Steroid characteristics of mineralocorticoid adrenocortical hypertension

1991 ◽  
Vol 37 (10) ◽  
pp. 1843-1848 ◽  
Author(s):  
E G Biglieri ◽  
C E Kater
Keyword(s):  
Plasma Renin ◽  
Zona Glomerulosa ◽  
Zona Fasciculata ◽  
Hydroxylase Deficiency ◽  
Aldosterone Production ◽  
Apparent Mineralocorticoid Excess ◽  
Tomography Scan ◽  
Apparent Mineralocorticoid Excess Syndrome ◽  
Hydroxy Steroid ◽  
Steroid Dehydrogenase

Abstract Adrenocortical causes of hypertension are established by examining the mineralocorticoid hormones produced in the zona glomerulosa and zona fasciculata. In the zona glomerulosa, aldosterone excess leads to hypertension, hypokalemia, and suppressed plasma renin activity, with increased concentrations of urinary aldosterone (either as the 18-glucuronide or free aldosterone) as an index of its production. Identifying a tumor by computed tomography scan verifies the diagnosis of a correctable lesion. If no tumor is found, several maneuvers are used to identify primary adrenal hyperplasia, a disorder with autonomous aldosterone production, for which reduction of adrenal mass is curative. The zona fasciculata has two major pathways: the 17-deoxy pathway, where deoxycorticosterone (DOC) and corticosterone are the significant steroids, and the 17-hydroxy pathway, which leads to cortisol production. Tumors of the 17-deoxy pathway, DOC-producing adenomas, have increased concentrations of DOC and its precursor steroids, normal concentrations of cortisol, and suppression of aldosterone production secondary to suppression of the renin system. Two enzymatic defects in the zona fasciculata, 11 beta- and 17 alpha-hydroxylase deficiency, can be first readily identified by the virilization in the former, hypogonadal features in the latter. Steroid patterns are diagnostic. DOC is produced in excess in both deficiencies and is the cause of the hypertension. Deficient or impaired 11 beta-hydroxy steroid dehydrogenase in the apparent mineralocorticoid excess syndrome or after licorice ingestion retards the conversion of cortisol to inactive cortisone in the kidney, leading to mineralocorticoid hypertension; this leads to suppression of the renin system and subsequently of aldosterone.

scholarly journals Quantitative assessment of CYP11B1 and CYP11B2 expression in aldosterone-producing adenomas

2002 ◽  
pp. 795-802 ◽  
Author(s):  
F Fallo ◽  
V Pezzi ◽  
L Barzon ◽  
P Mulatero ◽  
F Veglio ◽  
...  
Keyword(s):  
Real Time ◽  
Secretory Activity ◽  
Zona Glomerulosa ◽  
Zona Fasciculata ◽  
Mrna Levels ◽  
Rt Pcr ◽  
Pathophysiological Role ◽  
Aldosterone Production

BACKGROUND: The presence and pathophysiological role of CYP11B1 (11beta-hydroxylase) gene in the zona glomerulosa of human adrenal cortex is still controversial. METHODS: In order to specifically quantify CYP11B1, CYP11B2 (aldosterone synthase) and CYP17(17alpha-hydroxylase) mRNA levels, we developed a real-time RT-PCR assay and examined the expression in a series of adrenal tIssues, including six normal adrenals from patients adrenalectomized for renal cancer and twelve aldosterone-producing adenomas (APA) from patients with primary aldosteronism. RESULTS: CYP11B1 mRNA levels were clearly detected in normal adrenals, which comprised both zona glomerulosa and fasciculata/reticularis cells, but were also measured at a lower range (P<0.05) in APA. The levels of CYP11B2 mRNA were lower (P<0.005) in normal adrenals than in APA. CYP17 mRNAlevels were similar in normal adrenals and in APA. In patients with APA, CYP11B2 and CYP11B1 mRNA levels were not correlated either with basal aldosterone or with the change from basal aldosterone in response to posture or to dexamethasone. No correlation between CYP11B1 mRNA or CYP11B2 mRNA and the percentage of zona fasciculata-like cells was observed in APA. CONCLUSIONS: Real-time RT-PCR can be reliably used to quantify CYP11B1 and CYP11B2 mRNA levels in adrenal tIssues. Expression of CYP11B1 in hyperfunctioning zona glomerulosa suggests an additional formation of corticosterone via 11beta-hydroxylase, providing further substrate for aldosterone biosynthesis. CYP11B1 and CYP11B2 mRNA levels in APA are not related to the in vivo secretory activity of glomerulosa cells, where post-transcriptional factors might ultimately regulate aldosterone production.

