protein expression by 48% and 34%, respectively. The aldosterone-mediated increase of TRPM7 current was inhibited by eplerenone, a mineralocorticoid receptor (MR) blocker, and GSK-650394, an inhibitor of the serum- and glucocorticoid-regulated kinase 1 (SGK1). SGK1 blockade also prevented the aldosterone-induced increase of TRPM7 plasma membrane protein. It was further determined that K1648R-TRPM7, the phosphotransferase-inactive TRPM7 mutant, was unresponsive to aldosterone. Therefore, chronic aldosterone treatment increases the plasma membrane expression of TRPM7, which is associated with an increase of TRPM7 current. This process occurs via an MR-dependent, genomic signaling cascade involving SGK1 and a functioning TRPM7 α-kinase domain. We suggest that this mechanism may be of general relevance when interpreting the effects of aldosterone because the MR receptor is found in multiple tissues, and TRPM7 and SGK1 are ubiquitously expressed. PMID:27466368

Aldosterone Upregulates Transient Receptor Potential Melastatin 7 (TRPM7).

PubMed

Valinsky, William C; Jolly, Anna; Miquel, Perrine; Touyz, Rhian M; Shrier, Alvin

2016-09-16

Transient receptor potential melastatin 7 (TRPM7) is a ubiquitously expressed Mg(2+)-permeable ion channel fused to a C-terminal α-kinase domain. Recently, aldosterone was shown to increase intracellular Mg(2+) levels and alter inflammatory signaling in TRPM7-expressing HEK293 cells. This study was undertaken to assess whether these effects were related to an aldosterone-mediated increase of TRPM7 current and/or plasma membrane localization. Using HEK293 cells stably expressing WT-TRPM7, we found that 18-h application of aldosterone significantly increased TRPM7 current and TRPM7 plasma membrane protein expression by 48% and 34%, respectively. The aldosterone-mediated increase of TRPM7 current was inhibited by eplerenone, a mineralocorticoid receptor (MR) blocker, and GSK-650394, an inhibitor of the serum- and glucocorticoid-regulated kinase 1 (SGK1). SGK1 blockade also prevented the aldosterone-induced increase of TRPM7 plasma membrane protein. It was further determined that K1648R-TRPM7, the phosphotransferase-inactive TRPM7 mutant, was unresponsive to aldosterone. Therefore, chronic aldosterone treatment increases the plasma membrane expression of TRPM7, which is associated with an increase of TRPM7 current. This process occurs via an MR-dependent, genomic signaling cascade involving SGK1 and a functioning TRPM7 α-kinase domain. We suggest that this mechanism may be of general relevance when interpreting the effects of aldosterone because the MR receptor is found in multiple tissues, and TRPM7 and SGK1 are ubiquitously expressed. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Double NF1 Inactivation Affects Adrenocortical Function in NF1Prx1 Mice and a Human Patient

PubMed Central

Kobus, Karolina; Hartl, Daniela; Ott, Claus Eric; Osswald, Monika; Huebner, Angela; von der Hagen, Maja; Emmerich, Denise; Kühnisch, Jirko; Morreau, Hans; Hes, Frederik J.; Mautner, Victor F.; Harder, Anja; Tinschert, Sigrid; Mundlos, Stefan; Kolanczyk, Mateusz

2015-01-01

Background Neurofibromatosis type I (NF1, MIM#162200) is a relatively frequent genetic condition, which predisposes to tumor formation. Apart from tumors, individuals with NF1 often exhibit endocrine abnormalities such as precocious puberty (2,5–5% of NF1 patients) and some cases of hypertension (16% of NF1 patients). Several cases of adrenal cortex adenomas have been described in NF1 individuals supporting the notion that neurofibromin might play a role in adrenal cortex homeostasis. However, no experimental data were available to prove this hypothesis. Materials and Methods We analysed Nf1Prx1 mice and one case of adrenal cortical hyperplasia in a NF1patient. Results In Nf1Prx1 mice Nf1 is inactivated in the developing limbs, head mesenchyme as well as in the adrenal gland cortex, but not the adrenal medulla or brain. We show that adrenal gland size is increased in NF1Prx1 mice. Nf1Prx1 female mice showed corticosterone and aldosterone overproduction. Molecular analysis of Nf1 deficient adrenals revealed deregulation of multiple proteins, including steroidogenic acute regulatory protein (StAR), a vital mitochondrial factor promoting transfer of cholesterol into steroid making mitochondria. This was associated with a marked upregulation of MAPK pathway and a female specific increase of cAMP concentration in murine adrenal lysates. Complementarily, we characterized a patient with neurofibromatosis type I with macronodular adrenal hyperplasia with ACTH-independent cortisol overproduction. Comparison of normal control tissue- and adrenal hyperplasia- derived genomic DNA revealed loss of heterozygosity (LOH) of the wild type NF1 allele, showing that biallelic NF1 gene inactivation occurred in the hyperplastic adrenal gland. Conclusions Our data suggest that biallelic loss of Nf1 induces autonomous adrenal hyper-activity. We conclude that Nf1 is involved in the regulation of adrenal cortex function in mice and humans. PMID:25775093

Enzyme-linked immunosorbent assays for determination of plasma aldosterone using highly specific polyclonal antibodies.

PubMed

Schwartz, F; Hadas, E; Harnik, M; Solomon, B

1990-01-01

Two enzyme-linked immunosorbent assays were established and compared for the estimation of plasma aldosterone. In the first method immobilized aldosterone-protein complexes on the ELISA plates compete with aldosterone to be determined for the binding of certain amount of anti-aldosterone antibodies. The sensitivity of this method depends on the protein carrier used to conjugate with aldosterone. In the second method, anti-aldosterone antibodies adsorbed on ELISA plates compete for binding of known amount of the enzyme-labeled aldosterone and aldosterone to be determined. The highly specific rabbit anti-aldosterone antibodies were obtained by injection of aldosterone-oxime thyroglobulin. The detection limit of aldosterone in both methods ranged between 2-20 pg. The proposed assays are suitable for the determination of aldosterone in biological fluids compared with other reported ELISA assays, as well as with RIA.

Adrenal Vein Sampling for Conn’s Syndrome: Diagnosis and Clinical Outcomes

PubMed Central

Deipolyi, Amy R.; Bailin, Alexander; Wicky, Stephan; Alansari, Shehab; Oklu, Rahmi

2015-01-01

Adrenal vein sampling (AVS) is the gold standard test to determine unilateral causes of primary aldosteronism (PA). We have retrospectively characterized our experience with AVS including concordance of AVS results and imaging, and describe the approach for the PA patient in whom bilateral AVS is unsuccessful. We reviewed the medical records of 85 patients with PA and compared patients who were treated medically and surgically on pre-procedure presentation and post-treatment outcomes, and evaluated how technically unsuccessful AVS results were used in further patient management. Out of the 92 AVS performed in 85 patients, AVS was technically successful bilaterally in 58 (63%) of cases. Either unsuccessful AVS prompted a repeat AVS, or results from the contralateral side and from CT imaging were used to guide further therapy. Patients who were managed surgically with adrenalectomy had higher initial blood pressure and lower potassium levels compared with patients who were managed medically. Adrenalectomy results in significantly decreased blood pressure and normalization of potassium levels. AVS can identify surgically curable causes of PA, but can be technically challenging. When one adrenal vein fails to be cannulated, results from the contralateral vein can be useful in conjunction with imaging and clinical findings to suggest further management. PMID:26854152

Prenatal diagnosis of Bartter syndrome: amniotic fluid aldosterone.

PubMed

Rachid, Myriam L; Dreux, Sophie; Pean de Ponfilly, Gauthier; Vargas-Poussou, Rosa; Czerkiewicz, Isabelle; Chevenne, Didier; Oury, Jean-François; Deschênes, Georges; Muller, Françoise

2016-01-01

Bartter syndrome is a severe inherited tubulopathy characterized by postnatal salt wasting, severe polyuria, dehydration, failure to thrive and secondary hyperaldosteronism. Prenatally, the disease is usually discovered following the onset of severe polyhydramnios in the second trimester. We studied amniotic fluid aldosterone concentration in Bartter syndrome and in controls. Amniotic fluid aldosterone was assayed by radioimmunoassay. We undertook a retrospective case-control study based on 36 cases of prenatally suspected and postnatally confirmed Bartter syndrome (22 with identified mutations): and 72 gestational age matched controls presenting with polyhydramnios and 72 without polyhydramnios. Amniotic fluid aldosterone was compared between the three groups. The median amniotic fluid aldosterone concentration in the Bartter syndrome group (90 pg/mL) was not different from that in the controls with polyhydramnios (90 pg/mL, P = 0.33) or without polyhydramnios (87 pg/mL, P = 0.41). Amniotic fluid aldosterone assay cannot be used for prenatal diagnosis of Bartter syndrome. © 2015 John Wiley & Sons, Ltd. © 2015 John Wiley & Sons, Ltd.

Vascular Consequences of Aldosterone Excess and Mineralocorticoid Receptor Antagonism.

PubMed

Chrissobolis, Sophocles

2017-01-01

Aldosterone binds to mineralocorticoid receptors (MRs) on renal epithelial cells to regulate sodium and water reabsorption, and therefore blood pressure. Recently, the actions of aldosterone outside the kidney have been extensively investigated, with numerous reports of aldosterone having detrimental actions, including in the vasculature. Notably, elevated aldosterone levels are an independent cardiovascular risk factor, and in addition to causing an increase in blood pressure, aldosterone can have blood pressure-dependent and -independent effects commonly manifested in the vasculature in cardiovascular diseases, including oxidative stress, endothelial dysfunction, inflammation, remodeling, stiffening, and plaque formation. Receptor-dependent mechanisms mediating these actions include the MR expressed on vascular endothelial and smooth muscle cells, but also include the angiotensin II type 1 receptor, epidermal growth factor receptor and vascular endothelial growth factor receptor 1, with downstream mechanisms including NADPH oxidase, cyclooxygenase, glucose-6-phosphate dehydrogenase, poly-(ADP ribose) polymerase and placental growth factor. The beneficial actions of MR antagonism in experimental hypertension include improved endothelial function, reduced hypertrophy and remodeling, and in atherosclerosis beneficial actions include reduced plaque area, inflammation, oxidative stress and endothelial dysfunction. Aldosterone excess is detrimental and MR antagonism is beneficial in humans also. The emerging concept of the contribution of aldosterone/MR-induced immunity to vascular pathology will also be discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Resistant hypertension and aldosterone: an update.

PubMed

Clark, Donald; Ahmed, Mustafa I; Calhoun, David A

2012-05-01

Resistant hypertension (RHTN) is defined as a blood pressure remaining above goal despite the concurrent use of 3 antihypertensive medications of different classes, including, ideally a diuretic. RHTN is an important health problem with a prevalence rate expected to increase as populations become older, more obese, and at higher risk of having diabetes and chronic kidney disease, all of which are important risk factors for development of RHTN. The role of aldosterone has gained increasing recognition as a significant contributor to antihypertensive treatment resistance. In prospective studies, the prevalence of primary aldosteronism (PA) has ranged from 14%-21% in patients with RHTN, which is considerably higher than in the general hypertensive population. Furthermore, marked antihypertensive effects are seen when mineralocorticoid antagonists are added to the treatment regimen of patients with RHTN, further supporting aldosterone excess as an important cause of RHTN. A close association exists between hyperaldosteronism, RHTN, and obstructive sleep apnea (OSA) based upon recent studies which indicate that OSA is worsened by aldosterone-mediated fluid retention. This interaction is supported by preliminary data which demonstrates improvement in OSA severity after treatment with spironolactone. Copyright © 2012 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

Aldosterone mediates its rapid effects in vascular endothelial cells through GPER activation.

