The improvement of postoperative blood pressure and associated factors in patients with hormone-negative adrenal adenoma and hypertension.

OBJECTIVE: To investigate the effect of adrenal surgery on blood pressure (BP) improvements in patients with hormone-negative adrenal adenoma (HNA) concomitant with hypertension and analyze associated prognostic factors. METHODS: We retrospectively reviewed the clinical data of patients with HNA and hypertension and patients with aldosterone-producing adenoma (APA) and hypertension who underwent adrenal surgery at our center between 2019 and 2022. Hypertension outcomes were evaluated in all patients and subjects were divided into three groups according to follow-up BP and the administration of anti-hypertensive agents: a clinical curation group, an improvement group, and a no-improvement group. Logistic regression analysis was performed to predict factors associated with clinical curation in patients with HNA post-surgery. RESULTS: Of the 182 patients with HNA, clinical curation was achieved in 58 patients (31.9%), improvement in 72 (39.5%), and no improvement in 52 (28.6%). The clinical curation, improvement and no improvement rates in patients with APA were 64.8% (n = 118), 15.9% (n = 29), and 19.2% (n = 35). Multivariate logistic regression analysis indicated that a duration of hypertension ≤6 years and a plasma aldosterone level >160 pg/ml were both independent factors for the clinical curation of hypertension in patients with HNA after adrenal surgery. CONCLUSION: Adrenal surgery can cure or improve hypertension in most patients with HNA, especially in a short duration of hypertension and high plasma levels of aldosterone.

Cardiovascular Outcomes of KCNJ5 Mutated Aldosterone-Producing Adenoma: A Systematic Review.

BACKGROUND: While clinical features of KCNJ5-mutated aldosterone-producing adenoma (APA) have been reported, evidence of its clinical outcomes is lacking. We aimed to synthesize available literature about the associations between KCNJ5 mutation with cardiovascular and metabolic outcomes among patients with APA. METHODS: In this systematic review of observational studies, MEDLINE and Embase were searched through August 2022. Two independent authors screened the search results and extracted data from eligible observational studies investigating cardiovascular or metabolic outcomes between KCNJ5-mutated APAs and KCNJ5-non-mutated APAs. Risk of Bias In Non-randomized Studies of Interventions was used to assess the quality of the included studies. RESULTS: A total of 573 titles/abstracts were screened and after the expert opinion of the literature, full text was read in 20 titles/abstracts, of which 12 studies were included. Across 3 studies comparing the baseline or change in the cardiac function between KCNJ5-mutated APAs and KCNJ5-non-mutated APAs, all studies reported the association between impaired cardiac functions and KCNJ5 mutation status. Among 6 studies evaluating the cure of hypertension after surgery, all studies showed that KCNJ5 mutation was significantly associated with the cure of hypertension. In quality assessment, 7 studies were at serious risk of bias, while the remaining studies were at moderate risk of bias. CONCLUSIONS: This systematic review provided evidence of the significant association between KCNJ5 mutation and unfavorable cardiovascular outcomes in patients with primary aldosteronism. Further research is needed to improve the quality of evidence on this topic and elucidate the underlying mechanisms of the potential burden of KCNJ5 mutation.

Epigenetic alterations of 11beta-hydroxysteroid dehydrogenase 1 gene in the adipose tissue of patients with primary aldosteronism.

11Beta-hydroxysteroid dehydrogenase 1 (11ß-HSD1) is a key enzyme involved in metabolic syndrome. Transcript-specific epigenetic regulation of the gene encoding 11ß-HSD1 (HSD11B1) has been reported. We examined the mRNA level and methylation status of the HSD11B1 promoter region in the adipose tissue of patients with primary aldosteronism (PA). We compared 10 tissue specimens from patients with PA caused by aldosterone-producing adenoma (APA) with 8 adipose tissue specimens from patients with subclinical Cushing's syndrome (SCS) caused by cortisol-producing adenomas, 4 tissue specimens from patients with Cushing's adenoma (Cu), or 7 tissue specimens from patients with non-functioning adrenal adenoma (NFA). PA, SCS, and Cu were diagnosed according to the guideline of the Japan Endocrine Society. The mRNA level of HSD11B1 was quantified using real-time PCR. Isolated DNA was treated with bisulfite and amplified using primers specific to the human HSD11B1 promoter region. The glycohemoglobin level was significantly higher in patients with APA, SCS, or Cu than in those with NFA (p < 0.05). Blood pressure was significantly higher in patients with APA than in those with SCS, Cu, or NFA (p < 0.01). The HSD11B1 mRNA level was significantly increased in the adipose tissues of APA or SCS patients compared with Cu or NFA patients (p < 0.05). The methylation ratio was significantly lower in SCS patients than in APA, Cu, or NFA patients (p < 0.05). HSD11B1 expression is partly controlled by an epigenetic mechanism in human tissues. The pathophysiological role of epigenetic regulation of HSD11B1 expression in adipose tissue requires further study.