Abstract 097: Effects of Lysine-specific Demethylase 1 Deficiency on Aldosterone Production and Salt-sensitive Hypertension in Female Mice

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Yuefei Huang ◽  
Tham M Yao ◽  
Paul Loutraris ◽  
Isis K Rangel ◽  
Pei Yee Ting ◽  
...  
Keyword(s):  
Salt Intake ◽  
Ex Vivo ◽  
Plasma Renin ◽  
Zona Glomerulosa ◽  
Cardiovascular Outcomes ◽  
Female Mice ◽  
Urine Albumin ◽  
Aldosterone Production ◽  
Similar Phenotype ◽  
Salt Sensitive Hypertension

Lysine-Specific Demethylase1 (LSD1) is an epigenetic factor modulated by salt intake. Previously, we documented the male heterozygote LSD1 knockout mice (LSD1+/-) had dysregulation of aldosterone (ALDO) production on a liberal salt diet (1.6% Na+) associated with salt-sensitive hypertension. This study assessed if: 1) female LSD1+/- mice have a similar phenotype; and 2) the effect of aging on this phenotype. Methods: Female LSD1+/- and wild type mice (LSD1+/+) were randomly assigned for sacrifice at the ages of 18-week, 52-week, and 75-week and the following were assessed at each time point: blood pressure (BP); plasma renin activity (PRA) and ALDO; urine albumin; and ex vivo ALDO production from isolated adrenal zona glomerulosa cells. Results: BP and urine albumin in the LSD1+/- compared to the LSD1+/+ were not different at any age (Table). However, the LSD1+/- had greater ALDO/PRA ratios at 18 weeks compared with the LSD1+/+, but lower ALDO levels and ex vivo ALDO production at 52 and 75 weeks. Associated with this phenotype, the LSD1+/- showed significantly higher rate of all-cause mortality than the LSD1+/+. Conclusion: Lack of LSD1 caused dysregulation of ALDO production in both male and female mice. But the cardiovascular outcomes are different. The LSD1+/- females in contrast to males do not develop hypertension or albuminuria even at 75 weeks of age. However, the females do die at a faster rate than the males of a variety of causes. Thus, there is considerable sexual dimorphism in the pathogenesis of cardiovascular outcomes associated with dysregulation of adrenal ALDO production mediated by lack of LSD1.

DIFFICULTIES IN THE DIAGNOSIS OF THE ADRENOGENITAL SYNDROME IN INFANCY

PEDIATRICS ◽  
1972 ◽  
Vol 49 (2) ◽  
pp. 198-205
Author(s):  
C. H. Shackleton ◽  
F. L. Mitchell ◽  
J. W. Farquhar
Keyword(s):  
Hydroxylase Deficiency ◽  
Adrenogenital Syndrome ◽  
Steroid Excretion ◽  
21 Hydroxylase Deficiency ◽  
Hydroxy Steroid ◽  
Steroid Dehydrogenase

Pregnanetriol was not excreted by an infant (7 days old) who was later shown to have a defect in steroid 21-hydroxylase. However, the excretion of this compound increased during the following days (1.2 mg on the thirteenth day of life). A high excretion of 3β-hydroxy-Δ steroids was the most noticeable abnormality in steroid excretion noted on the seventh day of life (e.g., 3β, 16α-dihydroxy-5-pregnen-20-one, 15 mg; 3β, 21-dihydroxy-5-pregnen-20-one, 1.4 mg and 3β, 16α-dihydroxy-5-androsten-17-one, 7.4 mg). This high 3β-hydroxy-Δ steroid excretion results in difficulties in distinguishing a defect in 3β-hydroxy steroid dehydrogenase from a 21-hydroxylase deficiency. At the age of 14 months the principal steroids excreted were those predominant in other cases of 21-hydroxylase deficiency, viz. pregnanetriol and 5β-pregnane-3α, 17α, 20α-triol-11-one (11-oxo-pregnanetriol).