PubMed

Gros, Robert; Ding, Qingming; Liu, Bonan; Chorazyczewski, Jozef; Feldman, Ross D

2013-03-01

The importance of the rapid vascular effects of aldosterone is increasingly appreciated. Through these rapid pathways, aldosterone has been shown to regulate vascular contractility, cell growth, and apoptosis. In our most recent studies, we demonstrated the effects of aldosterone on cell growth and contractility in vascular smooth muscle cells. We showed that these effects could occur via activation of the classic mineralocorticoid receptor, as well the recently characterized G protein-coupled estrogen receptor (GPER), initially characterized as an estrogen-specific receptor. However, the mechanisms underlying aldosterone's endothelium-dependent actions are unknown. Furthermore, the ERK regulatory and proapoptotic effects of aldosterone mediated by GPER activation in cultured vascular smooth muscle cells were only apparent when GPER was reintroduced into these cells by gene transfer. Whether GPER activation via aldosterone might be an important regulator in native vascular cells has been questioned. Therefore, to determine the role of GPER in mediating aldosterone's effects on cell growth and vascular reactivity in native cells, we examined rat aortic vascular endothelial cells, a model characterized by persistent robust expression of GPER, but without detectable mineralocorticoid receptor expression. In these endothelial cells, the GPER agonist G1 mediates a rapid increase in ERK phosphorylation that is wholly GPER-dependent, paralleling the actions of aldosterone. The effects of G1 and aldosterone to stimulate ERK phosphorylation paralleled their proapoptotic and antiproliferative effects. In previous studies, we reported that aldosterone mediates a rapid endothelium-dependent vasodilatory effect, antagonistic to its direct vasoconstrictor effect in endothelium-denuded preparations. Using a rat aortic ring/organ bath preparation to determine the GPER dependence of aldosterone's endothelium-dependent vasodilator effects, we demonstrate that aldosterone inhibits

Aldosterone, Cognitive Function, and Cerebral Hemodynamics in Hypertension and Antihypertensive Therapy

PubMed Central

Hart, Meaghan; Mack, Wendy; Lipsitz, Lewis A.

2015-01-01

BACKGROUND Animal studies suggest that the renin–angiotensin–aldosterone system is involved in neurocognitive function and the response to antihypertensive therapy. We investigated the impact of circulating aldosterone and renin activity on cognition and cerebral hemodynamics at baseline and after antihypertensive therapy for 1 year. METHODS Participants were older adults (n = 47; mean age = 71 years) enrolled in a clinical trial. Routine antihypertensive medications were replaced with the study regimen to achieve a blood pressure <140/90mm Hg. Executive function, memory, cerebral hemodynamics (blood flow velocity), CO2 vasoreactivity (measured using transcranial Doppler ultrasonography), plasma renin activity, and aldosterone were measured at baseline and at 6 and 12 months after the initiation of treatment. RESULTS At baseline, higher levels of circulating aldosterone were associated with lower blood flow velocity (β = −0.02; P = 0.03), lower CO2 vasoreactivity (β = −0.11; P = 0.007), and decreased autoregulation abilities (β = −0.09; P = 0.01). Those with higher levels of aldosterone at baseline demonstrated the greatest improvement in executive function (P = 0.014 for the aldosterone effect) and in CO2 vasoreactivity (P = 0.026 for the aldosterone effect) after 12 months of lowering blood pressure (<140/90mm Hg). Plasma renin activity was not associated with any of the measures. CONCLUSIONS Higher levels of aldosterone may be associated with decreased cerebrovascular function in hypertension. Those with higher aldosterone levels may benefit the most from lowering blood pressure. The role of aldosterone in brain health warrants further investigation in a larger trial. PMID:25213687

SFE/SFHTA/AFCE consensus on primary aldosteronism, part 5: Genetic diagnosis of primary aldosteronism.

PubMed

Zennaro, Maria-Christina; Jeunemaitre, Xavier

2016-07-01

While the majority of cases of primary aldosteronism (PA) are sporadic, four forms of autosomal-dominant inheritance have been described: familial hyperaldosteronism (FH) types I to IV. FH-I, also called glucocorticoid-remediable aldosteronism, is characterized by early and severe hypertension, usually before the age of 20 years. It is due to the formation of a chimeric gene between the adjacent CYP11B2 and CYP11B1 genes (coding for aldosterone synthase and 11β-hydroxylase, respectively). FH-I is often associated with family history of stroke before 40years of age. FH-II is clinically and biochemically indistinguishable from sporadic forms of PA and is only diagnosed on the basis of two or more affected family members. No causal genes have been identified so far and no genetic test is available. FH-III is characterized by severe and early-onset hypertension in children and young adults, resistant to treatment and associated with severe hypokalemia. Mild forms, resembling FH-II, have been described. FH-III is due to gain-of-function mutations in the KCNJ5 gene. Recently, a new autosomal-dominant form of familial PA, FH-IV, associated with mutations in the CACNA1H gene, was described in patients with hypertension and PA before the age of 10years. In rare cases, PA may be associated with complex neurologic disorder involving epileptic seizures and cerebral palsy (Primary Aldosteronism, Seizures, and Neurologic Abnormalities [PASNA]) due to de novo germline CACNA1D mutations. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Aldosterone and mortality in hemodialysis patients: role of volume overload.

PubMed

Hung, Szu-Chun; Lin, Yao-Ping; Huang, Hsin-Lei; Pu, Hsiao-Fung; Tarng, Der-Cherng

2013-01-01

Elevated aldosterone is associated with increased mortality in the general population. In patients on dialysis, however, the association is reversed. This paradox may be explained by volume overload, which is associated with lower aldosterone and higher mortality. We evaluated the relationship between aldosterone and outcomes in a prospective cohort of 328 hemodialysis patients stratified by the presence or absence of volume overload (defined as extracellular water/total body water >48%, as measured with bioimpedance). Baseline plasma aldosterone was measured before dialysis and categorized as low (<140 pg/mL), middle (140 to 280 pg/mL) and high (>280 pg/mL). Overall, 36% (n = 119) of the hemodialysis patients had evidence of volume overload. Baseline aldosterone was significantly lower in the presence of volume overload than in its absence. During a median follow-up of 54 months, 83 deaths and 70 cardiovascular events occurred. Cox multivariate analysis showed that by using the low aldosterone as the reference, high aldosterone was inversely associated with decreased hazard ratios for mortality (0.49; 95% confidence interval, 0.25-0.76) and first cardiovascular event (0.70; 95% confidence interval, 0.33-0.78) in the presence of volume overload. In contrast, high aldosterone was associated with an increased risk for mortality (1.97; 95% confidence interval, 1.69-3.75) and first cardiovascular event (2.01; 95% confidence interval, 1.28-4.15) in the absence of volume overload. The inverse association of aldosterone with adverse outcomes in hemodialysis patients is due to the confounding effect of volume overload. These findings support treatment of hyperaldosteronemia in hemodialysis patients who have achieved strict volume control.

Aldosterone induces a vascular inflammatory phenotype in the rat heart.

PubMed

Rocha, Ricardo; Rudolph, Amy E; Frierdich, Gregory E; Nachowiak, Denise A; Kekec, Beverly K; Blomme, Eric A G; McMahon, Ellen G; Delyani, John A

2002-11-01

Vascular inflammation was examined as a potential mechanism of aldosterone-mediated myocardial injury in uninephrectomized rats receiving 1% NaCl-0.3% KCl to drink for 1, 2, or 4 wk and 1) vehicle, 2) aldosterone infusion (0.75 microg/h), or 3) aldosterone infusion (0.75 microg/h) plus the selective aldosterone blocker eplerenone (100 mg. kg(-1). day(-1)). Aldosterone induced severe hypertension at 4 wk [systolic blood pressure (SBP), 210 +/- 3 mmHg vs. vehicle, 131 +/- 2 mmHg, P < 0.001], which was partially attenuated by eplerenone (SBP, 180 +/- 7 mmHg; P < 0.001 vs. aldosterone alone and vehicle). No significant increases in myocardial interstitial collagen fraction or hydroxyproline concentration were detected throughout the study. However, histopathological analysis of the heart revealed severe coronary inflammatory lesions, which were characterized by monocyte/macrophage infiltration and resulted in focal ischemic and necrotic changes. The histological evidence of coronary lesions was preceded by and associated with the elevation of cyclooxygenase-2 (up to approximately 4-fold), macrophage chemoattractant protein-1 (up to approximately 4-fold), and osteopontin (up to approximately 13-fold) mRNA expression. Eplerenone attenuated proinflammatory molecule expression in the rat heart and subsequent vascular and myocardial damage. Thus aldosterone and salt treatment in uninephrectomized rats led to severe hypertension and the development of a vascular inflammatory phenotype in the heart, which may represent one mechanism by which aldosterone contributes to myocardial disease.

[Monosymptomatic hyperthyroidism and TSH-producing adenoma: successful therapy with octreotide].

PubMed

Mayinger, B; Axelos, D; Pavel, M; Hahn, E G; Hensen, J

1999-01-29

Magnetic resonance imaging (MRI) of the central nervous system was performed on a 72-year-old woman who was hyperthyroid without suppression of the thyroid-stimulating hormone (TSH) and had complained of a recent onset of headaches. MRI demonstrated a space-occupying lesion, 1 cm in diameter, in the anterior pituitary. The clinical symptoms were marked by a long-standing monosymptomatic illness of rapidly changing mood swings with depressive and manic phases. Endocrinological-biochemical tests showed hyperthyroidism (fT3 10.55 pmol/l and fT4 39 pmol/l) but no TSH suppression (TSH: 2.9 microU/ml). Octreotide scintigraphy documented an activity-rich area in the anterior pituitary and the upper anterior mediastinum. Mediastinal MRI revealed a 5 cm space-occupying mass lying on the right atrium. 131I scintigraphy identified the mass as a retrosternal goitre. As an operation on the anterior pituitary would have carried a high risk for the patient who was in a poor general condition and she had refused to be operated, treatment with octreotide, a long-acting somatostatin analogue, was initiated. This achieved a euthyroid state with partly suppressed TSH, and the patient's emotional swings ceased. If hyperthyroidism coexists with non-suppressed TSH levels, a TSH-producing hypophyseal adenoma should be considered in the differential diagnosis despite its rarity. Octreotide administration is an effective and safe treatment and is the method of choice, especially when there are contraindications to surgical resection of the anterior pituitary.

Aldosterone, cognitive function, and cerebral hemodynamics in hypertension and antihypertensive therapy.