In Situ Metabolomics of Cortisol-Producing Adenomas.

BACKGROUND: Recent advances in omics techniques have allowed detailed genetic characterization of cortisol-producing adrenal adenoma (CPA). In contrast, the pathophysiology of CPAs has not been elucidated in detail on the level of tumor metabolic alterations. METHODS: The current study conducted a comprehensive mass spectrometry imaging (MSI) map of CPAs in relation to clinical phenotypes and immunohistochemical profiles of steroidogenic enzymes. The study cohort comprised 46 patients with adrenal tumors including CPAs (n 35) and nonfunctional adenomas (n 11). RESULTS: Severity of cortisol hypersecretion was significantly correlated with 29 metabolites (adjusted P 0.05). Adrenal androgens derived from the classic androgen pathway were inversely correlated with both cortisol secretion (rs 0.41, adjusted P 0.035) and CYP11B1 expression (rs 0.77, adjusted P 2.00E-08). The extent of cortisol excess and tumor CYP11B1 expression further correlated with serotonin (rs 0.48 and 0.62, adjusted P 0.008 and 2.41E-05). Tumor size was found to be correlated with abundance of 13 fatty acids (adjusted P 0.05) and negatively associated with 9 polyunsaturated fatty acids including phosphatidic acid 38:8 (rs 0.56, adjusted P 0.009). CONCLUSIONS: MSI reveals novel metabolic links between endocrine function and tumorigenesis, which will further support the understanding of CPA pathophysiology.

Association of Nrf2 expression and mutation with Weiss and Helsinki scores in adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare malignant tumor. Genetic abnormalities that may represent therapeutic targets and prognostic factors in ACC remain unclear. Besides being one of the main cellular defense mechanisms that regulates antioxidant pathways for detoxifying reactive oxygen species (ROS), the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) promotes tumor proliferation by increasing metabolic activity. In surgical specimens from 12 cases of nonmetastatic ACCs and nine cases of benign adrenocortical adenoma (ACA), we investigated gene mutation and protein expressions for Nrf2 and the preoperative maximum standard glucose uptake (SUVmax) on [18 F]fluorodeoxy-glucose positron emission tomography. Three of five ACCs with a Weiss score of 7 to 9 were Nrf2 mutants; these ACCs had higher expression of Nrf2 and higher preoperative SUVmax. The other seven ACCs had a Weiss score of 3 to 6; these seven ACCs and all the ACAs were non-Nrf2 gene mutants. Patients with a Weiss score of 7 to 9 and Nrf2 mutant ACC had shorter overall survival. Based on Helsinki scoring, three ACCs with a Helsinki score greater than 17 had Nrf2 mutants, higher expression of Nrf2, higher preoperative SUVmax, and shorter overall survival. Our findings indicate that Nrf2 activation and the associated increase in metabolism play roles in ACC, in particular in ACC with a Weiss score of 7 to 9 and a Helsinki score of greater than 17.

Intracranial hypertension and empty Sella from adrenal adenoma and excessive and prolonged steroid usage: a case report.