scholarly journals Aldosterone secretion in patients with septic shock: a prospective study

2013 ◽  
Vol 57 (8) ◽  
pp. 636-641 ◽  
Author(s):  
Rafael Barberena Moraes ◽  
Gilberto Friedman ◽  
Marina Verçoza Viana ◽  
Tiago Tonietto ◽  
Henrique Saltz ◽  
...  
Keyword(s):  
Septic Shock ◽  
Serum Levels ◽  
Zona Glomerulosa ◽  
High Dose ◽  
Zona Fasciculata ◽  
Cortisol Secretion ◽  
Aldosterone Secretion ◽  
Acth Stimulation ◽  
Aldosterone Production ◽  
A Prospective Study

OBJECTIVE: To assess serum levels of the main factors that regulate the activation of the zona glomerulosa and aldosterone production in patients with septic shock, as well as their response to a high-dose (250 µg) adrenocorticotropic hormone (ACTH) stimulation test. SUBJECTS AND METHODS: In 27 patients with septic shock, baseline levels of aldosterone, cortisol, ACTH, renin, sodium, potassium, and lactate were measured, followed by a cortrosyn test. RESULTS: Renin correlated with baseline aldosterone and its variation after cortrosyn stimulation. Baseline cortisol and its variation did not correlate with ACTH. Only three patients had concomitant dysfunction of aldosterone and cortisol secretion. CONCLUSIONS: Activation of the zona glomerulosa and zona fasciculata are independent. Aldosterone secretion is dependent on the integrity of the renin-angiotensin-aldosterone system, whereas cortisol secretion does not appear to depend predominantly on the hypothalamic-pituitary-adrenal axis. These results suggest that activation of the adrenal gland in critically ill patients occurs by multiple mechanisms.

scholarly journals Oxygen-dependence of ACTH-stimulated aldosterone and corticosterone synthesis in the rat adrenal cortex: developmental aspects

2002 ◽  
Vol 172 (3) ◽  
pp. 595-604 ◽  
Author(s):  
ED Bruder ◽  
AK Nagler ◽  
H Raff
Keyword(s):  
Enzyme Activity ◽  
Age Groups ◽  
Maximal Activity ◽  
Zona Glomerulosa ◽  
Zona Fasciculata ◽  
Steroid Synthesis ◽  
Camp Generation ◽  
Aldosterone Production ◽  
Health And Disease

The control of ACTH-stimulated steroidogenesis under decreasing levels of O(2) is not fully understood. The purpose of this study was to examine the effects of decreased O(2) in vitro on rat adrenocortical steroid synthesis at different stages of development. Of interest was the evaluation of the effect of low O(2) on steroidogenesis during the stress hyporesponsive period of the neonate. Rats were killed at 7, 14, or 42 days of age, adrenals collected and capsules (zona glomerulosa, ZG) separated from subcapsules (zona fasciculata/reticularis, ZFR). Cells were dispersed and placed into glass vials each gassed with a different level of O(2) (21, 5, 2, 1, or 0% O(2)). The entire steroidogenic pathway was analyzed by measuring ACTH-stimulated cAMP, corticosterone and aldosterone production during a 2 h incubation. In addition, the early (P450 scc) and late (P450c11 beta and P450 aldo) pathway activities were examined in the presence of cyanoketone. The PO(2) for half-maximal activity (P(50)) for aldosterone synthesis in ZG cells from 7- and 42-day-old rats was approximately 28 mmHg and 7 mmHg respectively, indicating that cells from older rats were more resistant to inhibition by low O(2). The P(50) for cAMP production from the ZG was approximately 14 mmHg for both age groups. The P(50) for corticosterone synthesis was approximately 28 mmHg and <7 mmHg in ZFR cells from 7- and 42-day-old cells respectively. The only enzyme activities affected by low O(2) (<35 mmHg) were P450 aldo and P450 scc. Moderate decreases in O(2) (from approximately 150 mmHg) decreased aldosteronogenesis, possibly due to observed decreases in cAMP generation, but not due to decreases in steroidogenic enzyme activity (7-day-old). Severe decreases in O(2) presumably inhibited P450 aldo through a direct effect on enzyme activity (both ages). P450 scc activity (including cholesterol transport) also seems to be decreased by very low O(2) (7-day-old). These findings illustrate a novel developmental alteration in O(2)-regulated steroid production, and may have implications for neonatal health and disease.

