Showing papers on "Adrenal cortex published in 2010"
TL;DR: Investigating the localization of CYP11B2 and -B1 in human adrenal specimens by using developed antibodies capable of distinguishing the two enzymes from each other revealed a variegated zonation with cell clusters constitutively expressing CYP 11B2, which may provide a pathological confirmatory diagnosis of adrenocortical adenomas.
Abstract: Context: Aldosterone synthase (CYP11B2) and steroid 11β-hydroxylase (CYP11B1) catalyze the terminal steps for aldosterone and cortisol syntheses, respectively, thereby determining the functional differentiation of human adrenocortical cells. Little is known, however, about how the cells expressing the enzymes are actually distributed in the adrenals under normal and pathological conditions. Objective: The objective of the study was to determine the localization of CYP11B2 and -B1 in human adrenal specimens by using developed antibodies capable of distinguishing the two enzymes from each other. Results: Under normal conditions, CYP11B2 was sporadically detected in the zona glomerulosa, whereas CYP11B1 was entirely detected in the zonae fasciculata-reticularis. Adrenocortical cells lacking both enzymes were observed in the outer cortical regions. In addition to conventional zonation, we found a variegated zonation consisting of a subcapsular cell cluster expressing CYP11B2, which we termed aldosterone-produ...
246 citations
TL;DR: In this article, constitutive activation of beta-catenin in the adrenal cortex of transgenic mice resulted in progressive steroidogenic and undifferentiated spindle-shaped cells hyperplasia as well as dysplasia of the cortex and medulla.
Abstract: Adrenocortical carcinoma is a rare but aggressive cancer with unknown aetiology. Constitutive activation of beta-catenin is the most frequent alteration in benign and malignant adrenocortical tumours in patients. Here, we show that constitutive activation of beta-catenin in the adrenal cortex of transgenic mice resulted in progressive steroidogenic and undifferentiated spindle-shaped cells hyperplasia as well as dysplasia of the cortex and medulla. Over a 17 months time course, transgenic adrenals developed malignant characteristics such as uncontrolled neovascularization and loco-regional metastatic invasion. These oncogenic events were accompanied by ectopic differentiation of glomerulosa at the expense of fasciculata cells, which caused primary hyperaldosteronism. Altogether these observations demonstrate that constitutively active beta-catenin is an adrenal oncogene which triggers benign aldosterone-secreting tumour development and promotes malignancy.
214 citations
TL;DR: Transcriptional phenotyping is not in favor of this being an intermediate step toward the formation of aldosterone-producing adenoma, but Transcriptome profiling indicates a close relationship between peritumoral and control adrenal cortex.
Abstract: Primary aldosteronism is the most common form of secondary hypertension with hypokalemia and suppressed renin-angiotensin system caused by autonomous aldosterone production. Our aim was to compare zona glomerulosa (ZG) structure and function between control adrenals and the peritumoral tissue from patients operated on for aldosterone-producing adenoma. ZG morphology and CYP11B1, CYP11B2, and disabled 2 expression were studied in 15 control adrenals and 25 adrenals with aldosterone-producing adenoma. A transcriptome analysis was done using publicly available data sets. In control adrenals, ZG was discontinuous, and CYP11B2 expression was focal or partly continuous and localized to 3 structures, foci, megafoci, and aldosterone-producing cell clusters. CYP11B2 expression was restricted to a limited number of ZG cells expressing Dab2 but not CYP11B1; aldosterone-producing cell clusters were composed of cells with an intermediate phenotype expressing CYP11B2 but not disabled 2 or CYP11B1. In peritumoral tissue, large remodeling of the adrenal cortex was observed with increased nodulation and decreased vascularization that were not correlated with CYP11B2 expression. In 17 out of 25 adrenals, hyperplasia of adjacent ZG was observed with persistent expression of CYP11B2 that was extended to the entire ZG. In all of the adrenals from patients with aldosterone-producing adenoma, CYP11B2 expression was present in foci, megafoci, and aldosterone-producing cell clusters. Transcriptome profiling indicates a close relationship between peritumoral and control adrenal cortex. In conclusion, adrenal cortex remodeling, reduced vascularization, and ZG hyperplasia are major features of adrenals with aldosterone-producing adenoma. Transcriptional phenotyping is not in favor of this being an intermediate step toward the formation of aldosterone-producing adenoma.
129 citations
TL;DR: Investigation of alterations in diurnal cortisol rhythm in ovarian cancer patients, and potential links with depression, life stress, and functional disability is investigated.