PubMed

Hajjar, Ihab; Hart, Meaghan; Mack, Wendy; Lipsitz, Lewis A

2015-03-01

Animal studies suggest that the renin-angiotensin-aldosterone system is involved in neurocognitive function and the response to antihypertensive therapy. We investigated the impact of circulating aldosterone and renin activity on cognition and cerebral hemodynamics at baseline and after antihypertensive therapy for 1 year. Participants were older adults (n = 47; mean age = 71 years) enrolled in a clinical trial. Routine antihypertensive medications were replaced with the study regimen to achieve a blood pressure <140/90 mm Hg. Executive function, memory, cerebral hemodynamics (blood flow velocity), CO2 vasoreactivity (measured using transcranial Doppler ultrasonography), plasma renin activity, and aldosterone were measured at baseline and at 6 and 12 months after the initiation of treatment. At baseline, higher levels of circulating aldosterone were associated with lower blood flow velocity (β = -0.02; P = 0.03), lower CO2 vasoreactivity (β = -0.11; P = 0.007), and decreased autoregulation abilities (β = -0.09; P = 0.01). Those with higher levels of aldosterone at baseline demonstrated the greatest improvement in executive function (P = 0.014 for the aldosterone effect) and in CO2 vasoreactivity (P = 0.026 for the aldosterone effect) after 12 months of lowering blood pressure (<140/90 mm Hg). Plasma renin activity was not associated with any of the measures. Higher levels of aldosterone may be associated with decreased cerebrovascular function in hypertension. Those with higher aldosterone levels may benefit the most from lowering blood pressure. The role of aldosterone in brain health warrants further investigation in a larger trial. © American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Analysis of postoperative biochemical values and clinical outcomes after adrenalectomy for primary aldosteronism.

PubMed

Swearingen, Andrew J; Kahramangil, Bora; Monteiro, Rosebel; Krishnamurthy, Vikram; Jin, Judy; Shin, Joyce; Siperstein, Allan; Berber, Eren

2018-04-01

Primary aldosteronism causes hypertension and hypokalemia and is often surgically treatable. Diagnosis includes elevated plasma aldosterone, suppressed plasma renin activity, and elevated aldosterone renin ratio. Adrenalectomy improves hypertension and hypokalemia. Postoperative plasma aldosterone and plasma renin activity may be useful in documenting cure or failure. A retrospective analysis of patients who underwent adrenalectomy for primary aldosteronism from 2010 to 2016 was performed, analyzing preoperative and postoperative plasma aldosterone, plasma renin activity, hypertension, and hypokalemia. The utility of postoperative testing was assessed. Clinical cure was defined as improved hypertension control and resolution of potassium loss. Biochemical cure was defined as aldosterone renin ratio reduction to <23.6. Forty-four patients were included; 20 had plasma aldosterone and plasma renin activity checked on postoperative day 1. In the study, 40/44 (91%) were clinically cured. All clinical failures had of biochemical failure at follow-up. Postoperative day 1aldosterone renin ratio <23.6 had PPV of 95% for clinical cure. Cured patients had mean plasma aldosterone drop of 33.1 ng/dL on postoperative day 1; noncured patient experienced 3.9 ng/dL increase. A cutoff of plasma aldosterone decrease of 10 ng/dL had high positive predictive value for clinical cure. Changes in plasma aldosterone and plasma renin activity after adrenalectomy correlate with improved hypertension and hypokalemia. The biochemical impact of adrenalectomy manifests as early as postoperative day 1. We propose a plasma aldosterone decrease of 10 ng/dL as a criterion to predict clinical cure. Copyright © 2017 Elsevier Inc. All rights reserved.

The Spectrum of Subclinical Primary Aldosteronism and Incident Hypertension: A Cohort Study

PubMed Central

Brown, Jenifer M.; Robinson-Cohen, Cassianne; Fernandez, Miguel Angel Luque; Allison, Matthew A.; Baudrand, Rene; Ix, Joachim H.; Kestenbaum, Bryan; de Boer, Ian H.; Vaidya, Anand

2018-01-01

Background Primary aldosteronism is recognized as a severe form of “renin-independent aldosteronism” that results in excessive mineralocorticoid receptor (MR) activation. Objective To investigate whether there is a spectrum of subclinical renin-independent aldosteronism among normotensives that increases risk for hypertension. Design Cohort study. Setting National community-based study. Participants 850 untreated normotensive participants in the Multi-Ethnic Study of Atherosclerosis with measurements of serum aldosterone, plasma renin activity (PRA). Measurements Longitudinal analyses investigated whether aldosterone concentrations, in the context of physiologic PRA phenotypes (suppressed: ≤0.50; indeterminate: 0.51–0.99; unsuppressed: ≥1.0 μg/L/h), associated with incident hypertension, defined as SBP≥140, DBP≥90 mmHg, or initiation of anti-hypertensive medications. Cross-sectional analyses investigated associations of aldosterone with MR activity, assessed via serum potassium and urinary fractional excretion of potassium. Results A suppressed renin phenotype was associated with a higher rate of incident hypertension when compared to other PRA phenotypes (85.4 [73.4, 99.3] vs. 53.3 [42.8, 66.4] vs. 54.5 [41.8, 71.0] cases per 1000 person-years of follow-up). With renin suppression, higher aldosterone concentrations were independently associated with an increased risk for incident hypertension; whereas no association between aldosterone and hypertension was observed when renin was not suppressed. Higher aldosterone concentrations were associated with lower serum potassium and higher urinary excretion of potassium, but only when renin was suppressed. Limitations Measurements of sodium and potassium occurred several years before renin and aldosterone. Conclusions Suppression of renin, and higher aldosterone concentrations in the context of this renin suppression, associated with an increased risk for developing hypertension and possibly also with

[Primary hyperaldosteronism: problems of diagnostic approaches].

PubMed

Widimský, Jiří

2015-05-01

Primary hyperaldosteronism (PH) is common cause of endocrine/secondary hypertension with autonomous aldosterone overproduction by adrenal cortex. PH is typically characterized by hypertension, hypokalemia, high plasma aldosterone/renin ratio, high aldosterone, suppressed renin and nonsupressibilty of aldosterone during confirmatory tests. Diagnosis of PH can be difficult since hypokalemia is found only in 50 % of cases and measurement of the parameters of renin-angiotensin-aldosterone system can be influenced by several factors. Morphological dia-gnosis requires in majority of cases adrenal venous sampling. Early diagnostic and therapeutic measures are very important due to high prevalence of PH and potential cure. Patients with suspicion to PH should be investigated in experienced hypertensive centers due to relatively difficult laboratory and morphological diagnostic approaches.

Hypertension: renin-angiotensin-aldosterone system alterations.

PubMed

Te Riet, Luuk; van Esch, Joep H M; Roks, Anton J M; van den Meiracker, Anton H; Danser, A H Jan

2015-03-13

Blockers of the renin-angiotensin-aldosterone system (RAAS), that is, renin inhibitors, angiotensin (Ang)-converting enzyme (ACE) inhibitors, Ang II type 1 receptor antagonists, and mineralocorticoid receptor antagonists, are a cornerstone in the treatment of hypertension. How exactly they exert their effect, in particular in patients with low circulating RAAS activity, also taking into consideration the so-called Ang II/aldosterone escape that often occurs after initial blockade, is still incompletely understood. Multiple studies have tried to find parameters that predict the response to RAAS blockade, allowing a personalized treatment approach. Consequently, the question should now be answered on what basis (eg, sex, ethnicity, age, salt intake, baseline renin, ACE or aldosterone, and genetic variance) a RAAS blocker can be chosen to treat an individual patient. Are all blockers equal? Does optimal blockade imply maximum RAAS blockade, for example, by combining ≥2 RAAS blockers or by simply increasing the dose of 1 blocker? Exciting recent investigations reveal a range of unanticipated extrarenal effects of aldosterone, as well as a detailed insight in the genetic causes of primary aldosteronism, and mineralocorticoid receptor blockers have now become an important treatment option for resistant hypertension. Finally, apart from the deleterious ACE-Ang II-Ang II type 1 receptor arm, animal studies support the existence of protective aminopeptidase A-Ang III-Ang II type 2 receptor and ACE2-Ang-(1 to 7)-Mas receptor arms, paving the way for multiple new treatment options. This review provides an update about all these aspects, critically discussing the many controversies and allowing the reader to obtain a full understanding of what we currently know about RAAS alterations in hypertension. © 2015 American Heart Association, Inc.

Dietary sodium modulation of aldosterone activation and renal function during the progression of experimental heart failure.

PubMed

Miller, Wayne L; Borgeson, Daniel D; Grantham, J Aaron; Luchner, Andreas; Redfield, Margaret M; Burnett, John C

2015-02-01

Aldosterone activation is central to the sodium–fluid retention that marks the progression of heart failure (HF). The actions of dietary sodium restriction, a mainstay in HF management, on cardiorenal and neuroendocrine adaptations during the progression of HF are poorly understood. The study aim was to assess the role of dietary sodium during the progression of experimental HF. Experimental HF was produced in a canine model by rapid right ventricular pacing which evolves from early mild HF to overt, severe HF. Dogs were fed one of three diets: (i) high sodium [250 mEq (5.8 g) per day, n =6]; (ii) standard sodium [58 mEq (1.3 g) per day, n =6]; and (iii) sodium restriction [11 mEq (0.25 g) per day, n =6]. During the 38-day study, haemodynamics, renal function, plasma renin activity (PRA), and aldosterone were measured. Changes in haemodynamics at 38 days were similar in all three groups, as were changes in renal function. Aldosterone activation was demonstrated in all three groups; however, dietary sodium restriction, in contrast to high sodium, resulted in early (10 days) activation of PRA and aldosterone. High sodium demonstrated significant suppression of aldosterone activation over the course of HF progression. Excessive dietary sodium restriction particularly in early stage HF results in early aldosterone activation, while normal and excess sodium intake are associated with delayed or suppressed activation. These findings warrant evaluation in humans to determine if dietary sodium manipulation, particularly during early stage HF, may have a significant impact on neuroendocrine disease progression.

The effect of a low potassium diet on the glomerular zone of the adrenal cortex of rats.

PubMed

Kawai, K; Sugihara, H; Tsuchiyama, H

1979-05-01

Rats were fed on low potassium diets in order to observe the effect of dietary low potassium on the adrenal cortex. The authors clarified morphological changes of the hypofunctional glomerular zone and compared these changes with those of the hyperfunctional glomerular zone. Three weeks after or 2 months after the start of a low potassium diet, slight narrowing of the glomerular zone of the adrenal cortex was observed followed by miniaturization of cells, presence of binuclear cells and an increase of lipid with enlarged lipid drops. Electron microscope mainly disclosed changes of mitochondrial cristae consisting of markedly reduced, enlarged and irregularly dilated cristae with shortening or elongation. Granules appeared in mitochondria. Lysosomes or dense bodies were enlarged. The Golgi's apparatus was atrophied but endoplasmic reticulum did not show remarkable changes. These changes were directly opposite to those of the hyperfunctional glomerular zone noted after a pottasium load or seen in sodium deficiency. Consequently, these changes were considered to be the changes of the hypofunctional glomerular zone associated with decrease of aldosterone production.

21 CFR 862.1665 - Sodium test system.

Code of Federal Regulations, 2010 CFR

2010-04-01

... of aldosteronism (excessive secretion of the hormone aldosterone), diabetes insipidus (chronic... disease (caused by destruction of the adrenal glands), dehydration, inappropriate antidiuretic hormone...

21 CFR 862.1665 - Sodium test system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... of aldosteronism (excessive secretion of the hormone aldosterone), diabetes insipidus (chronic... disease (caused by destruction of the adrenal glands), dehydration, inappropriate antidiuretic hormone...

Interleukin-33/ST2 system attenuates aldosterone-induced adipogenesis and inflammation.