BACKGROUND: There is only one documented case of intracranial hypertension (IH) and empty sella from cortisol-producing adrenal adenoma so far. And IH and empty sella caused by long-term exogenous hypercortisolism has never been reported before. The purpose of this case report is to alert clinicians to glucocorticoid-induced IH. CASE PRESENTATION: We present retrospectively a 50-year-old woman with cortisol-secreting adrenal adenoma, who progressed to intractable intracranial hypertension and a markedly expanded empty sella due to improper treatment. In 2011, the patient presented with hypertension, lack of cortisol circadian rhythm, low ACTH, a left adrenal adenoma and a partial empty sella, but did not receive low-dose dexamethasone suppression test (LDDST) and 24-h urinary cortisol. In 2014, she exhibited truncal obesity, raised cortisol, LDDST non-suppression, high urinary free cortisol and low ACTH, proving her cortisol-producing adrenal adenoma. She was simultaneously diagnosed with unexplained IH because of papilledema and elevated intracranial pressure, and her partial empty sella changed to a complete empty sella. In 2015, she underwent adrenal adenoma resection. From 2015 to 2018, she kept taking dexamethasone at least 2 mg daily without her doctors' consent. During this period, she developed transient cerebrospinal fluid rhinorrhea, and her empty sella further worsened. After switching to low dose hydrocortisone, her papilledema disappeared completely, but optic atrophy has become irreversible. CONCLUSIONS: The patient seems to be just an extreme case, but it may reveal and illustrate a general phenomenon: Both cortisol-producing adrenal adenoma and long-term exogenous hypercortisolism could cause varying degrees of elevated intracranial pressure and empty sella. Clinicians should remain vigilant for this phenomenon in patients with cortisol-producing adrenal adenoma or excessive and prolonged steroid usage and give them corresponding examinations to identify this complication.

Update on the Genetics of Primary Aldosteronism and Aldosterone-Producing Adenomas.

PURPOSE OF THE REVIEW: Primary aldosteronism (PA) is the leading cause of secondary hypertension, accounting for over 10% of patients with high blood pressure. It is characterized by autonomous production of aldosterone from the adrenal glands leading to low-renin levels. The two most common forms arise from bilateral adrenocortical hyperplasia (BAH) and aldosterone-producing adenoma (APA). We discuss recent discoveries in the genetics of PA. RECENT FINDINGS: Most APAs harbor variants in the KCNJ5, CACNA1D, ATP1A1, ATP2B3, and CTNNB1 genes. With the exception of ß-catenin (CTNNB1), all other causative genes encode ion channels; pathogenic variants found in PA lead to altered ion transportation, cell membrane depolarization, and consequently aldosterone overproduction. Some of these genes are found mutated in the germline state (CYP11B2, CLCN2, KCNJ5, CACNA1H, and CACNA1D), leading then to familial hyperaldosteronism, and often BAH rather than single APAs. Several genetic defects in the germline or somatic state have been identified in PA. Understanding how these molecular abnormalities lead to excess aldosterone contributes significantly to the elucidation of the pathophysiology of low-renin hypertension. It may also lead to new and more effective therapies for this disease acting at the molecular level.

Development of Human Adrenocortical Adenoma (HAA1) Cell Line from Zona Reticularis.

The human adrenal cortex is composed of distinct zones that are the main source of steroid hormone production. The mechanism of adrenocortical cell differentiation into several functionally organized populations with distinctive identities remains poorly understood. Human adrenal disease has been difficult to study, in part due to the absence of cultured cell lines that faithfully represent adrenal cell precursors in the early stages of transformation. Here, Human Adrenocortical Adenoma (HAA1) cell line derived from a patient's macronodular adrenocortical hyperplasia and was treated with histone deacetylase inhibitors (HDACis) and gene expression was examined. We describe a patient-derived HAA1 cell line derived from the zona reticularis, the innermost zone of the adrenal cortex. The HAA1 cell line is unique in its ability to exit a latent state and respond with steroidogenic gene expression upon treatment with histone deacetylase inhibitors. The gene expression pattern of differentiated HAA1 cells partially recreates the roster of genes in the adrenal layer that they have been derived from. Gene ontology analysis of whole genome RNA-seq corroborated increased expression of steroidogenic genes upon HDAC inhibition. Surprisingly, HDACi treatment induced broad activation of the Tumor Necrosis Factor (TNF) alpha pathway. This novel cell line we developed will hopefully be instrumental in understanding the molecular and biochemical mechanisms controlling adrenocortical differentiation and steroidogenesis.