Abstract: Many physiological processes are governed by circadian rhythms in healthy humans and animals. However, in tumor-bearing organisms, the integrity of circadian rhythms is frequently compromised.1 Profound alterations in serum cortisol patterns have been reported in 15 of 20 ovarian cancer patients, including unusually high values of cortisol across the 24-hour cycle, erratic peaks and troughs, and flattened profiles.2 Abnormal diurnal cortisol profiles have been linked with poor performance status,3 persistent fatigue,4 and with poorer survival in breast cancer patients.5
Circadian rhythms align the organism with the light-dark cycle of the earth.6 Cortisol levels rise in the early morning, followed by a decrease over the course of the day, and reach a nadir during sleep.7 Morning light triggers the suprachiasmatic nucleus (SCN) of the hypothalamus to activate the hypothalamic-pituitary-adrenal (HPA) axis,6 leading to cortisol secretion by the adrenal cortex, with subsequent release of energy for daily activities.8
Cortisol also provides energy during the stress response.8 Acute cortisol elevations are observed in response to brief stressors.9,10 With chronic stress, the negative feedback system regulating cortisol becomes impaired,11 leading to chronically elevated cortisol, particularly at night.12 Depressed individuals also have impaired cortisol feedback and chronically elevated nocturnal cortisol.13 For example, depression has been associated with restricted diurnal cortisol variation in patients with advanced meta-static cancers of various types,14 and poor quality social support is associated with higher mean daily cortisol in breast cancer.15
Age-related and experimentally induced impairments in cortisol feedback have been shown to lead to greater tumor growth in animal models.16 For example, implanted tumors grow faster in mice with SCN lesions and consequently altered corticosterone rhythms.17 In humans, nocturnal shift work, with accompanying changes in diurnal rhythms, is associated with increased breast cancer risk.18 Alternatively, tumor tissues may influence circadian regulation in the host. For example tumor-bearing mice show alterations in corticosterone rhythms.19
Salivary cortisol is considered a reliable measure of the amount of unbound, biologically active cortisol in the blood. Repeated cortisol sampling during the day can provide information on circadian rhythm alterations and can suggest possible dysregulation of HPA feedback mechanisms.9
We have previously reported associations between elevated nocturnal cortisol and depression in a small sample of ovarian cancer patients.20 Depression has multiple components, including fatigue, vegetative symptoms, and distressed mood, which can be difficult to tease apart in medical patients. To better understand these relationships in the context of ovarian cancer, we examined 1) disturbances in the cortisol circadian rhythm in ovarian cancer patients, and 2) whether circadian cortisol alterations are associated with psychological factors such as stress or depressed mood and/or with functional disability and fatigue. To control for the stress of anticipated cancer surgery, we included a comparison group of women who underwent surgery for suspected ovarian cancer but were found to have benign disease. A reference group of healthy women not undergoing surgery was also included.
This approach enabled examination of whether dys-regulated cortisol is associated with psychological factors per se (such as distressed mood or perceived stress), and whether vegetative and potentially disease-related symptoms (such as fatigue and functional disability) are the primary correlates of dysregulated cortisol. These questions are of particular significance for understanding the etiology of cortisol dysregulation and vegetative symptoms in ovarian cancer.
On the basis of previous findings2,5 we hypothesized that women with ovarian cancer would demonstrate altered cortisol rhythms, including lower morning cortisol and elevations in afternoon and evening cortisol, resulting in reduced cortisol variability. Furthermore, we hypothesized that altered diurnal cortisol rhythms in ovarian cancer patients would be associated with functional disability, fatigue, and psychosocial factors such as stress and depressed mood.
107 citations
TL;DR: The results provide the genetic evidence to support that the adrenal capsule contributes to the growth of adrenocortex in both fetal and adult life but also identify a novel role of Shh in this process.
Abstract: The adrenal capsule is postulated to harbor stem/progenitor cells, the progenies of which contribute to the growth of adrenocortex. We discovered that cells in the adrenal capsule are positive for Ptch1 and Gli1, genes indicative of responsiveness to the stimulation of Hedgehog (Hh) ligands. On the other hand, Sonic hedgehog (Shh), one of the mammalian Hh ligands, is expressed in the adrenocortex underneath the adrenal capsule, possibly acting upon the Hh-Responsive capsule. To investigate the functional significance of Shh in adrenal growth, we ablated Shh in an adrenocortex-specific manner using the Steroidogenic factor 1-Cre mouse. Loss of Shh in the adrenocortex led to reduced proliferation of capsular cells and a 50-75% reduction in adrenocortex thickness and adrenal size. The remaining adrenocortex underwent proper zonation and was able to synthesize steroids, indicating that Shh is dispensable for differentiation of adrenocortex. When these animals reached adulthood, their adrenocortex did not undergo compensatory growth in response to a high level of plasma ACTH, and the size of the adrenal remained significantly smaller than the control adrenal. Using a genetic lineage-tracing model, we further demonstrated that the Hh-responding cells in the adrenal capsule migrated centripetally into the adrenocortex. Our results not only provide the genetic evidence to support that the adrenal capsule contributes to the growth of adrenocortex in both fetal and adult life but also identify a novel role of Shh in this process.
105 citations
TL;DR: The data provide the first in vivo evidence that loss of R1α is sufficient to induce autonomous adrenal hyper-activity and bilateral hyperplasia, both observed in human PPNAD, and demonstrates that deregulated PKA activity favors the emergence of a new cell population potentially arising from the fetal adrenal, giving new insight into the mechanisms leading to PPN AD.