scholarly journals The Orphan Nuclear Receptors NURR1 and NGFIB Regulate Adrenal Aldosterone Production

2004 ◽  
Vol 18 (2) ◽  
pp. 279-290 ◽  
Author(s):  
Mary H. Bassett ◽  
Takashi Suzuki ◽  
Hironobu Sasano ◽  
Perrin C. White ◽  
William E. Rainey
Keyword(s):  
Kinase Inhibitor ◽  
Zona Glomerulosa ◽  
Zona Fasciculata ◽  
Related Factor ◽  
Mrna Levels ◽  
Ang Ii ◽  
Orphan Nuclear Receptors ◽  
Protein Levels ◽  
Aldosterone Production

Abstract Aldosterone biosynthesis in the zona glomerulosa of the adrenal cortex is regulated by transcription of CYP11B2 (encoding aldosterone synthase). The effects of nerve growth factor-induced clone B (NGFIB) (NR4A1), Nur-related factor 1 (NURR1) (NR4A2), and steroidogenic factor-1 (SF-1) (NR5A1) on transcription of human CYP11B2 (hCYP11B2) and hCYP11B1 (11β-hydroxylase) were compared in human H295R adrenocortical cells. hCYP11B2 expression was increased by NGFIB and NURR1. Although hCYP11B1 was activated by SF-1, cotransfection with SF-1 inhibited activation of hCYP11B2 by NGFIB and NURR1. NGFIB and NURR1 transcript and protein levels were strongly induced by angiotensin (Ang) II, the major regulator of hCYP11B2 expression in vivo. Sequential deletion and mutagenesis of the hCYP11B2 promoter identified two functional NGFIB response elements (NBREs), one located at −766/−759 (NBRE-1) and the previously studied Ad5 element at −129/−114. EMSAs suggested that both elements bound NGFIB and NURR1. In human adrenals, NURR1 immunoreactivity was preferentially localized in the zona glomerulosa and to a lesser degree in the zona fasciculata, whereas NGFIB was detected in both zones. The calmodulin kinase inhibitor KN93 partially blocked K+-stimulated transcription of NGFIB and NURR1. KN93 partially inhibited the effect of Ang II on NURR1 mRNA levels but did not modify the effect on expression of NGFIB. Mutation of the NBRE-1, Ad5, and Ad1/cAMP response element (CRE) cis-elements reduced both basal and Ang II-induced levels of hCYP11B2, demonstrating that all three elements are important for maximal transcriptional activity. Our results suggest that NGFIB and NURR1 are key regulators of hCYP11B2 expression and may partially mediate the regulation of hCYP11B2 by Ang II.

Roles of type I and type II isoenzymes of cyclic AMP-dependent protein kinase in steroidogenesis in rat adrenal cells

1994 ◽  
Vol 12 (2) ◽  
pp. 195-202 ◽  
Author(s):  
B J Whitehouse ◽  
D R E Abayasekara
Keyword(s):  
Cyclic Amp ◽  
Cell Function ◽  
Zona Glomerulosa ◽  
Zona Fasciculata ◽  
Type I ◽  
Type Ii ◽  
Aldosterone Production ◽  
Dependent Protein ◽  
Glomerulosa Cells ◽  
Zona Glomerulosa Cells