Determination of adrenal hypersecretion in primary Aldosteronism without aldosterone-production adenomas.

BACKGROUND: Primary aldosteronism (PA) is highly prevalent in hypertensive population. Adrenal vein sampling (AVS) is the only procedure to assess adrenal aldosterone hypersecretion in PA. PA patients without aldosterone-producing adenomas (APA) frequently have unilateral aldosterone hypersecretion (UAH). These patients could bear inappropriate adrenalectomy without AVS. This study aims to identify which clinical characteristics should be recommended to perform AVS in these PA patients. METHODS: This study was performed from January 2018 to July 2019 at a center for hypertension and metabolic diseases. Adrenal computed tomography (CT) scan, biochemical evaluation, and AVS were performed. RESULTS: Total 141 patients were included in this study. Aldosterone to renin ratio (ARR) after confirmatory test is highly associated with adrenal laterality. The specificity of ARR > 10 (ng/dL)/(mU/L) after confirmatory test is 100%. After confirmatory test, patients with ARR > 10 (ng/dL)/(mU/L) had higher plasma aldosterone concentration and incidences of ischemic heart diseases and renal damage(p < 0.05). CONCLUSIONS: After confirmatory tests, ARR > 10 (ng/dL)/(mU/L) indicates adrenal laterality, with increasingly cardiorenal damage in PA patients without APA. Thus, AVS should be recommended in these patients before surgery. TRIAL REGISTRATION: NCT03398785 , Date of Registration: December 24, 2017.

Wnt-Signaling Regulated by Glucocorticoid-Induced miRNAs.

Glucocorticoids (GCs) are pleiotropic hormones which regulate innumerable physiological processes. Their comprehensive effects are due to the diversity of signaling mechanism networks. MiRNAs, small, non-coding RNAs contribute to the fine tuning of signaling pathways and reciprocal regulation between GCs and miRNAs has been suggested. Our aim was to investigate the expressional change and potential function of GC mediated miRNAs. The miRNA expression profile was measured in three models: human adrenocortical adenoma vs. normal tissue, steroid-producing H295R cells and in hormonally inactive HeLa cells before and after dexamethasone treatment. The gene expression profile in 82 control and 57 GC-affected samples was evaluated in GC producing and six different GC target tissue types. Tissue-specific target prediction (TSTP) was applied to identify the most relevant miRNA-mRNA interactions. Glucocorticoid treatment resulted in cell type-dependent miRNA expression changes. However, 19.5% of the influenced signaling pathways were common in all three experiments, of which the Wnt-signaling pathway seemed to be the most affected. Transcriptome data and TSTP showed similar results, as the Wnt pathway was significantly altered in both the GC-producing adrenal gland and all investigated GC target tissue types. In different cell types, different miRNAs led to the regulation of similar pathways. Wnt signaling may be one of the most important signaling pathways affected by hypercortisolism. It is, at least in part, regulated by miRNAs that mediate the glucocorticoid effect. Our findings on GC producing and GC target tissues suggest that the alteration of Wnt signaling (together with other pathways) may be responsible for the leading symptoms observed in Cushing's syndrome.

ATP1A1 Mutant in Aldosterone-Producing Adenoma Leads to Cell Proliferation.

The molecular mechanisms by which ATP1A1 mutation-mediated cell proliferation or tumorigenesis in aldosterone-producing adenomas (APAs) have not been elucidated. First, we investigated whether the APA-associated ATP1A1 L104R mutation stimulated cell proliferation. Second, we aimed to clarify the molecular mechanisms by which the ATP1A1 mutation-mediated cell proliferated. We performed transcriptome analysis in APAs with ATP1A1 mutation. ATP1A1 L104R mutation were modulated in human adrenocortical carcinoma (HAC15) cells (ATP1A1-mutant cells), and we evaluated cell proliferation and molecular signaling events. Transcriptome and immunohistochemical analysis showed that Na/K-ATPase (NKA) expressions in ATP1A1 mutated APA were more abundant than those in non-functioning adrenocortical adenoma or KCNJ5 mutated APAs. The significant increase of number of cells, amount of DNA and S-phase population were shown in ATP1A1-mutant cells. Fluo-4 in ATP1A1-mutant cells were significantly increased. Low concentration of ouabain stimulated cell proliferation in ATP1A1-mutant cells. ATP1A1-mutant cells induced Src phosphorylation, and low concentration of ouabain supplementation showed further Src phosphorylation. We demonstrated that NKAs were highly expressed in ATP1A1 mutant APA, and the mutant stimulated cell proliferation and Src phosphorylation in ATP1A1-mutant cells. NKA stimulations would be a risk factor for the progression and development to an ATP1A1 mutant APA.