Abstract: Carney complex (CNC) is an inherited neoplasia syndrome with endocrine overactivity. Its most frequent endocrine manifestation is primary pigmented nodular adrenocortical disease (PPNAD), a bilateral adrenocortical hyperplasia causing pituitary-independent Cushing's syndrome. Inactivating mutations in PRKAR1A, a gene encoding the type 1 α-regulatory subunit (R1α) of the cAMP–dependent protein kinase (PKA) have been found in 80% of CNC patients with Cushing's syndrome. To demonstrate the implication of R1α loss in the initiation and development of PPNAD, we generated mice lacking Prkar1a specifically in the adrenal cortex (AdKO). AdKO mice develop pituitary-independent Cushing's syndrome with increased PKA activity. This leads to autonomous steroidogenic genes expression and deregulated adreno-cortical cells differentiation, increased proliferation and resistance to apoptosis. Unexpectedly, R1α loss results in improper maintenance and centrifugal expansion of cortisol-producing fetal adrenocortical cells with concomitant regression of adult cortex. Our data provide the first in vivo evidence that loss of R1α is sufficient to induce autonomous adrenal hyper-activity and bilateral hyperplasia, both observed in human PPNAD. Furthermore, this model demonstrates that deregulated PKA activity favors the emergence of a new cell population potentially arising from the fetal adrenal, giving new insight into the mechanisms leading to PPNAD.
102 citations
TL;DR: Carboetomidate is a promising new sedative hypnotic for potential use in critically ill patients in whom adrenocortical suppression is undesirable, but it is dramatically less potent as an inhibitor of adrenOCortical steroid synthesis.
Abstract: Background Etomidate is a sedative hypnotic that is often used in critically ill patients because it provides superior hemodynamic stability. However, it also binds with high affinity to 11beta-hydroxylase, potently suppressing the synthesis of steroids by the adrenal gland that are necessary for survival. The authors report the results of studies to define the pharmacology of (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate), a pyrrole analog of etomidate specifically designed not to bind with high affinity to 11beta-hydroxylase. Methods The hypnotic potency of carboetomidate was defined in tadpoles and rats using loss of righting reflex assays. Its ability to enhance wild-type alpha1beta2gamma2l and etomidate-insensitive mutant alpha1beta2M286Wgamma2l human gamma-aminobutyric acid type A receptor activities was assessed using electrophysiologic techniques. Its potency for inhibiting in vitro cortisol synthesis was defined using a human adrenocortical cell assay. Its effects on in vivo hemodynamic and adrenocortical function were defined in rats. Results Carboetomidate was a potent hypnotic in tadpoles and rats. It increased currents mediated by wild-type but not etomidate-insensitive mutant gamma-aminobutyric acid type A receptors. Carboetomidate was a three orders of magnitude less-potent inhibitor of in vitro cortisol synthesis by adrenocortical cells than was etomidate. In rats, carboetomidate caused minimal hemodynamic changes and did not suppress adrenocortical function at hypnotic doses. Conclusions Carboetomidate is an etomidate analog that retains many beneficial properties of etomidate, but it is dramatically less potent as an inhibitor of adrenocortical steroid synthesis. Carboetomidate is a promising new sedative hypnotic for potential use in critically ill patients in whom adrenocortical suppression is undesirable.
79 citations
TL;DR: A higher frequency of SF-1 overexpression and gene amplification in pediatric than in adult adrenocortical tumors is demonstrated, suggesting an important role ofSF-1 in pediatric adrenOCortical tumorigenesis.
Abstract: Background: Steroidogenic factor 1 (SF-1) is a key determinant of endocrine development and function of adrenal cortex. SF-1 overexpression and gene amplification were previously demonstrated in a small group of pediatric adrenocortical tumors. Objective: Our objective was to determine the frequency of SF-1 protein expression and gene amplification in a large cohort of pediatric and adult adrenocortical tumors. Patients: SF-1 protein expression was assessed in a cohort of 103 adrenocortical tumors from 36 children and 67 adults, whereas gene amplification was studied in 38 adrenocortical tumors (17 from children). Methods: Tissue microarray, multiplex ligation-dependent probe amplification, and quantitative real-time PCR were used. Results: A strong nuclear SF-1 expression was detected by tissue microarray in 56% (20 of 36) and 19% (13 of 67) of the pediatric and adult adrenocortical tumors, respectively (P = 0.0004). Increased SF-1 copy number was identified in 47% (eight of 17) and 10% (two of 21) of th...
68 citations
TL;DR: Generation of SR-BI knockout mice has significantly contributed to the knowledge of the physiological role ofSR-BI and is identified as a multi-purpose player in cholesterol and steroid metabolism because it has distinct roles in reverse cholesterol transport, adrenal steroidogenesis, and platelet function.
Abstract: Scavenger receptor class B type I (SR-BI) is an important member of the scavenger receptor family of integral membrane glycoproteins. This review highlights studies in SR-BI knockout mice, which concern the role of SR-BI in cholesterol and steroid metabolism. SR-BI in hepatocytes is the sole molecule involved in selective uptake of cholesteryl esters from high-density lipoprotein (HDL). SR-BI plays a physiological role in binding and uptake of native apolipoprotein B (apoB)-containing lipoproteins by hepatocytes, which identifies SR-BI as a multi-purpose player in lipid uptake from the blood circulation into hepatocytes in mice. In adrenocortical cells, SR-BI mediates the selective uptake of HDL-cholesteryl esters, which is efficiently coupled to the synthesis of glucocorticoids (i.e. corticosterone). SR-BI knockout mice suffer from adrenal glucocorticoid insufficiency, which suggests that functional SR-BI protein is necessary for optimal adrenal steroidogenesis in mice. SR-BI in macrophages plays a dual role in cholesterol metabolism as it is able to take up cholesterol associated with HDL and apoB-containing lipoproteins and can possibly facilitate cholesterol efflux to HDL. Absence of SR-BI is associated with thrombocytopenia and altered thrombosis susceptibility, which suggests a novel role for SR-BI in regulating platelet number and function in mice. Transgenic expression of cholesteryl ester transfer protein in humanized SR-BI knockout mice normalizes hepatic delivery of HDL-cholesteryl esters. However, other pathologies associated with SR-BI deficiency, i.e. increased atherosclerosis susceptibility, adrenal glucocorticoid insufficiency, and impaired platelet function are not normalized, which suggests an important role for SR-BI in cholesterol and steroid metabolism in man. In conclusion, generation of SR-BI knockout mice has significantly contributed to our knowledge of the physiological role of SR-BI. Studies using these mice have identified SR-BI as a multi-purpose player in cholesterol and steroid metabolism because it has distinct roles in reverse cholesterol transport, adrenal steroidogenesis, and platelet function.