PubMed

Martínez-Martínez, Ernesto; Cachofeiro, Victoria; Rousseau, Elodie; Álvarez, Virginia; Calvier, Laurent; Fernández-Celis, Amaya; Leroy, Céline; Miana, María; Jurado-López, Raquel; Briones, Ana M; Jaisser, Frederic; Zannad, Faiez; Rossignol, Patrick; López-Andrés, Natalia

2015-08-15

Interleukin-33 (IL-33) but not soluble ST2 (sST2) exerts anti-inflammatory and protective effects in several tissues. Aldosterone, a proinflammatory mediator which promotes adipogenesis, is elevated in obese patients. The aim of this study was to investigate the interactions between IL-33/ST2 system and Aldosterone in adipose tissue. Rats fed a high fat diet presented increased sST2 expression, diminished IL-33/sST2 ratio and enhanced levels of differentiation and inflammation in adipose tissue as compared to controls. A similar pattern was observed in adipose tissue from C57BL/6 Aldosterone-treated mice. In both animal models, Aldosterone was correlated with sST2. Treatment of 3T3-L1 adipocytes with IL-33 delayed adipocyte differentiation diminished lipid accumulation and decreased inflammation. Aldosterone decreased IL-33 and increased sST2 expressions in differentiated adipocytes. Aldosterone-induced adipocyte differentiation and inflammation were blocked by IL-33 treatment, but sST2 did not exert any effects. The crosstalk between IL-33/ST2 and Aldosterone could be relevant in the metabolic consequences of obesity. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Mechanisms of connecting tubule glomerular feedback enhancement by aldosterone

PubMed Central

Ren, YiLin; Janic, Branislava; Kutskill, Kristopher; Peterson, Edward L.

2016-01-01

Connecting tubule glomerular feedback (CTGF) is a mechanism where an increase in sodium (Na) concentration in the connecting tubule (CNT) causes the afferent arteriole (Af-Art) to dilate. We recently reported that aldosterone within the CNT lumen enhances CTGF via a nongenomic effect involving GPR30 receptors and sodium/hydrogen exchanger (NHE), but the signaling pathways of this mechanism are unknown. We hypothesize that aldosterone enhances CTGF via cAMP/protein kinase A (PKA) pathway that activates protein kinase C (PKC) and stimulates superoxide (O2−) production. Rabbit Af-Arts and their adherent CNTs were microdissected and simultaneously perfused. Two consecutive CTGF curves were elicited by increasing the CNT luminal NaCl. We found that the main effect of aldosterone was to sensitize CTGF and we analyzed data by comparing NaCl concentration in the CNT perfusate needed to achieve half of the maximal response (EC50). During the control period, the NaCl concentration that elicited a half-maximal response (EC50) was 37.0 ± 2.0 mmol/l; addition of aldosterone (10−8 mol/l) to the CNT lumen decreased EC50 to 19.3 ± 1.3 mmol/l (P ≤ 0.001 vs. Control). The specific adenylyl cyclase inhibitor 2′,3′-dideoxyadenosine (ddA; 2 × 10−4 mol/l) and the PKA inhibitor H-89 dihydrochloride hydrate (H-89; 2 × 10−6 mol/l) prevented the aldosterone effect. The selective PKC inhibitor GF109203X (10−8 mol/l) also prevented EC50 reduction caused by aldosterone. CNT intraluminal addition of O2− scavenger tempol (10−4 mol/l) blocked the aldosterone effect. We conclude that aldosterone inside the CNT lumen enhances CTGF via a cAMP/PKA/PKC pathway and stimulates O2− generation and this process may contribute to renal damage by increasing glomerular capillary pressure. PMID:27413197

Endoscopic management of colorectal adenomas.

PubMed

Meier, Benjamin; Caca, Karel; Fischer, Andreas; Schmidt, Arthur

2017-01-01

Colorectal adenomas are well known precursors of invasive adenocarcinoma. Colonoscopy is the gold standard for adenoma detection. Colonoscopy is far more than a diagnostic tool, as it allows effective treatment of colorectal adenomas. Endoscopic resection of colorectal adenomas has been shown to reduce the incidence and mortality of colorectal cancer. Difficult resection techniques are available, such as endoscopic mucosal resection, endoscopic submucosal dissection and endoscopic full-thickness resection. This review aims to provide an overview of the different endoscopic resection techniques and their indications, and summarizes the current recommendations in the recently published guideline of the European Society of Gastrointestinal Endoscopy.

Endoscopic management of colorectal adenomas

PubMed Central

Meier, Benjamin; Caca, Karel; Fischer, Andreas; Schmidt, Arthur

2017-01-01

Colorectal adenomas are well known precursors of invasive adenocarcinoma. Colonoscopy is the gold standard for adenoma detection. Colonoscopy is far more than a diagnostic tool, as it allows effective treatment of colorectal adenomas. Endoscopic resection of colorectal adenomas has been shown to reduce the incidence and mortality of colorectal cancer. Difficult resection techniques are available, such as endoscopic mucosal resection, endoscopic submucosal dissection and endoscopic full-thickness resection. This review aims to provide an overview of the different endoscopic resection techniques and their indications, and summarizes the current recommendations in the recently published guideline of the European Society of Gastrointestinal Endoscopy. PMID:29118553

Aldosterone dysregulation with aging predicts renal vascular function and cardiovascular risk.

PubMed

Brown, Jenifer M; Underwood, Patricia C; Ferri, Claudio; Hopkins, Paul N; Williams, Gordon H; Adler, Gail K; Vaidya, Anand

2014-06-01

Aging and abnormal aldosterone regulation are both associated with vascular disease. We hypothesized that aldosterone dysregulation influences the age-related risk of renal vascular and cardiovascular disease. We conducted an analysis of 562 subjects who underwent detailed investigations under conditions of liberal and restricted dietary sodium intake (1124 visits) in the General Clinical Research Center. Aldosterone regulation was characterized by the ratio of maximal suppression to stimulation (supine serum aldosterone on a liberal sodium diet divided by the same measure on a restricted sodium diet). We previously demonstrated that higher levels of this Sodium-modulated Aldosterone Suppression-Stimulation Index (SASSI) indicate greater aldosterone dysregulation. Renal plasma flow (RPF) was determined via p-aminohippurate clearance to assess basal renal hemodynamics and the renal vascular responses to dietary sodium manipulation and angiotensin II infusion. Cardiovascular risk was calculated using the Framingham Risk Score. In univariate linear regression, older age (β=-4.60; P<0.0001) and higher SASSI (β=-58.63; P=0.001) predicted lower RPF and a blunted RPF response to sodium loading and angiotensin II infusion. We observed a continuous, independent, multivariate-adjusted interaction between age and SASSI, where the inverse relationship between SASSI and RPF was most apparent with older age (P<0.05). Higher SASSI and lower RPF independently predicted higher Framingham Risk Score (P<0.0001) and together displayed an additive effect. Aldosterone regulation and age may interact to mediate renal vascular disease. Our findings suggest that the combination of aldosterone dysregulation and renal vascular dysfunction could additively increase the risk of future cardiovascular outcomes; therefore, aldosterone dysregulation may represent a modifiable mechanism of age-related vascular disease.

Aldosterone-Signaling Defect Exacerbates Sodium Wasting in Very Preterm Neonates: The Premaldo Study.

PubMed

Martinerie, Laetitia; Pussard, Eric; Yousef, Nadya; Cosson, Claudine; Lema, Ingrid; Husseini, Khaled; Mur, Sébastien; Lombès, Marc; Boileau, Pascal

2015-11-01

The neonatal period, notably in preterm infants, is characterized by high sodium wasting, implying that aldosterone, the main hormone regulating sodium reabsorption, is unable to maintain sodium homeostasis. This study sought to assess aldosterone secretion and action in neonates according to gestational age (GA). This was a multicenter prospective study (NCT01176162) conducted between 2011 and 2014 at five neonatology departments in France. Infants were followed during their first 3 months. The 155 newborns included were classified into three groups: Group 1 (n = 46 patients), <33 gestational weeks (GW); Group 2 (n = 67 patients), 33-36 GW; and Group 3 (n = 42 patients), ≥37 GW. Plasma aldosterone was measured in umbilical cord blood. Urinary aldosterone (UAldo) was assessed at day 0, day 3, month 1, and month 3 postnatal. The correlation between UAldo and the urinary Na/K ratio was determined as an index of renal aldosterone sensitivity. UAldo significantly increased with GA: from 8.8 ± 7.5 μg/mmol of creatinine (Group 1) to 21.1 ± 21.0 (Group 3) in correlation with plasma aldosterone levels in all groups (P < .001), demonstrating its reliability. The aldosterone/renin ratio significantly increased with GA, suggesting an aldosterone secretion defect in preterm infants. UAldo and urinary Na/K were correlated in very preterm but not in term neonates, consistent with very preterm neonates being renal-aldosterone sensitive and term neonates being aldosterone resistant. Very preterm infants have a previously unrecognized defective aldosterone secretion but conserved renal aldosterone sensitivity in the neonatal period, which modifies the current view of sodium balance in these infants and suggests alternative management approaches.

Evaluation of effects of an oral contraceptive containing ethinylestradiol combined with drospirenone on adrenal steroidogenesis in hyperandrogenic women with polycystic ovary syndrome.

PubMed

De Leo, Vincenzo; Morgante, Giuseppe; Piomboni, Paola; Musacchio, Maria Concetta; Petraglia, Felice; Cianci, Antonio

2007-07-01

To investigate whether the administration of an oral contraceptive containing the new antiandrogenic drospirenone is associated with reduced adrenal androgen synthesis in hyperandrogenic women with diagnosis of polycystic ovary syndrome. Drospirenone, an analogue of spironolactone and aldosterone antagonist, is a novel progestin under clinical development that is similar to the natural hormone progesterone, combining potent progestogenic with antimineralocorticoid and antiandrogenic activities. Prospective study. Healthy volunteers in University Department of Obstetrics and Gynecology. Fifteen women ages 18 to 28 years with the diagnosis of polycystic ovary syndrome. Three months of contraceptive use (30 mcg ethinylestradiol, 3 mg drospirenone). An adrenocorticotropic hormone test was performed before and after the study. Adrenal production of cortisol was unchanged after therapy with oral contraceptives. An interesting observation was reduced basal concentrations of androgens such as androstenedione, dehydroepiandrosterone sulfate, testosterone, and free testosterone during therapy. The ratios of the areas of substrates to products before and after oral contraceptive administration were compared for differences in 17alpha-hydroxylase (17-hydroxyprogesterone/progesterone) and 17,20-lyase (androstenedione/17-hydroxyprogesterone); activities were significantly reduced, indicating a reduction in the activities of these enzymes. The present results show for the first time that oral contraceptives containing drospirenone affect adrenal steroidogenesis by reducing synthesis and release of androgens in response to adrenocorticotropic hormone, leaving adrenal production of cortisol unchanged.

Reversal of cycloheximide-induced memory disruption by AIT-082 (Neotrofin) is modulated by, but not dependent on, adrenal hormones.