ABSTRACT The role played by cyclic AMP (cAMP)-dependent protein kinases (PKAs) in rat adrenal steroidogenesis has been investigated using cAMP analogues which show partial selectivity for the type I and type II PKA isoenzymes. These were aminohexylamino-cAMP (AHA-cAMP; selective for site 1 on type I PKA), N6-benzoyl-cAMP (BZ-cAMP; selective for site 2 on PKA types I and II) and 8-thiomethyl-cAMP (TM-cAMP; selective for site 1 on type II PKA). Positive cooperativity exists between the two nucleotide-binding sites, thus the presence of type I PKA was inferred when synergistic increases in corticosteroid production were obtained with AHA-cAMP plus BZ-cAMP and that of type II PKA when synergistic increases were obtained with TM-cAMP plus BZ-cAMP. The effects of AHA-cAMP, TM-cAMP and BZ-cAMP (10–100 μmol/l) on aldosterone production by glomerulosa cell preparations and corticosterone production by fasciculata/reticularis cell preparations were compared. Dose-related stimulation of steroid production was obtained with each cAMP analogue in both types of cell preparation. Experiments were performed using the cAMP analogues in combination at doses which gave minimal stimulation individually. Cells were incubated with AHA-cAMP (66 and 100 μmol/l) or TM-cAMP (15, 30 and 45 μmol/l) in the presence and absence of 15μmol BZ-cAMP/l. Synergistic responses were obtained with both analogue pairs in both cell types. The synergism ratio in fasciculata/reticularis cell preparations for the type I PKA selective pair of analogues (100 μmol AHA-cAMP/l plus 15μmol BZ-cAMP/l) was significantly higher (P<0·01) than that for the type II selective pair (45μmol TM-cAMP/l plus 15μmol BZ-cAMP/l; 7·9±1·2 (mean±s.e.m.) and 2·6±0·3 respectively). In zona glomerulosa preparations the ratio was higher (P<0·05) for the type II selective pair (1·6±0·1 for AHA-cAMP plus BZ-cAMP and 2·8±0·4 for TM-cAMP plus BZ-cAMP). The effects of 100μmol AHA-cAMP/l and 45μmol TM-cAMP/l on the response to ACTH (1 pmol/l–10 nmol/l) were examined. Synergistic responses were obtained in fasciculata/reticularis cells with both analogues in combination with low concentrations of ACTH (10 and 100 pmol/l). In zona glomerulosa cells only the addition of TM-cAMP (45 μmol/l) in combination with 10 pmol ACTH/1 gave rise to synergistic increases in aldosterone production, which suggests that there may be some compartmentalization of the cAMP-dependent pathway in these cells. The results indicate that both isoenzymes of PKA are present in rat adrenocortical cells and can play a part in the control of steroidogenesis. Type I PKA activity appears dominant in the control of zona fasciculata/reticularis cell function whereas modulation of type II PKA activity plays a more significant role in the responses of zona glomerulosa cells.

scholarly journals Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands

2015 ◽  
Vol 112 (33) ◽  
pp. E4591-E4599 ◽  
Author(s):  
Koshiro Nishimoto ◽  
Scott A. Tomlins ◽  
Rork Kuick ◽  
Andi K. Cani ◽  
Thomas J. Giordano ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Secondary Hypertension ◽  
Zona Glomerulosa ◽  
Driver Mutations ◽  
Molecular Characteristics ◽  
Zona Fasciculata ◽  
Adrenal Tissue ◽  
Somatic Gene ◽  
Aldosterone Production ◽  
Normal Adrenal Tissue

Primary aldosteronism (PA) represents the most common cause of secondary hypertension, but little is known regarding its adrenal cellular origins. Recently, aldosterone-producing cell clusters (APCCs) with high expression of aldosterone synthase (CYP11B2) were found in both normal and PA adrenal tissue. PA-causing aldosterone-producing adenomas (APAs) harbor mutations in genes encoding ion channels/pumps that alter intracellular calcium homeostasis and cause renin-independent aldosterone production through increased CYP11B2 expression. Herein, we hypothesized that APCCs have APA-related aldosterone-stimulating somatic gene mutations. APCCs were studied in 42 normal adrenals from kidney donors. To clarify APCC molecular characteristics, we used microarrays to compare the APCC transcriptome with conventional adrenocortical zones [zona glomerulosa (ZG), zona fasciculata, and zona reticularis]. The APCC transcriptome was most similar to ZG but with an enhanced capacity to produce aldosterone. To determine if APCCs harbored APA-related mutations, we performed targeted next generation sequencing of DNA from 23 APCCs and adjacent normal adrenal tissue isolated from both formalin-fixed, paraffin-embedded, and frozen tissues. Known aldosterone driver mutations were identified in 8 of 23 (35%) APCCs, including mutations in calcium channel, voltage-dependent, L-type, α1D-subunit (CACNA1D; 6 of 23 APCCs) and ATPase, Na+/K+transporting, α1-polypeptide (ATP1A1; 2 of 23 APCCs), which were not observed in the adjacent normal adrenal tissue. Overall, we show three major findings: (i) APCCs are common in normal adrenals, (ii) APCCs harbor somatic mutations known to cause excess aldosterone production, and (iii) the mutation spectrum of aldosterone-driving mutations is different in APCCs from that seen in APA. These results provide molecular support for APCC as a precursor of PA.