67 citations
TL;DR: Both the physiology and pathophysiology of aldosterone action in the vascular endothelium are closely related, suggesting that chronically high concentrations of this hormone over extended time periods impair sodium homeostasis promoting endothelial dysfunction and the development of tissue fibrosis.
64 citations
TL;DR: It is suggested that ATF/CREB and NGFI-B family members play a crucial role in the transcriptional regulation of CYP11B2 and adrenal cell capacity to produce aldosterone.
Abstract: Aldosterone synthesis is regulated by angiotensin II (Ang II) and K(+) acting in the adrenal zona glomerulosa, in part through the regulation of aldosterone synthase (CYP11B2). Here, we analyzed the role of cAMP response element (CRE)-binding proteins (CREBs) in the regulation of CYP11B2. Expression analysis of activator transcription factor (ATF)/CREB family members, namely the ATF1 and ATF2, the CREB, and the CRE modulator, in H295R cells and normal human adrenal tissue was performed using quantitative real-time PCR. Ang II-induced phosphorylation of ATF/CREB members was analyzed by Western blot analysis, and their subsequent binding to the CYP11B2 promoter using chromatin immunoprecipitation assay. Aldosterone production and CYP11B2 expression were measured in small interfering RNA-transfected cells to knockdown the expression of ATF/CREB members. CYP11B2 promoter activity was measured in H295R cells cotransfected with NURR1 (NR4A2) alone or with constitutively active vectors for ATF/CREB members. Ang II induced phosphorylation of ATF1, ATF2, and CRE modulator in a time-dependent manner. Based on chromatin immunoprecipitation analysis, there was an increased association of these proteins with the CYP11B2 promoter after Ang II and K(+) treatment. Phosphorylated ATF/CREB members also bound the CYP11B2 promoter. Knockdown of ATF/CREB members reduced Ang II and K(+) induction of adrenal cell CYP11B2 mRNA expression and aldosterone production. The constitutively active ATF/CREB vectors increased the promoter activity of CYP11B2 and had a synergistic effect with NURR1. In summary, these results suggest that ATF/CREB and NGFI-B family members play a crucial role in the transcriptional regulation of CYP11B2 and adrenal cell capacity to produce aldosterone.
TL;DR: The nongenomic effects of adrenal steroids in the central nervous system are reviewed at the levels of behaviour, neural system activity, individual neurone activity and subcellular signalling activity.
Abstract: Mineralocorticoids and glucocorticoids are steroid hormones that are released by the adrenal cortex in response to stress and hydromineral imbalance. Historically, adrenocorticosteroid actions are attributed to effects on gene transcription. More recently, however, it has become clear that genome-independent pathways represent an important facet of adrenal steroid actions. These hormones exert nongenomic effects throughout the body, although a significant portion of their actions are specific to the central nervous system. These actions are mediated by a variety of signalling pathways, and lead to physiologically meaningful events in vitro and in vivo. We review the nongenomic effects of adrenal steroids in the central nervous system at the levels of behaviour, neural system activity, individual neurone activity and subcellular signalling activity. A clearer understanding of adrenal steroid activity in the central nervous system will lead to a better ability to treat human disease as well as reduce the side-effects of the steroid treatments already in use.
TL;DR: The results suggest the direct involvement of SPX in the regulation of adrenocortical cell proliferation; however, the mechanism of action remains unknown.
TL;DR: It is concluded that adrenal ECM supports endocrine function and proliferation of adrenocortical cells in vitro and may form the basis for biocompatible tissue-engineered adrenal replacements.
Abstract: Transplantation of functional adrenal cortex cells could reduce morbidity and increase the quality of life of patients with adrenal insufficiency. Our aim was to determine whether adrenal extracell...
TL;DR: It is concluded that single imidazoles and mixtures have specific effects on adrenal hormone secretion and can only partly be predicted using current models and need to be further analyzed in terms of in vivo relevance and human risk assessment.
TL;DR: Novel findings are reported on 1alpha,25-dihydroxyvitamin D(3)-mediated effects on hormone production and regulation of genes and enzymes involved in steroidogenesis in the adrenocortical NCI-H295R cell line, a model for human adrenal cortex.
TL;DR: It is concluded that all cases of adrenocortical hypertrophy require further investigation or evidence to ascribe such findings to either stress or adrenocortsical inhibition/insufficiency, and that all Cases of adrencortical insufficiency represent a serious adverse effect that must be properly considered in toxicological risk assessment.