PubMed

Yan, Rongzi; Nguyen, Quang; Gonzaga, James; Johnson, Mai; Ritzmann, Ronald F; Taylor, Eve M

2003-04-01

AIT-082 (Neotrofin), a hypoxanthine derivative, has been shown to improve memory in both animals and humans. In animals, adrenal hormones modulate the efficacy of many memory-enhancing compounds, including piracetam and tacrine (Cognex). To investigate the role of adrenal hormones in the memory-enhancing action of AIT-082. Plasma levels of adrenal hormones (corticosterone and aldosterone) in mice were significantly reduced by surgical or chemical (aminoglutethimide) adrenalectomy or significantly elevated by oral administration of corticosterone. The effects of these hormone level manipulations on the memory-enhancing activity of AIT-082 and piracetam were evaluated using a cycloheximide-induced amnesia/passive avoidance model. As previously reported by others, the memory enhancing action of piracetam was abolished by adrenalectomy. In contrast, the memory enhancement by 60 mg/kg AIT-082 (IP) was unaffected. However, a sub-threshold dose of AIT-082 (0.1 mg/kg, IP) that did not improve memory in control animals did improve memory in adrenalectomized animals. These data suggested that, similar to piracetam and tacrine, the memory enhancing action of AIT-082 might be inhibited by high levels of adrenal hormones. As expected, corticosterone (30 and 100 mg/kg) inhibited the action of piracetam, however no dose up to 100 mg/kg corticosterone inhibited the activity of AIT-082. These data suggest that while AIT-082 function is not dependent on adrenal hormones, it is modulated by them. That memory enhancement by AIT-082 was not inhibited by high plasma corticosterone levels may have positive implications for its clinical utility, given that many Alzheimer's disease patients have elevated plasma cortisol levels.

The Role of Aldosterone in Obesity-Related Hypertension

PubMed Central

Kawarazaki, Wakako

2016-01-01

Obese subjects often have hypertension and related cardiovascular and renal diseases, and this has become a serious worldwide health problem. In obese subjects, impaired renal-pressure natriuresis causes sodium retention, leading to the development of salt-sensitive hypertension. Physical compression of the kidneys by visceral fat and activation of the sympathetic nervous system, renin–angiotensin systems (RAS), and aldosterone/mineralocorticoid receptor (MR) system are involved in this mechanism. Obese subjects often exhibit hyperaldosteronism, with increased salt sensitivity of blood pressure (BP). Adipose tissue excretes aldosterone-releasing factors, thereby stimulating aldosterone secretion independently of the systemic RAS, and aldosterone/MR activation plays a key role in the development of hypertension and organ damage in obesity. In obese subjects, both salt sensitivity of BP, enhanced by obesity-related metabolic disorders including aldosterone excess, and increased dietary sodium intake are closely related to the incidence of hypertension. Some salt sensitivity-related gene variants affect the risk of obesity, and together with salt intake, its combination is possibly associated with the development of hypertension in obese subjects. With high salt levels common in modern diets, salt restriction and weight control are undoubtedly important. However, not only MR blockade but also new diagnostic modalities and therapies targeting and modifying genes that are related to salt sensitivity, obesity, or RAS regulation are expected to prevent obesity and obesity-related hypertension. PMID:26927805

“Unclassical” Combination of Smell Dysfunction, Altered Abdominal Nociception and Human Hypertension Associated “Classical” Adrenal-Augmentation

PubMed Central

Leon-Ariza, Daniel S.; Leon-Ariza, Juan S.; Leon-Sarmiento, Fidias E.

2015-01-01

We report a 33-year-old female patient, who arrived to the emergency ward with an abdominal pain that suddenly started 10 days before admission. Simultaneously, the patient developed sudden arterial hypertension and smell disturbances. Conventional medical treatment for pain and arterial hypertension was effortless. Laboratory tests ruled out pancreatitis. Metanephrines in her urine were also normal. A dual-phase intravenous contrast computed tomography of the abdomen showed a large mass within left adrenal gland. Adrenocortical adenoma was diagnosed. The mass was not hypervascularized but positive for synaptophysin and chromogranin A. Importantly, these proteins are heavily involved with acetylcholine metabolism. The triad of olfactory disorders, pain and arterial hypertension normalized after surgically extracting the adrenal mass. To our knowledge, this medical case is the first reported patient exhibiting immediate recovery of such unclassical triad of local and remote findings. The function and dysfunction of key nanocholinergic pathways involved with smell, blood pressure and nociception would explain the pathophysiology of this unique medical case. PMID:26688704

Vascular effects of aldosterone: sorting out the receptors and the ligands.

PubMed

Feldman, Ross D; Gros, Robert

2013-12-01

Aldosterone has actions far beyond its role as a renal regulator of sodium reabsorption, and broader mechanisms of action than simply a transcriptional regulator. Aldosterone has a number of vascular effects, including regulation of vascular reactivity and vascular growth and/or development. Aldosterone-mediated effects on vascular reactivity reflect a balance between its endothelial-dependent vasodilator effects and its direct smooth muscle vasoconstrictor effects. The endothelial vasodilator effects of aldosterone are mediated by phosphatidylinositol 3-kinase-dependent activation of nitric oxide synthase. G-Protein oestrogen receptor (GPER) is a recently recognized G-protein coupled receptor (GPCR) that is activated by steroid hormones. It was first recognized as the GPCR mediating the rapid effects of oestrogens. Activation of GPER also mediates at least some of the vascular effects of aldosterone in smooth muscle and endothelial cells. In vascular endothelial cells, aldosterone activation of GPER mediates vasodilation. In contrast, activation of endothelial mineralocorticoid receptors has been linked to enhanced vasoconstrictor and/or impaired vasodilator responses. © 2013 Wiley Publishing Asia Pty Ltd.

Thyroid and adrenal relationships

PubMed Central

Parsons, Victor; Ramsay, Ian

1968-01-01

A brief review of the actions of adrenal medullary and thyroid hormones is presented and the ways in which they interact are examined. It is concluded that thyroid hormone produces the necessary intracellular environment without which the steady state and emergency actions of cathecholamines would be vitiated. In hyperthyroidism the increased concentration of thyroid hormones results in a lowering of the threshold for catecholamine action. For this reason it is possible to alleviate many of the symptoms of thyrotoxicosis by means of drugs which block β-adrenergic receptors. Attention is also drawn to the simultaneous occurrence of thyroid and adrenal disease, in the hope that this will encourage the search for further links in this field of endocrinology. PMID:5655216

Adrenal venous sampling in a patient with adrenal Cushing syndrome

PubMed Central

Villa-Franco, Carlos Andrés; Román-Gonzalez, Alejandro; Velez-Hoyos, Alejandro; Echeverri-Isaza, Santiago

2015-01-01

The primary bilateral macronodular adrenal hyperplasia or the independent adrenocorticotropic hormone bilateral nodular adrenal hyperplasia is a rare cause hypercortisolism, its diagnosis is challenging and there is no clear way to decide the best therapeutic approach. Adrenal venous sampling is commonly used to distinguish the source of hormonal production in patients with primary hyperaldosteronism. It could be a useful tool in this context because it might provide information to guide the treatment. We report the case of a patient with ACTH independent Cushing syndrome in whom the use of adrenal venous sampling with some modifications radically modified the treatment and allowed the diagnosis of a macronodular adrenal hyperplasia. PMID:26309345

Distal Renal Tubules Are Deficient in Aggresome Formation and Autophagy upon Aldosterone Administration

PubMed Central

Cheema, Muhammad Umar; Damkier, Helle Hasager; Nielsen, Jakob; Poulsen, Ebbe Toftgaard; Enghild, Jan J.; Fenton, Robert A.; Praetorius, Jeppe

2014-01-01

Prolonged elevations of plasma aldosterone levels are associated with renal pathogenesis. We hypothesized that renal distress could be imposed by an augmented aldosterone-induced protein turnover challenging cellular protein degradation systems of the renal tubular cells. Cellular accumulation of specific protein aggregates in rat kidneys was assessed after 7 days of aldosterone administration. Aldosterone induced intracellular accumulation of 60 s ribosomal protein L22 in protein aggregates, specifically in the distal convoluted tubules. The mineralocorticoid receptor inhibitor spironolactone abolished aldosterone-induced accumulation of these aggregates. The aldosterone-induced protein aggregates also contained proteasome 20 s subunits. The partial de-ubiquitinase ataxin-3 was not localized to the distal renal tubule protein aggregates, and the aggregates only modestly colocalized with aggresome transfer proteins dynactin p62 and histone deacetylase 6. Intracellular protein aggregation in distal renal tubules did not lead to development of classical juxta-nuclear aggresomes or to autophagosome formation. Finally, aldosterone treatment induced foci in renal cortex of epithelial vimentin expression and a loss of E-cadherin expression, as signs of cellular stress. The cellular changes occurred within high, but physiological aldosterone concentrations. We conclude that aldosterone induces protein accumulation in distal renal tubules; these aggregates are not cleared by autophagy that may lead to early renal tubular damage. PMID:25000288

Cushing's disease due to mixed pituitary adenoma-gangliocytoma of the posterior pituitary gland presenting with Aspergillus sp. sinus infection.

PubMed

Bridenstine, Mark; Kerr, Janice M; Lillehei, Kevin O; Kleinschmidt-DeMasters, Bette K

2013-01-01

Gangliocytic lesions of the pituitary gland producing Cushing's disease are extremely rare entities that may exist with or without a pituitary adenoma. The latter have been designated mixed pituitary adenoma-gangliocytomas, the majority of which produce growth hormone, not adrenocorticotropin (ACTH), and are localized to the anterior gland. We now report an immunocompetent woman with hypercortisolism who presented with an intranasal aspergilloma eroding the bony sellar floor. The fungal ball was contiguous with, and extended into, a large neurohypophyseal-centered mass. Transsphenoidal resection revealed a gangliocytic lesion of the posterior gland with small clusters of intimately admixed ACTH-immunoreactive adenoma cells as the cause of her Cushing's disease. Rare transitional sizes and shapes of cells coupled with immunohistochemical findings supported interpretation as advanced neuronal metaplasia within an ACTH adenoma. This mixed ACTH adenoma-gangliocytoma is the first example to present clinically with an opportunistic infection.

Measurement of salivary aldosterone: validation by low-dose ACTH test and gender differences.

PubMed

Hlavacova, N; Kerlik, J; Radikova, Z; Izakova, L; Jezova, D

2013-10-01

The aim of the present study was to validate the feasibility of measurement of the salivary aldosterone concentrations by performing a low-dose adrenocorticotropic hormone (ACTH) test. Moreover, the presence of gender differences in salivary aldosterone, considering the phase of the menstrual cycle in women, was verified. The sample consisted of 107 volunteers (60 men, 21 women in the follicular phase and 26 women in the luteal phase of the menstrual cycle). Saliva samples were taken by the subjects themselves around 08:00 AM, at least 60 min after awaking. A separate group of female subjects in the follicular phase underwent low-dose ACTH test (1µg synthetic ACTH i.v.) performed at 08:30 AM with blood and saliva sampling every 30 min for 120 min. Modification of the commercial aldosterone radioimmunoassay methodology for the salivary aldosterone measurement was performed. Salivary aldosterone concentrations rose in response to low-dose ACTH test and positive significant correlation in aldosterone concentrations between plasma and saliva was found. The results showed that women in the luteal phase of the menstrual cycle exhibited significantly higher morning concentrations in salivary aldosterone than men and women in the follicular phase. This study clearly demonstrates suitability of measurement of salivary aldosterone concentrations in the low-dose ACTH test and reveals gender differences in salivary aldosterone levels. The results show high validity of the presented method and its usefulness for assessment of the aldosterone concentrations in saliva.

Increased Aldosterone Release During Head-Up Tilt in Early Primary Hypertension.