Immunohistochemistry of the Human Adrenal CYP11B2 in Normal Individuals and in Patients with Primary Aldosteronism.

The CYP11B2 enzyme is the terminal enzyme in the biosynthesis of aldosterone. Immunohistochemistry using antibodies against CYP11B2 defines cells of the adrenal ZG that synthesize aldosterone. CYP11B2 expression is normally stimulated by angiotensin II, but becomes autonomous in primary hyperaldosteronism, in most cases driven by recently discovered somatic mutations of ion channels or pumps. Cells expressing CYP11B2 in young normal humans form a continuous band beneath the adrenal capsule; in older individuals they form discrete clusters, aldosterone-producing cell clusters (APCC), surrounded by non-aldosterone producing cells in the outer layer of the adrenal gland. Aldosterone-producing adenomas may exhibit a uniform or heterogeneous expression of CYP11B2. APCC frequently persist in the adrenal with an aldosterone-producing adenoma suggesting autonomous CYP11B2 expression in these cells as well. This was confirmed by finding known mutations that drive aldosterone production in adenomas in the APCC of clinically normal people. Unilateral aldosteronism may also be due to multiple CYP11B2-expressing nodules of various sizes or a continuous band of hyperplastic ZG cells expressing CYP11B2. Use of CYP11B2 antibodies to identify areas for sequencing has greatly facilitated the detection of aldosterone-driving mutations.

MicroRNAs and Adrenocortical Tumors: Where do we Stand on Primary Aldosteronism?

MicroRNAs, the endogenous mediators of RNA interference, interact with the renin-angiotensin-aldosterone system, regulate aldosterone secretion and aldosterone effects. Some novel data show that the expression of some microRNAs is altered in primary aldosteronism, and some of these appear to have pathogenic relevance, as well. Differences in the circulating microRNA expression profiles between the two major forms of primary aldosteronism, unilateral aldosterone-producing adenoma and bilateral adrenal hyperplasia have also been shown. Here, we present a brief synopsis of these findings focusing on the potential relevance of microRNA in primary aldosteronism.

Angiotensin II Type 1 Receptor Autoantibodies in Primary Aldosteronism.

Primary aldosteronism (PA) is the most common form of endocrine hypertension. Agonistic autoantibodies against the angiotensin II type 1 receptor (AT1R-Abs) have been described in transplantation medicine and women with pre-eclampsia and more recently in patients with PA. Any functional role of AT1R-Abs in either of the two main subtypes of PA (aldosterone-producing adenoma or bilateral adrenal hyperplasia) requires clarification. In this review, we discuss the studies performed to date on AT1R-Abs in PA.

Hypokalemia and the Prevalence of Primary Aldosteronism.

Hypokalemia is closely linked with the pathophysiology of primary aldosteronism (PA). Although hypokalemic PA is less common than the normokalemic course of the disease, hypokalemia is of particular importance for the manifestation and development of comorbidities. Specifically, a growing body of evidence demonstrates that hypokalemia in PA patients is associated with a more severe disease course regarding cardiovascular and metabolic morbidity and mortality. It is also well appreciated that low potassium levels per se can promote or exacerbate hypertension. The spectrum of hypokalemia-related symptoms ranges from asymptomatic courses to life-threatening conditions. Hypokalemia is found in 9-37% of all cases of PA with a predominance in patients with aldosterone producing adenoma. Conversely, hypokalemia resolves in almost 100% of cases after both, specific medical or surgical treatment of the disease. However, to date, high-level evidence about the prevalence of primary aldosteronism in a hypokalemic population is missing. Epidemiological data are expected from the recently launched IPAHK+study ("Incidence of Primary Aldosteronism in Patients with Hypokalemia").