Abstract: The primary cause of adrenocortical hypertrophy is increased adrenocorticotrophic hormone (ACTH) stimulation. In toxicology studies, such a condition can arise as a result of the stress response, but it may also occur due to deficient glucocorticoid feedback regulation of ACTH due to toxicity to the adrenal cortex. This latter condition is defined as adrenocortical insufficiency and represents a serious adverse toxic effect on the function of the adrenal cortex. Adrenocortical hypertrophy may occur in the absence of other adrenocortical lesions such that a toxicopathological mechanism is not obvious, for example by pharmacological inhibition of steroidogenesis at the biochemical level. This review discusses the different aetiological factors and mechanisms producing adrenocortical hypertrophy. The need for further evidence in ascribing findings to stress is discussed, as is a protocol for establishing differential diagnoses between stress-induced and toxicity-induced adrenocortical hypertrophy, which is useful in cases where there are no other histopathological lesions in the adrenal cortex. It is concluded that all cases of adrenocortical hypertrophy require further investigation or evidence to ascribe such findings to either stress or adrenocortical inhibition/insufficiency, and that all cases of adrenocortical insufficiency (whether due to a histopathological lesion or reversible pharmacological enzyme inhibition) represent a serious adverse effect that must be properly considered in toxicological risk assessment.
TL;DR: Using an antibody panel consisting of chromogranin plus the nuclear antibody SF-1 and either calretinin or inhibin, while requiring a high-staining intensity threshold, helps to eliminate interpretative issues of artifactual or background reactivity, improves diagnostic sensitivity/specificity, and makes for an effective immunohistochemical approach in distinguishing adrenal cortical lesions from pheochromocytomas.
Abstract: We have encountered an increasing number of image-guided adrenal mass biopsies in which the differential diagnosis is adrenal cortical lesion versus pheochromocytoma. This distinction is sometimes difficult because of confounding clinical presentations, overlapping morphologies, and some degree of immunophenotypic overlap including focal staining with markers of purported lineage specificity. Interventional radiologists commonly use narrow gauge biopsy needles in this setting, which yield scant diagnostic tissue and further complicate pathologic evaluation. In this study, a detailed immunoprofile of 63 adrenal cortical lesions (3 adrenal rests, 6 adrenal cortical hyperplasias, 43 adrenal cortical adenomas, 4 adrenal cortical neoplasms of uncertain malignant potential, and 7 adrenal cortical carcinomas) was compared with 35 pheochromocytomas using traditional (calretinin, chromogranin, inhibin, melanA, and synaptophysin) and novel [steroidogenic factor-1 (SF-1), microtubule-associated protein 2, and mammalian achaete-scute homolog-1] antibodies, using tissue microarray technology to simulate small image-guided biopsies. Staining extent and intensity were each scored semiquantitatively for each antibody. A comparison of sensitivity and specificity using different intensity thresholds required for a "positive" result (> or = 1+ vs. > or = 2+) was performed. Staining results based on a > or = 1+ and (> or = 2+) intensity threshold were as follows: calretinin-95% (89%) in adrenal cortical lesions and 14% (0%) in pheochromocytomas; chromogranin-0% in adrenal cortical lesions and 100% in pheochromocytomas; inhibin-97% (86%) in adrenal cortical lesions and 6% (0%) in pheochromocytomas; microtubule-associated protein 2-29% (16%) in adrenal cortical lesions and 100% (89%) in pheochromocytomas; mammalian achaete-scute homolog-1-0% in both adrenal cortical lesions and pheochromocytomas; melanA-94% (86%) in adrenal cortical lesions and 6% (0%) in pheochromocytomas; SF-1-87% (86%) in adrenal cortical lesions and 0% in pheochromocytomas; synaptophysin-67% (59%) in adrenal cortical lesions and 100% in pheochromocytomas. Using an antibody panel consisting of chromogranin plus the nuclear antibody SF-1 and either calretinin or inhibin, while requiring a high-staining intensity threshold, helps to eliminate interpretative issues of artifactual or background reactivity, improves diagnostic sensitivity/specificity, and makes for an effective immunohistochemical approach in distinguishing adrenal cortical lesions from pheochromocytomas.
TL;DR: Recent data in the literature showing the implication of SF-1 and the importance of its dosage not only during development but also for adrenal cortex tumorigenesis in humans and mice are discussed.
Abstract: Steroidogenic factor-1 (SF-1/Ad4-binding protein; NR5A1) is an essential regulator of tissue-specific gene expression in steroidogenic cells and of adrenogonadal development. Here, I discuss recent data in the literature showing the implication of SF-1 and the importance of its dosage not only during development but also for adrenal cortex tumorigenesis in humans and mice.
TL;DR: It is hypothesize that a rise in intraadrenal cortisol during childhood growth may lead to inhibition of 3βHSD2 activity and contribute to the initiation of adrenarche.
Abstract: Context: Initiating factors leading to production of adrenal androgens are poorly defined. Cortisol is present in high concentrations within the adrenal gland, and its production rises with growth during childhood.
Objective: Our aim was to characterize the effect of cortisol and other glucocorticoids on androgen secretion from a human adrenocortical cell line and from nonadrenal cells transfected with CYP17A1 or HSD3B2.