PubMed

Reinold, Annemarie; Schneider, Andreas; Kalizki, Tatjana; Raff, Ulrike; Schneider, Markus P; Schmieder, Roland E; Schmidt, Bernhard M W

2017-05-01

Hyperaldosteronism is well known cause of secondary hypertension. However, the importance of aldosterone for the much larger group of patients with primary hypertension is less clear. We hypothesized that in young subjects with primary hypertension, the rise of plasma aldosterone levels in response to head-up tilt testing as a stress stimulus is exaggerated. Hemodynamics (blood pressure (BP), heart rate (HR), cardiac index (CI), and total peripheral vascular resistance index (TPRI), all by TaskForce monitor) and hormones (plasma renin activity (PRA), angiotensin II (Ang II), aldosterone) were measured before and during 30 minutes of head-up tilt in 45 young hypertensive and 45 normotensive subjects. BP, HR, CI, and TPRI all increased in response to head-up tilt, with no difference between groups. There was no difference in baseline PRA, Ang II, and aldosterone between groups. During head-up tilt, PRA, and Ang II levels increased similarly. However, aldosterone levels increased to a greater extent in the hypertensive vs. normotensive subjects (P = 0.0021). Our data suggest that an increased release of aldosterone in response to orthostatic stress is a feature of early primary hypertension. The similar increase in PRA and Ang II suggests a potential role for secretagogues of aldosterone other than Ang II in this response. In addition to its established role in secondary hypertension, dysregulation of aldosterone release might contribute to the development of primary arterial hypertension. © American Journal of Hypertension, Ltd 2017. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Comparison of C-arm computed tomography and on-site quick cortisol assay for adrenal venous sampling: A retrospective study of 178 patients.

PubMed

Chang, Chin-Chen; Lee, Bo-Ching; Chang, Yeun-Chung; Wu, Vin-Cent; Huang, Kuo-How; Liu, Kao-Lang

2017-12-01

To compare the performance of on-site quick cortisol assay (QCA) and C-arm computed tomography (CT) assistance on adrenal venous sampling (AVS) without adrenocorticotropic hormone stimulation. The institutional review board at our hospital approved this retrospective study, which included 178 consecutive patients with primary aldosteronism. During AVS, we used C-arm CT to confirm right adrenal cannulation between May 2012 and June 2015 (n = 100) and QCA for bilateral adrenal cannulation between July 2015 and September 2016 (n = 78). Successful AVS required a selectivity index (cortisol adrenal vein /cortisol peripheral ) of ≥ 2.0 bilaterally. The overall success rate of C-arm CT-assisted AVS was 87%, which increased to 97.4% under QCA (P = .013). The procedure time (C-arm CT, 49.5 ± 21.3 min; QCA, 37.5 ± 15.6 min; P < .001) and radiation dose (C-arm CT, 673.9 ± 613.8 mGy; QCA, 346.4 ± 387.8 mGy; P < .001) were also improved. The resampling rate was 16% and 21.8% for C-arm CT and QCA, respectively. The initial success rate of the performing radiologist remained stable during the study period (C-arm CT 75%; QCA, 82.1%, P = .259). QCA might be superior to C-arm CT for improving the performance of AVS. • Adrenal venous sampling (AVS) is a technically challenging procedure. • C-arm CT and quick cortisol assay (QCA) are efficient for assisting AVS. • QCA might outperform C-arm CT in enhancing AVS performance.

Massive pleural and pericardial effusion due to hypothyroidism in a patient with a surgically treated thyroid-stimulating hormone-producing pituitary adenoma.

PubMed

Lee, Ji-Hoon; Park, MinA; Park, Myung Jae; Jo, Yong Suk

2018-05-14

Hypothyroidism is relatively rare etiology of serositis with effusion, but massive pleural effusion is very unusual. This is a report of massive pleural effusion in patient taking methimazole after surgical resection of thyroid-stimulating hormone (TSH)-producing pituitary adenoma (TSHoma). The patient was clinically and biochemically hypothyroid and responded well to discontinuation of methimazole and thyroid hormone replacement therapy. When assessing patients with pleural effusion, we should not rely on laboratory test results alone, as a detailed medical history and thorough physical examination could be more useful.

Failure mode analysis in adrenal vein sampling: a single-center experience.

PubMed

Trerotola, Scott O; Asmar, Melissa; Yan, Yan; Fraker, Douglas L; Cohen, Debbie L

2014-10-01

To analyze failure modes in a high-volume adrenal vein sampling (AVS) practice in an effort to identify preventable causes of nondiagnostic sampling. A retrospective database was constructed containing 343 AVS procedures performed over a 10-year period. Each nondiagnostic AVS procedure was reviewed for failure mode and correlated with results of any repeat AVS. Data collected included selectivity index, lateralization index, adrenalectomy outcomes if performed, and details of AVS procedure. All AVS procedures were performed after cosyntropin stimulation, using sequential technique. AVS was nondiagnostic in 12 of 343 (3.5%) primary procedures and 2 secondary procedures. Failure was right-sided in 8 (57%) procedures, left-sided in 4 (29%) procedures, bilateral in 1 procedure, and neither in 1 procedure (laboratory error). Failure modes included diluted sample from correctly identified vein (n = 7 [50%]; 3 right and 4 left), vessel misidentified as adrenal vein (n = 3 [21%]; all right), failure to locate an adrenal vein (n = 2 [14%]; both right), cosyntropin stimulation failure (n = 1 [7%]; diagnostic by nonstimulated criteria), and laboratory error (n = 1 [7%]; specimen loss). A second AVS procedure was diagnostic in three of five cases (60%), and a third AVS procedure was diagnostic in one of one case (100%). Among the eight patients in whom AVS ultimately was not diagnostic, four underwent adrenalectomy based on diluted AVS samples, and one underwent adrenalectomy based on imaging; all five experienced improvement in aldosteronism. A substantial percentage of AVS failures occur on the left, all related to dilution. Even when technically nondiagnostic per strict criteria, some "failed" AVS procedures may be sufficient to guide therapy. Repeat AVS has a good yield. Copyright © 2014 SIR. Published by Elsevier Inc. All rights reserved.

Epidermal growth factor receptor signaling mediates aldosterone-induced profibrotic responses in kidney

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sheng, Lili; Yang, Min; Ding, Wei

Aldosterone has been recognized as a risk factor for the development of chronic kidney disease (CKD). Studies have indicated that enhanced activation of epidermal growth factor receptor (EGFR) is associated with the development and progression of renal fibrosis. But if EGFR is involved in aldosterone-induced renal fibrosis is less investigated. In the present study, we examined the effect of erlotinib, an inhibitor of EGFR tyrosine kinase activity, on the progression of aldosterone-induced renal profibrotic responses in a murine model underwent uninephrectomy. Erlotinib-treated rats exhibited relieved structural lesion comparing with rats treated with aldosterone alone, as characterized by glomerular hypertrophy, mesangialmore » cell proliferation and expansion. Also, erlotinib inhibited the expression of TGF-β, α-SMA and mesangial matrix proteins such as collagen Ⅳ and fibronectin. In cultured mesangial cells, inhibition of EGFR also abrogated aldosterone-induced expression of extracellular matrix proteins, cell proliferation and migration. We also demonstrated that aldosterone induced the phosphorylation of EGFR through generation of ROS. And the activation of EGFR resulted in the phosphorylation of ERK1/2, leading to the activation of profibrotic pathways. Taken together, we concluded that aldosterone-mediated tissue fibrosis relies on ROS induced EGFR/ERK activation, highlighting EGFR as a potential therapeutic target for modulating renal fibrosis. - Highlights: • EGFR was involved in aldosterone-induced renal profibrotic responses. • Aldosterone-induced EGFR activation was mediated by MR-dependent ROS generation. • EGFR activated the MAPK/ERK1/2 signaling to promote renal fibrosis.« less

Meat, meat cooking methods and preservation, and risk for colorectal adenoma.

PubMed

Sinha, Rashmi; Peters, Ulrike; Cross, Amanda J; Kulldorff, Martin; Weissfeld, Joel L; Pinsky, Paul F; Rothman, Nathaniel; Hayes, Richard B

2005-09-01

Cooking meat at high temperatures produces heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs). Processed meats contain N-nitroso compounds. Meat intake may increase cancer risk as HCAs, PAHs, and N-nitroso compounds are carcinogenic in animal models. We investigated meat, processed meat, HCAs, and the PAH benzo(a)pyrene and the risk of colorectal adenoma in 3,696 left-sided (descending and sigmoid colon and rectum) adenoma cases and 34,817 endoscopy-negative controls. Dietary intake was assessed using a 137-item food frequency questionnaire, with additional questions on meats and meat cooking practices. The questionnaire was linked to a previously developed database to determine exposure to HCAs and PAHs. Intake of red meat, with known doneness/cooking methods, was associated with an increased risk of adenoma in the descending and sigmoid colon [odds ratio (OR), 1.26; 95% confidence interval (95% CI), 1.05-1.50 comparing extreme quintiles of intake] but not rectal adenoma. Well-done red meat was associated with increased risk of colorectal adenoma (OR, 1.21; 95% CI, 1.06-1.37). Increased risks for adenoma of the descending colon and sigmoid colon were observed for the two HCAs: 2-amino-3,8-dimethylimidazo[4,5]quinoxaline and 2-amino-1-methyl-6-phenylimidazo[4,5]pyridine (OR, 1.18; 95% CI, 1.01-1.38 and OR, 1.17, 95% CI, 1.01-1.35, respectively) as well as benzo(a)pyrene (OR, 1.18; 95% CI, 1.02-1.35). Greater intake of bacon and sausage was associated with increased colorectal adenoma risk (OR, 1.14; 95% CI, 1.00-1.30); however, total intake of processed meat was not (OR, 1.04; 95% CI, 0.90-1.19). Our study of screening-detected colorectal adenomas shows that red meat and meat cooked at high temperatures are associated with an increased risk of colorectal adenoma.

Physiological basis for the etiology, diagnosis, and treatment of adrenal disorders: Cushing's syndrome, adrenal insufficiency, and congenital adrenal hyperplasia.

PubMed

Raff, Hershel; Sharma, Susmeeta T; Nieman, Lynnette K

2014-04-01

The hypothalamic-pituitary-adrenal (HPA) axis is a classic neuroendocrine system. One of the best ways to understand the HPA axis is to appreciate its dynamics in the variety of diseases and syndromes that affect it. Excess glucocorticoid activity can be due to endogenous cortisol overproduction (spontaneous Cushing's syndrome) or exogenous glucocorticoid therapy (iatrogenic Cushing's syndrome). Endogenous Cushing's syndrome can be subdivided into ACTH-dependent and ACTH-independent, the latter of which is usually due to autonomous adrenal overproduction. The former can be due to a pituitary corticotroph tumor (usually benign) or ectopic ACTH production from tumors outside the pituitary; both of these tumor types overexpress the proopiomelanocortin gene. The converse of Cushing's syndrome is the lack of normal cortisol secretion and is usually due to adrenal destruction (primary adrenal insufficiency) or hypopituitarism (secondary adrenal insufficiency). Secondary adrenal insufficiency can also result from a rapid discontinuation of long-term, pharmacological glucocorticoid therapy because of HPA axis suppression and adrenal atrophy. Finally, mutations in the steroidogenic enzymes of the adrenal cortex can lead to congenital adrenal hyperplasia and an increase in precursor steroids, particularly androgens. When present in utero, this can lead to masculinization of a female fetus. An understanding of the dynamics of the HPA axis is necessary to master the diagnosis and differential diagnosis of pituitary-adrenal diseases. Furthermore, understanding the pathophysiology of the HPA axis gives great insight into its normal control. © 2014 American Physiological Society.