The Potential Role of Aldosterone-Producing Cell Clusters in Adrenal Disease.

Primary aldosteronism (PA) is the most common cause of secondary hypertension. The hallmark of PA is adrenal production of aldosterone under suppressed renin conditions. PA subtypes include adrenal unilateral and bilateral hyperaldosteronism. Considerable progress has been made in defining the role for somatic gene mutations in aldosterone-producing adenomas (APA) as the primary cause of unilateral PA. This includes the use of next-generation sequencing (NGS) to define recurrent somatic mutations in APA that disrupt calcium signaling, increase aldosterone synthase (CYP11B2) expression, and aldosterone production. The use of CYP11B2 immunohistochemistry on adrenal glands from normal subjects, patients with unilateral and bilateral PA has allowed the identification of CYP11B2-positive cell foci, termed aldosterone-producing cell clusters (APCC). APCC lie beneath the adrenal capsule and like APA, many APCC harbor somatic gene mutations known to increase aldosterone production. These findings suggest that APCC may play a role in pathologic progression of PA. Herein, we provide an update on recent research directed at characterizing APCC and also discuss the unanswered questions related to the role of APCC in PA.

Pregnancy-induced Cushing's syndrome with an adrenocortical adenoma overexpressing LH/hCG receptors: a case report.

BACKGROUND: Pregnancy-induced Cushing's syndrome (CS) with an adrenocortical adenoma overexpressing luteinizing hormone (LH)/human choriogonadotropin (hCG) receptors (LHCGR) has been rarely reported in the literatures. This peculiar condition challenges the canonical diagnosis and management of CS. CASE PRESENTATION: A 27-year-old woman (G2P0A1) presented at 20 weeks gestational age (GA) with overt Cushingoid clinical features. Adrenocorticotropic hormone (ACTH)-independent CS was diagnosed based on undetectable ACTH and unsuppressed cortisol levels by dexamethasone. Magnetic resonance imaging (MRI) scanning without contrast revealed a left adrenal nodule while pituitary MRI scanning was normal. A conservative treatment strategy of controlling Cushingoid comorbidities was conducted. At 36 weeks GA, a caesarean operation was performed and a live female infant was delivered. At 8 weeks after parturition, our patient achieved normalization of blood pressure, blood glucose, serum potassium, and urinary cortisol level spontaneously. During non-pregnancy period, stimulation testing with exogenous hCG significantly evoked a cortisol increase. The woman underwent resection of the adrenal tumor at 6 months after parturition. Immunohistochemistry (IHC) showed the tumor tissue that stained positive for luteinizing hormone (LH)/human choriogonadotropin (hCG) receptor (LHCGR), whereas negative for both melanocortin 2 receptor (MC2R) and G protein-coupled receptor-1 (GPER-1). CONCLUSIONS: Stimulation test with exogenous hCG after parturition is necessary for the diagnosis of pregnancy-induced CS. LHCGR plays an essential role in the pathogenesis of this rare condition.

Overestimation of glomerular filtration rate calculated from serum creatinine as compared with cystatin C in patients with subclinical hypercortisolism: Hyogo Adrenal Metabolic Registry.