Design/Setting: This study was performed in cultured cells, at an academic medical center.
Methods: The effects of cortisol upon steroid production in human adrenal NCI-H295R cells were measured by immunoassay, tandem mass spectrometry, and thin-layer chromatography. The effects of cortisol upon the activities of 17, 20 lyase and 3βHSD2 were measured in NCI-H295R cells and in transfected COS-7 cells.
Results: Cortisol markedly and rapidly stimulated dehydroepiandrosterone (DHEA) in a dose-dependent manner at cortisol concentrations ≥50 μm. Cortisone and 11-deoxycortisol were also potent stimulators of DHEA secretion, whereas prednisolone and dexamethasone were not. Treatment with cortisol did not affect expression of CYP17A1 or HSD3B2 mRNAs. Stimulation of DHEA secretion by cortisol was associated with competitive inhibition of 3βHSD2 activity.
Conclusions: Cortisol inhibits 3βHSD2 activity in adrenal cells and in COS-7 cells transfected with HSD3B2. Thus, it is possible that intraadrenal cortisol may participate in the regulation of adrenal DHEA secretion through inhibition of 3βHSD2. We hypothesize that a rise in intraadrenal cortisol during childhood growth may lead to inhibition of 3βHSD2 activity and contribute to the initiation of adrenarche.
TL;DR: It is postulate that most cases of PA are due to the activation by unknown mechanisms of subset of cells resulting in the formation of a multiple foci or nodules of hyperactive zona glomerulosa cells, which implies that one or several yet unidentified stimuli can drive ald testosterone overproduction, as well as the proliferation of aldosterone-producing cells.
Abstract: Primary Aldosteronism (PA) is a disorder of the adrenal zona glomerulosa (ZG) in which aldosterone secretion is increased and is relatively autonomous of normal regulatory mechanisms. A recent conference in Munich organized by Prof. Reincke addressed advances and challenges related to the screening, diagnosis, and identification of uni- and bilateral involvement of the diseased adrenal of PA. Some infrequently addressed issues are described herein. We postulate that most cases of PA are due to the activation by unknown mechanisms of subset of cells resulting in the formation of a multiple foci or nodules of hyperactive zona glomerulosa cells. This implies that one or several yet unidentified stimuli can drive aldosterone overproduction, as well as the proliferation of aldosterone-producing cells. Current diagnostic procedures allow to determine whether inappropriate aldosterone production is driven by one or both adrenal glands and thus to establish optimal treatment.
TL;DR: Dicer1 is dispensable for formation and differentiation of fetal tissues derived from the SF1-positive adrenogonadal primordium and development of the ovary from fetal stages to postnatal day 5 does not require the presence of Dicer1.
Abstract: The synthesis of microRNA (miRNA) is a multi-step process that requires the action of the ribonuclease Dicer1. Dicer1 is responsible for the final processing of miRNA and has been implicated in cellular processes such as proliferation, apoptosis, and differentiation. Mouse embryos lacking Dicer1 die in early embryogenesis. In this study, we investigated whether Dicer1 is required for development of adrenal, testis, and ovary in mouse embryos. To target Dicer1 deletion specifically in developing adrenals and gonads, we used Steroidogenic factor 1-cre (Sf1/Cre) line in which Cre recombinase is active in the progenitor cells of adrenals and gonads. Lack of Dicer1 in the SF1-positive cells did not affect formation and early differentiation of the adrenals and gonads. However, increasing numbers of apoptotic cells were first detected in the Dicer1 knockout adrenal cortex at 18.5 days post coitum (dpc), followed by apoptosis of somatic cells and germ cells in the testis at postnatal day 0. Affected adrenal and testes underwent complete degeneration 48 hrs after the onset of apoptosis. However, ovaries were not affected at least until postnatal day 5, when the animals died due to adrenal insufficiency. Dicer1 is dispensable for formation and differentiation of fetal tissues derived from the SF1-positive adrenogonadal primordium. Dicer1 is essential for maintaining cell survival in adrenal and testis; however, development of the ovary from fetal stages to postnatal day 5 does not require the presence of Dicer1. Our results reveal a tissue-specific requirement of Dicer1 and microRNAs. Future research is needed to understand how the tissue-specific role of Dicer1 is established.
TL;DR: The data suggest that modifications of the adrenocortical K(+) conductances could also contribute to autonomic aldosterone production and primary hyperaldosteronism in humans.
Abstract: Potassium channels control the membrane volt- age of aldosterone-producing zona glomerulosa cells. They are responsible for the unique K + sen- sitivity of these cells and are important molecu- lar targets of angiotensin II signaling. Among the 78 pore-forming K + channels in human genome only a few are found in adrenal glands. The 2- P-domain K + channels TASK1 and TASK3 are strongly expressed in the adrenal cortex and produce a background K + conductance, which is pivotal for the regulation of the aldosterone secretion in zona glomerulosa cells. Disrup- tion of the TASK1 gene in mice resulted in an autonomous aldosterone production and caused a remarkable aberrant expression of aldosterone synthase in zona fasciculata cells that normally produce glucocorticoids. After puberty, only in male mice aldosterone production was switched off in the zona fasciculata and regular zonation of aldosterone synthase occurred. In double mutant TASK1 - / - / TASK3 - / - mice, also adult male mice dis- played primary hyperaldosteronism. Therefore, these knockout mice are interesting models to study mechanisms of autonomous aldosterone production and adrenocortical zonation. These data suggest that modifi cations of the adreno- cortical K + conductances could also contribute to autonomic aldosterone production and primary hyperaldosteronism in humans.