Aldosterone breakthrough during aliskiren, valsartan, and combination (aliskiren + valsartan) therapy.

PubMed

Bomback, Andrew S; Rekhtman, Yelena; Klemmer, Philip J; Canetta, Pietro A; Radhakrishnan, Jai; Appel, Gerald B

2012-01-01

Aldosterone levels increase in 30%-40% of patients on angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers over the long term. This "aldosterone breakthrough" may carry important clinical consequences given aldosterone's nonepithelial, pro-fibrotic actions. The renin inhibitor, aliskiren, by suppressing the renin-angiotensin-aldosterone system (RAAS) proximally, may limit breakthrough compared to conventional RAAS blockade. This open-label study (NCT01129557) randomized subjects to aliskiren 300 mg daily (A), valsartan 320 mg daily (V), or aliskiren 150 mg + valsartan 160 mg daily (A+V) for 9 months. Eligible subjects had proteinuria >300 mg/day, estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m(2), and systolic blood pressure (BP) >130 or diastolic BP >80 mm Hg. Serum and 24-hour urine aldosterone (indexed to 24-hour urine Na) were checked before initiation of therapy and at 3, 6, and 9 months. Aldosterone breakthrough was defined as a sustained increase from baseline aldosterone by study end. The study was intended to enroll 120 subjects but was terminated early by the sponsor. We present here the results of 33 subjects who completed the protocol, of which 12 were randomized to A, 11 were randomized to V, and 10 were randomized to A+V. Mean baseline eGFR was 75.5 (±23.3) mL/min/1.73 m(2); baseline proteinuria was 3104 (±2943) mg/day; and baseline BP was 134.7 (±10.5)/84.8 (±8.4) mm Hg. Three (27%) subjects on V, three (25%) subjects on A, and three (30%) subjects on A+V had aldosterone breakthrough. Mean proteinuria reduction was 31% from baseline in all subjects: 30% in subjects with breakthrough vs. 32% in subjects without breakthrough. Mean BP reduction was 11.0/8.8 mm Hg in all subjects: 8.4/6.1 mm Hg in subjects with breakthrough vs. 12.0/9.8 mm Hg in subjects without breakthrough. Aliskiren, alone or in combination with valsartan, did not reduce the incidence of aldosterone breakthrough in subjects with hypertension

An oxidized metabolite of linoleic acid increases intracellular calcium in rat adrenal glomerulosa cells.

PubMed

Payet, Marcel D; Goodfriend, Theodore L; Bilodeau, Lyne; Mackendale, Cherilu; Chouinard, Lucie; Gallo-Payet, Nicole

2006-12-01

EKODE, an epoxy-keto derivative of linoleic acid, was previously shown to stimulate aldosterone secretion in rat adrenal glomerulosa cells. In the present study, we investigated the effect of exogenous EKODE on cytosolic [Ca(2+)] increase and aimed to elucidate the mechanism involved in this process. Through the use of the fluorescent Ca(2+)-sensitive dye Fluo-4, EKODE was shown to rapidly increase intracellular [Ca(2+)] ([Ca(2+)](i)) along a bell-shaped dose-response relationship with a maximum peak at 5 microM. Experiments performed in the presence or absence of Ca(2+) revealed that this increase in [Ca(2+)](i) originated exclusively from intracellular pools. EKODE-induced [Ca(2+)](i) increase was blunted by prior application of angiotensin II, Xestospongin C, and cyclopiazonic acid, indicating that inositol trisphosphate (InsP(3))-sensitive Ca(2+) stores can be mobilized by EKODE despite the absence of InsP(3) production. Accordingly, EKODE response was not sensitive to the phospholipase C inhibitor U-73122. EKODE mobilized a Ca(2+) store included in the thapsigargin (TG)-sensitive stores, although the interaction between EKODE and TG appears complex, since EKODE added at the plateau response of TG induced a rapid drop in [Ca(2+)](i). 9-oxo-octadecadienoic acid, another oxidized derivative of linoleic acid, also increases [Ca(2+)](i), with a dose-response curve similar to EKODE. However, arachidonic and linoleic acids at 10 microM failed to increase [Ca(2+)](i) but did reduce the amplitude of the response to EKODE. It is concluded that EKODE mobilizes Ca(2+) from an InsP(3)-sensitive store and that this [Ca(2+)](i) increase is responsible for aldosterone secretion by glomerulosa cells. Similar bell-shaped dose-response curves for aldosterone and [Ca(2+)](i) increases reinforce this hypothesis.

Body Mass Index Predicts 24-Hour Urinary Aldosterone Levels in Patients With Resistant Hypertension.

PubMed

Dudenbostel, Tanja; Ghazi, Lama; Liu, Mingchun; Li, Peng; Oparil, Suzanne; Calhoun, David A

2016-10-01

Prospective studies indicate that hyperaldosteronism is found in 20% of patients with resistant hypertension. A small number of observational studies in normotensive and hypertensive patients suggest a correlation between aldosterone levels and obesity while others could not confirm these findings. The correlation between aldosterone levels and body mass index (BMI) in patients with resistant hypertension has not been previously investigated. Our objective was to determine whether BMI is positively correlated with plasma aldosterone concentration, plasma renin activity, aldosterone:renin ratio, and 24-hour urinary aldosterone in black and white patients. We performed a cross-sectional analysis of a large diverse cohort (n=2170) with resistant hypertension. The relationship between plasma aldosterone concentration, plasma renin activity, aldosterone:renin ratio, 24-hour urinary aldosterone, and BMI was investigated for the entire cohort, by sex and race (65.3% white, 40.3% men). We demonstrate that plasma aldosterone concentration and aldosterone:renin ratio were significantly correlated to BMI (P<0.0001) across the first 3 quartiles, but not from the 3rd to 4th quartile of BMI. Plasma renin activity was not correlated with BMI. Twenty-four-hour urinary aldosterone was positively correlated across all quartiles of BMI for the cohort (P<0.0001) and when analyzed by sex (men P<0.0001; women P=0.0013) and race (P<0.05), and stronger for men compared with women (r=0.19, P<0.001 versus r=0.05, P=0.431, P=0.028) regardless of race. In both black and white patients, aldosterone levels were positively correlated to increasing BMI, with the correlation being more pronounced in black and white men. These findings suggest that obesity, particularly the abdominal obesity typical of men, contributes to excess aldosterone in patients with resistant hypertension. © 2016 American Heart Association, Inc.

Isolated double adrenocorticotropic hormone-secreting pituitary adenomas: A case report and review of the literature

PubMed Central

PU, JIUJUN; WANG, ZHIMING; ZHOU, HUI; ZHONG, AILING; JIN, KAI; RUAN, LUNLIANG; YANG, GANG

2016-01-01

Only a few cases of double or multiple pituitary adenomas have previously been reported in the literature; however, isolated double adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas are even more rare. The present study reports a rare case of a 50-year-old female patient who presented with typical clinical features of Cushing's disease and was diagnosed with isolated double ACTH-secreting pituitary adenomas. Endocrinological examination revealed an ACTH-producing pituitary adenoma, and preoperative magnetic resonance imaging (MRI) demonstrated a microadenoma with a lower intensity on the right side of the pituitary gland. The patient underwent endoscopic endonasal transsphenoidal surgery, which revealed another pituitary tumor in the left side of the pituitary gland. The two, clearly separated, pituitary adenomas identified in the same gland were completely resected. Immunohistochemistry and pathology revealed that the clearly separated double pituitary adenomas were positive for ACTH, thyroid-stimulating, growth and prolactin hormones. Postoperatively, the levels of ACTH and cortisol hormone decreased rapidly. The case reported in the present study is considerably rare, due to the presence of a second pituitary adenoma in the same gland, which was not detected by preoperative MRI scan, but was noticed during surgery. Intraoperative evaluation may be important in the identification of double or multiple pituitary adenomas. PMID:27347184

Non-functioning pituitary adenoma: immunohistochemical analysis of 85 cases.

PubMed

Mahta, Ali; Haghpanah, Vahid; Lashkari, Anahita; Heshmat, Ramin; Larijani, Bagher; Tavangar, Seyed Mohammad

2007-01-01

Pituitary adenomas without clinically active hypersecretion are summarized under the term non-functioning pituitary adenoma (NFPA). Since there are no specific serum markers, the differential diagnosis and treatment imply special difficulties. By using immunohistochemical methods we will have new insight into the nature and pathogenesis of these tumours. Ki-67 is a nuclear antigen detected by the monoclonal antibody MIB-1 and its labelling index (LI) is considered a marker of normal and abnormal cell proliferation. The aim of this study was to investigate the possible role of immunohistochemistry and MIB1-LI determination in NFPAs to predict tumoural behaviour and better management. In this clinicopathological study, 85 cases of NFPAs were analysed immunohistochemically. MIB1-LI was also determined in studied cases. Clinical presentation, treatment and follow-up data were also reviewed and the correlation between clinical and pathologic findings was established. Eighteen adenomas (21.2%) were immunoreactive to one or two adenohypophysial hormones of which 4 GH positive adenomas had aggressive behaviour (2 significant juxtasellar extensions and 2 recurrences). MIB-1 LI was more than 5% in only 5 cases including 2 invasive adenomas but with no evidence of recurrence. No significant statistical difference between clinical presentations in immunoreactive and non-immunoreactive NFPAs was observed except for unilateral temporal hemianopia which was more common in immunoreactive adenomas (P=0.022). NFPAs comprise several pathologically different types of tumours, some of which are potentially hormone producing, but some defects in hormone secretion or production of biologically inactive or insufficient amount of hormone may be the culprit in the lack of evidence of rising serum hormone levels. MIB-1 LI may be indicative of invasiveness but not a predictor of recurrence. Silent somatotropinomas may have more aggressive behaviour in comparison with other NFPAs.

Normotensive blood pressure in pregnancy: the role of salt and aldosterone.

PubMed

Gennari-Moser, Carine; Escher, Geneviève; Kramer, Simea; Dick, Bernhard; Eisele, Nicole; Baumann, Marc; Raio, Luigi; Frey, Felix J; Surbek, Daniel; Mohaupt, Markus G

2014-02-01

A successful pregnancy requires an accommodating environment. Salt and water availability are critical for plasma volume expansion. Any changes in sodium intake would alter aldosterone, a hormone previously described beneficial in pregnancy. To date, it remains ambiguous whether high aldosterone or high salt intake is preferable. We hypothesized that increased aldosterone is a rescue mechanism and appropriate salt availability is equally effective in maintaining a normotensive blood pressure (BP) phenotype in pregnancy. We compared normotensive pregnant women (n=31) throughout pregnancy with young healthy female individuals (n=31-62) and performed salt sensitivity testing within the first trimester. Suppression of urinary tetrahydro-aldosterone levels by salt intake as measured by gas chromatography-mass spectrometry and urinary sodium excretion corrected for creatinine, respectively, was shifted toward a higher salt intake in pregnancy (P<0.0001). In pregnancy, neither high urinary tetrahydro-aldosterone nor sodium excretion was correlated with higher BP. In contrast, in nonpregnant women, systolic BP rose with aldosterone (P<0.05). Testing the impact of salt on BP, we performed salt sensitivity testing in a final cohort of 19 pregnant and 24 nonpregnant women. On salt loading, 24-hour mean arterial pressure rose by 3.6±1.5 and dropped by -2.8±1.5 mm Hg favoring pregnant women (P<0.01; χ(2)=6.04; P<0.02). Our data suggest first that salt responsiveness of aldosterone is alleviated in conditions of pregnancy without causing aldosterone-induced hypertension. Second, salt seems to aid in BP lowering in pregnancy for reasons incompletely elucidated, yet involving renin suppression and potentially placental sensing mechanisms. Further research should identify susceptible individuals and clarify effector mechanisms.