The skeletal muscle mass are decreased in the patients with hypercortisolism. Glomerular filtration rate (eGFR) is not accurately evaluated by calculation from serum creatinine (eGFRcre) in these patients. However, it is not known whether it applies to patients with subclinical hypercortisolism. We investigated the dissociation between eGFRcre and eGFR calculated from cystatin C (eGFRcys) in patients with subclinical hypercortisolism and its association with the skeletal muscle mass. This cross-sectional study includes 23 patients with overt Cushing's syndrome (CS), 84 patients with possible autonomous cortisol secretion (pACS) and 232 patients with non-functioning adenomas (NFA). eGFRcre, eGFRcys, the ratio of eGFRcre to eGFRcys (eGFRcre/eGFRcys) were calculated. Skeletal muscle index (SMI) was measured by a direct segmental multi-frequency bioelectrical impedance body composition analyzer. eGFRcre/eGFRcys was significantly higher (p < 0.01) in pACS (mean ± standard error: 1.15 ± 0.02) than NFA (1.06 ± 0.01). In multiple linear regression analysis, the presence of pACS (ß = 0.162, p < 0.01), and post 1 mg-DST cortisol levels (ß = 0.190, p < 0.01) were significantly associated with eGFRcre/eGFRcys independent of age, gender, BMI and diabetes. eGFRcre/eGFRcys was significantly and inversely associated with SMI (r = -0.164, p = 0.02). Furthermore, post 1 mg-DST cortisol levels was significantly associated with SMI in simple (r = -0.177, p = 0.01) and multiple (ß = -0.089, p = 0.01) regression analyses. In conclusion, dissociation between eGFRcre and eGFRcys was observed in patients with subclinical hypercortisolism at least partly explained by muscle mass. Our findings raise an important clinical point that eGFRcre value should be carefully evaluated even in the phase of subclinical hypercortisolism.

The landscape of molecular mechanism for aldosterone production in aldosterone-producing adenoma.

Primary aldosteronism is the most common form of secondary hypertension with a prevalence of 5-10% in hypertensive patients. Aldosterone-producing adenoma (APA) is a subtype of primary aldosteronism, and somatic mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, CLCN2, or CTNNB1 were identified and recognized to drive aldosterone production and/or contribute to tumorigenesis in APA. Mutations of KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CLCN2 are known to activate calcium signaling, and its activation potentiate CYP11B2 (aldosterone synthesis) transcription in adrenal cells. Transcriptome analyses combined with bioinformatics using APA samples were conductive for each gene mutation mediated pivotal pathway, gene ontology, and clustering. Several important intracellular molecules in increase aldosterone production were detected by transcriptome analysis, and additional functional analyses demonstrated intracellular molecular mechanisms of aldosterone production which focused on calcium signal, CYP11B2 transcription and translation. Furthermore, DNA methylation analysis revealed that promoter region of CYP11B2 was entirely hypomethylated, but that of other steroidogenic enzymes were not in APA. Integration of transcriptome and DNA methylome analysis clarified some DNA methylation associated gene expression, and the transcripts have a role for aldosterone production. In this article, we reviewed the intracellular molecular mechanisms of aldosterone production in APA, and discussed future challenges for basic studies leading to clinical practice.

A nationwide survey of adrenal incidentalomas in Japan: the first report of clinical and epidemiological features.

The aim of this study was to reveal clear epidemiologic and clinical characteristics of incidentally discovered adrenal masses, termed adrenal incidentalomas (AIs), and to establish appropriate managemental and therapeutic regimens in Japan. This study had been originally carried out as a project of a research proposed on behalf of the Japanese Ministry of Health, Labour and Welfare, from 1999 to 2004. This nationwide multicenter study on AIs included 3,672 cases with clinically diagnosed AIs, involving 1,874 males and 1,738 females, with mean age 58.1 ± 13.0 years (mean ± SD). In the present study, we focused on the investigation of the real prevalence of various adrenal disorders with AI. The mean nodule size of AI based on computed tomography was 3.0 ± 2.0 cm. Compared to non-functioning adenomas (NFAs), tumor diameters were significantly larger in adrenocortical carcinomas (ACCs), pheochromocytomas, cortisol-producing adenomas (CPAs), myelolipomas, metastatic tumors, cysts, and ganglioneuromas (p < 0.01). Endocrinological evaluations demonstrated that 50.8% of total AIs were non-functioning adenomas, while 10.5%, including 3.6% with subclinical Cushing's syndrome, were reported as CPAs, 8.5% as pheochromocytomas, and 5.1% as aldosterone-producing adenomas. ACCs were accounted for 1.4% (50 cases) among our series of AIs. In conclusion, while almost 50 % of AIs are non-functional adenomas, we must be particularly careful as AIs include pheochromocytomas or adrenal carcinomas, because they may be asymptomatic. To our knowledge, this is the first and the largest investigation of AI, thus providing basic information for the establishment of clinical guidelines for the management of AI.