TL;DR: It is demonstrated that LH signaling specifically up-regulates expression of TGFbeta2 in the subcapsular region of the adrenal cortex, which coincides with regions of aberrant Smad3 activation in Inha-/- adrenal glands, indicating that inhibin can specifically antagonize TGF beta2 signaling in cellular contexts where surface expression of betaglycan is limiting.
Abstract: Inhibin is an atypical member of the TGFβ family of signaling ligands and is classically understood to function via competitive antagonism of activin ligand binding. Inhibin-null (Inha−/−) mice develop both gonadal and adrenocortical tumors, the latter of which depend upon gonadectomy for initiation. We have previously shown that gonadectomy initiates adrenal tumorigenesis in Inha−/− mice by elevating production of LH, which drives aberrant proliferation and differentiation of subcapsular adrenocortical progenitor cells. In this study, we demonstrate that LH signaling specifically up-regulates expression of TGFβ2 in the subcapsular region of the adrenal cortex, which coincides with regions of aberrant Smad3 activation in Inha−/− adrenal glands. Consistent with a functional interaction between inhibin and TGFβ2, we further demonstrate that recombinant inhibin-A antagonizes signaling by TGFβ2 in cultured adrenocortical cells. The mechanism of this antagonism depends upon the mutual affinity of inhibin-A and...
TL;DR: It is now clear that adrenal steroids can be metabolized within bone tissue itself and local synthesis of cortisol within bone from its inactive precursor cortisone has been demonstrated and the amount of cortisol produced within osteoblasts appears to increase with age.
TL;DR: The results suggest that adrenic acid relaxations of bovine adrenal cortical arteries are mediated by endothelial and zona glomerulosa cell cytochrome P450 metabolites, which could function as endogenous endothelium-derived andZona glomersulosa-derived hyperpolarizing factors in the adrenal cortex and contribute to the regulation of adrenal blood flow.
Abstract: Adrenic acid (docosatetraenoic acid), an abundant fatty acid in the adrenal gland, is identical to arachidonic acid except for 2 additional carbons on the carboxyl end. Adrenic acid is metabolized by cyclooxygenases, cytochrome P450s, and lipoxygenases; however, little is known regarding the role of adrenic acid and its metabolites in vascular tone. Because of its abundance in the adrenal gland, we investigated the role of adrenic acid in vascular tone of bovine adrenal cortical arteries and its metabolism by bovine adrenal zona glomerulosa cells. In adrenal cortical arteries, adrenic acid caused concentration-dependent relaxations, which were inhibited by the epoxyeicosatrienoic acid antagonist 14,15-epoxyeicosa-5(Z)-enoic acid and the cytochrome P450 inhibitor SKF-525A. The large-conductance calcium-activated potassium channel blocker iberiotoxin or removal of the endothelium abolished these relaxations. Reverse-phase high-pressure liquid chromatography and liquid chromatography/mass spectrometry isolated and identified numerous adrenic acid metabolites from zona glomerulosa cells, including dihomo-epoxyeicosatrienoic acids and dihomo-prostaglandins. In denuded adrenal cortical arteries, adrenic acid caused concentration-dependent relaxations in the presence of zona glomerulosa cells but not in their absence. These relaxations were inhibited by SKF-525A, 14,15-epoxyeicosa-5(Z)-enoic acid, and iberiotoxin. Dihomo-16,17-epoxyeicosatrienoic acid caused concentration-dependent relaxations of adrenal cortical arteries, which were inhibited by 14,15-epoxyeicosa-5(Z)-enoic acid and high potassium. Our results suggest that adrenic acid relaxations of bovine adrenal cortical arteries are mediated by endothelial and zona glomerulosa cell cytochrome P450 metabolites. Thus, adrenic acid metabolites could function as endogenous endothelium-derived and zona glomerulosa-derived hyperpolarizing factors in the adrenal cortex and contribute to the regulation of adrenal blood flow.
TL;DR: Anandamide inhibited basal release and stimulated release of adrenocortical steroids (corticosterone and aldosterone) and this effect was reversed by CB1 antagonist (SR141716A); therefore, the endocannabinoid system at the level of the adrenal, can directly influence adrenOCortical steroidogenesis.
Abstract: Endogenous cannabinoids are important signaling molecules in neuroendocrine control of homeostatic and reproductive functions including stress response and energy metabolism. The hypothalamic paraventricular and supraoptic nuclei have been shown to release endocannabinoids, which act as retrograde messengers to modulate the synaptic release of glutamate during stress response. This study endeavors to elucidate possible interaction of the endocannabinoid system with the regulation of adrenocortical function at the adrenal level. Human adrenocortical NCI-H295R cells and normal human adrenal glands were used to study the possible effects of anandamide and cannabinoid receptor 1 (CB1) antagonist SR141716A on aldosterone and cortisol secretion. Our data indicate the expression of CB1 in human adrenal cortex and adrenocortical NCI-H295R cells; CB2 was not expressed. Furthermore, anandamide inhibited basal release and stimulated release of adrenocortical steroids (corticosterone and aldosterone); this effect was reversed by CB1 antagonist (SR141716A). Therefore, the endocannabinoid system at the level of the adrenal, can directly influence adrenocortical steroidogenesis.