Advanced colorectal adenoma related gene expression signature may predict prognostic for colorectal cancer patients with adenoma-carcinoma sequence.

PubMed

Li, Bing; Shi, Xiao-Yu; Liao, Dai-Xiang; Cao, Bang-Rong; Luo, Cheng-Hua; Cheng, Shu-Jun

2015-01-01

There are still no absolute parameters predicting progression of adenoma into cancer. The present study aimed to characterize functional differences on the multistep carcinogenetic process from the adenoma-carcinoma sequence. All samples were collected and mRNA expression profiling was performed by using Agilent Microarray high-throughput gene-chip technology. Then, the characteristics of mRNA expression profiles of adenoma-carcinoma sequence were described with bioinformatics software, and we analyzed the relationship between gene expression profiles of adenoma-adenocarcinoma sequence and clinical prognosis of colorectal cancer. The mRNA expressions of adenoma-carcinoma sequence were significantly different between high-grade intraepithelial neoplasia group and adenocarcinoma group. The biological process of gene ontology function enrichment analysis on differentially expressed genes between high-grade intraepithelial neoplasia group and adenocarcinoma group showed that genes enriched in the extracellular structure organization, skeletal system development, biological adhesion and itself regulated growth regulation, with the P value after FDR correction of less than 0.05. In addition, IPR-related protein mainly focused on the insulin-like growth factor binding proteins. The variable trends of gene expression profiles for adenoma-carcinoma sequence were mainly concentrated in high-grade intraepithelial neoplasia and adenocarcinoma. The differentially expressed genes are significantly correlated between high-grade intraepithelial neoplasia group and adenocarcinoma group. Bioinformatics analysis is an effective way to study the gene expression profiles in the adenoma-carcinoma sequence, and may provide an effective tool to involve colorectal cancer research strategy into colorectal adenoma or advanced adenoma.

ALDOSTERONE DYSREGULATION WITH AGING PREDICTS RENAL-VASCULAR FUNCTION AND CARDIO-VASCULAR RISK

PubMed Central

Brown, Jenifer M.; Underwood, Patricia C.; Ferri, Claudio; Hopkins, Paul N.; Williams, Gordon H.; Adler, Gail K.; Vaidya, Anand

2014-01-01

Aging and abnormal aldosterone regulation are both associated with vascular disease. We hypothesized that aldosterone dysregulation influences the age-related risk of renal- and cardio-vascular disease. We conducted an analysis of 562 subjects who underwent detailed investigations under conditions of liberal and restricted dietary sodium intake (1,124 visits) in a Clinical Research Center. Aldosterone regulation was characterized by the ratio of maximal suppression-to-stimulation (supine serum aldosterone on a liberal sodium diet divided by the same measure on a restricted sodium diet). We previously demonstrated that higher levels of this Sodium-modulated Aldosterone Suppression-Stimulation Index (SASSI) indicate greater aldosterone dysregulation. Renal plasma flow (RPF) was determined via p-aminohippurate clearance to assess basal renal hemodynamics, and the renal-vascular responses to dietary sodium manipulation and angiotensin II (AngII) infusion. Cardiovascular risk was calculated using the Framingham Risk Score. In univariate linear regression, older age (β= -4.60, p<0.0001) and higher SASSI (β= -58.63, p=0.001) predicted lower RPF and a blunted RPF response to sodium loading and AngII infusion. We observed a continuous, independent, multivariate-adjusted interaction between age and SASSI, where the inverse relationship between SASSI and RPF was most apparent with older age (p<0.05). Higher SASSI and lower RPF independently predicted higher Framingham Risk Score (p<0.0001) and together displayed an additive effect. Aldosterone regulation and age may interact to mediate renal-vascular disease. Our findings suggest that the combination of aldosterone dysregulation and renal-vascular dysfunction could additively increase the risk of future cardiovascular outcomes; therefore, aldosterone dysregulation may represent a modifiable mechanism of age-related vascular disease. PMID:24664291

Aldosterone affects blood flow and vascular tone regulated by endothelium-derived NO: therapeutic implications

PubMed Central

Toda, Noboru; Nakanishi, Sadanobu; Tanabe, Shinichi

2013-01-01

Aldosterone, in doses inappropriate to the salt status, plays an important role in the development of cardiovascular injury, including endothelial dysfunction, independent of its hypertensive effects. Acute non-genomic effects of aldosterone acting on mineralocorticoid receptors are inconsistent in healthy humans: vasoconstriction or forearm blood flow decrease via endothelial dysfunction, vasodilatation mediated by increased NO actions, or no effects. However, in studies with experimental animals, aldosterone mostly enhances vasodilatation mediated by endothelium-derived NO. Chronic exposure to aldosterone, which induces genomic responses, results in impairments of endothelial function through decreased NO synthesis and action in healthy individuals, experimental animals and isolated endothelial cells. Chronic aldosterone reduces NO release from isolated human endothelial cells only when extracellular sodium is raised. Oxidative stress is involved in the impairment of endothelial function by promoting NO degradation. Aldosterone liberates endothelin-1 (ET-1) from endothelial cells, which elicits ETA receptor–mediated vasoconstriction by inhibiting endothelial NO synthesis and action and through its own direct vasoconstrictor action. Ca2+ flux through T-type Ca2+ channels activates aldosterone synthesis and thus enhances unwanted effects of aldosterone on the endothelium. Mineralocorticoid receptor inhibitors, ETA receptor antagonists and T-type Ca2+ channel blockers appear to diminish the pathophysiological participation of aldosterone in cardiovascular disease and exert beneficial actions on bioavailability of endothelium-derived NO, particularly in resistant hypertension and aldosteronism. PMID:23190073

New Sides of Aldosterone Action in Cardiovascular System as Potential Targets for Therapeutic Intervention.

PubMed

Kolodziejczyk, Patrycjusz; Gromotowicz-Poplawska, Anna; Aleksiejczuk, Michal; Chabielska, Ewa; Tutka, Piotr; Miltyk, Wojciech

2018-03-26

Aldosterone, the main mineralocorticoid hormone, plays a crucial role in the regulation of electrolyte homeostasis and blood pressure. Although, this role is undoubtedly important, it is not a hormonal action that attracts the most attention. Aldosterone seems to be very important important as a local messenger in the pathology of cardiovascular diseases (CVD). In the last few years, the attention was focused on the correlation between raised aldosterone level and increased risk of cardiovascular events. It has been demonstrated that aldosterone contributes to fibrosis, inflammation, endothelial dysfunction, fibrinolytic disordes, and oxidative stress leading to CVD development and progression. It used to be thought that the effects of aldosterone are mediated via classic nuclear receptors - mineralocorticoid receptors (MR). Now we know that the mechanism of aldosterone action in cardiovascular system is much more complex, since experimental and clinical studies indicate that MR blockade may be not sufficient to abolish aldosterone-incuced harmful effects in the cardiovascular system. Therefore, the involvement of some other than MR, receptors and factors is suggested. Moreover, in addition to the generally known genomic action of aldosterone, which involves MR activation, the nongenomic pathways are postulated in the mode of hormone action. More and more attention is focused on the membrane-coupled receptors, which mediate the rapid effects of aldosterone and have been already confirmed in different cells and tissues of a cardiovascular system. The confirmation of multiple mechanisms of aldosterone action opens a new perspective for more effective therapeutic intervention in aldosterone-related CVD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Body mass index predicts aldosterone production in normotensive adults on a high-salt diet.

PubMed

Bentley-Lewis, Rhonda; Adler, Gail K; Perlstein, Todd; Seely, Ellen W; Hopkins, Paul N; Williams, Gordon H; Garg, Rajesh

2007-11-01

The mechanisms underlying obesity-mediated cardiovascular disease are not fully understood. Aldosterone and insulin resistance both are associated with obesity and cardiovascular disease. The objectives of this study were to test the hypotheses that aldosterone production is elevated and associated with insulin resistance in overweight adults on a high-sodium diet. Healthy normotensive adults were categorized as lean body mass index (BMI) less than 25 kg/m(2) (n = 63) or overweight BMI 25 kg/m(2) or greater (n = 57). After 7 d of a high-sodium diet, participants fasted overnight and remained supine throughout hemodynamic and laboratory assessments and angiotensin II (AngII) stimulation. The overweight group, compared with the lean group, had higher 24-h urinary aldosterone (9.0 +/- 0.8 vs. 6.6 +/- 0.5 microg per 24 h; P = 0.003) and higher AngII-stimulated serum aldosterone (11.4 +/- 1.0 vs. 9.0 +/- 0.6 ng/dl; P = 0.04). There were no differences in 24-h urinary cortisol or sodium or supine measurements of plasma renin activity, serum aldosterone, or serum potassium. The homeostasis model assessment of insulin resistance was predicted by urinary aldosterone excretion (r = 0.32, P = 0.03) and serum aldosterone response to AngII stimulation (r = 0.28, P = 0.02) independent of age and BMI. Urinary aldosterone excretion and AngII-stimulated aldosterone are increased in overweight, compared with lean, normotensive adults. The correlation of these measures of aldosterone production with insulin resistance suggests a potential role for aldosterone in the pathophysiology of obesity-mediated insulin resistance.

Diagnosis of adrenal insufficiency.

PubMed

Dorin, Richard I; Qualls, Clifford R; Crapo, Lawrence M

2003-08-05

The cosyntropin stimulation test is the initial endocrine evaluation of suspected primary or secondary adrenal insufficiency. To critically review the utility of the cosyntropin stimulation test for evaluating adrenal insufficiency. The MEDLINE database was searched from 1966 to 2002 for all English-language papers related to the diagnosis of adrenal insufficiency. Studies with fewer than 5 persons with primary or secondary adrenal insufficiency or with fewer than 10 persons as normal controls were excluded. For secondary adrenal insufficiency, only studies that stratified participants by integrated tests of adrenal function were included. Summary receiver-operating characteristic (ROC) curves were generated from all studies that provided sensitivity and specificity data for 250-microg and 1-microg cosyntropin tests; these curves were then compared by using area under the curve (AUC) methods. All estimated values are given with 95% CIs. At a specificity of 95%, sensitivities were 97%, 57%, and 61% for summary ROC curves in tests for primary adrenal insufficiency (250-microg cosyntropin test), secondary adrenal insufficiency (250-microg cosyntropin test), and secondary adrenal insufficiency (1-microg cosyntropin test), respectively. The area under the curve for primary adrenal insufficiency was significantly greater than the AUC for secondary adrenal insufficiency for the high-dose cosyntropin test (P < 0.001), but AUCs for the 250-microg and 1-microg cosyntropin tests did not differ significantly (P > 0.5) for secondary adrenal insufficiency. At a specificity of 95%, summary ROC analysis for the 250-microg cosyntropin test yielded a positive likelihood ratio of 11.5 (95% CI, 8.7 to 14.2) and a negative likelihood ratio of 0.45 (CI, 0.30 to 0.60) for the diagnosis of secondary adrenal insufficiency. Cortisol response to cosyntropin varies considerably among healthy persons. The cosyntropin test performs well in patients with primary adrenal insufficiency, but the