VERGLEICHENDE UNTERSUCHUNGEN ZUR BIOGENESE VON STEROIDHORMONEN BEI DURCHSTRÖMUNG ÜBERLEBENDER NEBENNIEREN EINER PATIENTIN MIT CUSHING- UND EINER PATIENTIN MIT CONN-SYNDROM

1963 ◽  
Vol 43 (3) ◽  
pp. 419-429 ◽  
Author(s):  
H. Schriefers ◽  
J. M. Bayer ◽  
M. Pittel
Keyword(s):  
Adrenal Gland ◽  
Adrenal Cortex ◽  
Zona Glomerulosa ◽  
Secretion Rate ◽  
Zona Fasciculata ◽  
Conn’S Syndrome ◽  
Adrenal Cortical Adenoma ◽  
Aldosterone Production ◽  
The Right

ABSTRACT In vitro perfusion experiments were carried out with adrenal glands surgically removed from a patient with Cushing's syndrome (hyperplasia of the adrenal cortex) and a patient with Conn's syndrome (adrenal cortical adenoma). From the perfusates the following steroids were extracted, estimated and identified: cortisol, corticosterone, 11β-hydroxyandrostenedione, cortisone and aldosterone. The secretion capacities of the right Cushing adrenal and of the adrenal gland bearing the adenoma were compared with each other. In both adrenals cortisol was the main secretion product and the secretion rates of aldosterone were lowest and practically equal. The Cushing adrenal differed from the adrenal gland with the adenoma in its higher secretion rate of all investigated steroids except aldosterone, in its higher cortisol/aldosterone ratio and in its response to the administration of ACTH. To this stimulus the aldosterone production of the Cushing adrenal reacted in the same rate as the cortisol release. The adrenal gland with the adenoma of the patient with Conn's syndrome had only a relatively higher aldosterone secretion rate in respect to its lower cortisol production (lower cortisol/aldosterone ratio). The total preparation consisting of the adrenal with the adenoma responded neither to ACTH nor to hypertensin. The missing response of the adrenal cortex not including the tumor to ACTH is explained by the structural change in the sense of the so called regressive transformation (small zona fasciculata with relative large zona glomerulosa and reticularis) which was found in our case. Dehydroepiandrosterone was demonstrable in none of the perfusate extracts even under the condition where the left adrenal of the Cushing patient was perfused with added 17α-hydroxy-pregnenolone.

Detection of Na+ and K+ in the Rat Adrenal Cortex with the Electron Microprobe

1977 ◽  
Vol 53 (5) ◽  
pp. 423-430 ◽  
Author(s):  
C. Decorzant ◽  
A. M. Riondel ◽  
M.-J. Philippe ◽  
J. Bertrand ◽  
M. B. Vallotton
Keyword(s):  
Adrenal Cortex ◽  
Electron Microprobe ◽  
Electrolyte Concentration ◽  
Zona Glomerulosa ◽  
Plasma Aldosterone ◽  
Zona Fasciculata ◽  
Aldosterone Secretion ◽  
Dietary Regimen ◽  
High K ◽  
Aldosterone Production

1. In order to demonstrate whether modification of aldosterone secretion is mediated by parallel changes of K+ in the adrenal zona glomerulosa, the total (intracellular + extracellular) Na+ and K+ content of the rat adrenal cortex was determined with the electron microprobe. 2. Groups of rats were submitted to one of the following dietary regimens: standard, low Na+, high K+ or high Na+. 3. Distribution of Na+ and K+ across the zona glomerulosa and zona fasciculata was compared. Standards of known electrolyte concentration were also analysed. 4. The [Na+] was found to be greater in the zona glomerulosa than in the zona fasciculata but K+ was distributed evenly in both zones. This was independent of dietary regimen. 5. Aldosterone production, assessed by plasma aldosterone concentrations, could not be correlated with zona glomerulosa K+ content.

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