TL;DR: PKA is confirmed as the central cAMP mediator in steroid hormone production and the involvement of EPAC2B in cAMP-induced effects on cytoskeleton integrity and cell migration is revealed.
Abstract: In the adrenal cortex, the biosynthesis of steroid hormones is controlled by the pituitary-derived hormone ACTH. The functions of ACTH are principally relayed by activating cAMP-dependent signaling pathways leading to the induction of genes encoding enzymes involved in the conversion of cholesterol to steroid hormones. Previously, protein kinase A (PKA) was thought to be the only direct effector of cAMP. However, the discovery of the cAMP sensors, exchange proteins directly activated by cAMP (EPAC1 and 2), has led to a reevaluation of this assumption. In the present study, we demonstrate the occurrence of the EPAC2 splicing variant EPAC2B in adrenocortical cancer cells. Immunocytochemistry demonstrated that EPAC2B is localized predominantly in the nucleus. EPAC2B is functional because it activates Rap1 in these cells. Using the cAMP analogs 8-p-chlorophenylthio-2'-O-methyl-cAMP and N6-benzoyl-cAMP, which specifically activate EPAC1/2 and PKA, respectively, we evaluated the contribution of these factors in steroid hormone production, cell morphology, actin reorganization, and migration. We demonstrate that the expression of cAMP-inducible factors involved in steroidogenesis (steroidogenic acute regulatory protein, cytochrome P450 11A1 and 17, and nerve growth factor-induced clone B) and the cAMP-induced biosynthesis of steroid hormones (cortisol and aldosterone) are mediated by PKA and not by EPAC2B. In contrast, both PKA- and EPAC-specific cAMP analogs induced cell rounding, loss of stress fibers, and blocked migration. Taken together, the presented data confirm PKA as the central cAMP mediator in steroid hormone production and reveal the involvement of EPAC2B in cAMP-induced effects on cytoskeleton integrity and cell migration.
TL;DR: Data indicate that LTH enhances adrenal cortical sensitivity to the inhibitory effects of NO on cortisol production, and nitric oxide may, therefore, play an important role in regulating ACTH-induced cortisol production in the LTH fetal adrenal.
Abstract: We previously reported that in the sheep fetus, long-term hypoxia (LTH) resulted in elevated basal plasma adrenocorticotropic hormone (ACTH(1- 39)) whereas the cortisol levels were not different from normoxic controls. We also showed that LTH enhances endothelial nitric oxide synthase (eNOS) expression in the fetal adrenal. This study was designed to determine the effect of NO on cortisol production in adrenocortical cells from LTH fetal sheep. Ewes were maintained at high altitude (3820 m) from ∼40 days' gestation (dG) to near term. Between 138 and 141 dG, fetal adrenal glands were collected from LTH and age-matched normoxic control fetuses. Adrenal cortical cells were pretreated with sodium nitroprusside (SNP), nitro-L-arginine methyl ester (L-NAME), L-arginine, or diethyleneamine NO (DETA-NO) and then challenged with 10 nmol/L ACTH. Cortisol responses were compared after 1 hour. Adrenocorticotropic hormone -induced cortisol secretion was significantly higher in LTH versus control (P < .01). Enhancement of NO with L-arginine resulted in a significant reduction of ACTH-mediated cortisol production in the LTH group. DETA-NO also caused a significant decrease in ACTH-mediated cortisol production (P < .05). Inhibition of NOS with L-NAME significantly increased cortisol production in the LTH group (P < .05 compared to ACTH alone), whereas the effect on the control group was not significant. Nitric oxide synthase activity was significantly higher in the LTH group compared to control, but this difference was eliminated following ACTH treatment. These data indicate that LTH enhances adrenal cortical sensitivity to the inhibitory effects of NO on cortisol production. Nitric oxide may, therefore, play an important role in regulating ACTH-induced cortisol production in the LTH fetal adrenal.
TL;DR: The pathologic findings in the adrenal glands of 4 patients, aged 10 to 38 years, with Cushing syndrome and germline inactivating mutations of the gene PDE11A4 that encodes phosphodiesterase 11A4 are presented.
Abstract: We present the pathologic findings in the adrenal glands of 4 patients, aged 10 to 38 years, with Cushing syndrome and germline inactivating mutations of the gene PDE11A4 that encodes phosphodiesterase11A4. The gene is expressed in the adrenal cortex and catalyses the hydrolysis of cyclic adenosine monophosphate and cyclic guanosine monophosphate. Two of the patients were mother and daughter; the third had no affected relative; the fourth patient inherited the mutation from her father. Three of the group, including the mother and daughter, had the same pathology, primary pigmented nodular adrenocortical disease, a disorder known to be caused by inactivating mutations of the PRKAR1A gene. In these cases, the adrenal glands were small and the pathologic change was deep in the cortex in which numerous pigmented micronodules developed. In the remaining patient, the glands were slightly enlarged primarily owing to a diffuse hyperplasia of the superficial cortex that extended into the epi-adrenal fat.