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Nonclassic apparent mineralocorticoid excess (NC-AME) is proposed as a novel clinical condition with a mild phenotypic spectrum that ranges from normotension to severe hypertension. This condition is mainly characterized by a high serum cortisol to cortisone ratio (F/E) and concomitant low cortisone (E), however further metabolic changes in NC-AME have not been studied. A cross-sectional study was performed in a primary-care cohort of 396 Chilean subjects, which were classified in two groups: NC-AME (n = 28) and healthy controls (n = 27). A discovery study based in untargeted metabolomics assay in serum samples from both groups was performed by UPLC-Q-TOF/MS. Global metabolomic variations were assayed by principal component analysis and further compared by orthogonal partial least-squares discriminant analysis (OPLS-DA). NC-AME subjects exhibited higher values of blood pressure, fractional excretion of potassium, and lower plasma renin activity and urinary sodium to potassium ratio. Metabolomic analyses showed 36 differentially regulated metabolites between NC-AME and control subjects. A ROC curve analyses identified eight metabolites with high discriminatory capacity between NC-AME and control subjects. Moreover, gamma-L-glutamyl-L-methionine sulfoxide and 5-sulfoxymethylfurfural, exhibited significant association with cortisone, which are potential biomarkers of NC-AME, however further assays should elucidate its biological role in setup and progression of this phenotype., (© 2021. The Author(s).)

The aim of the work was to describe the profile of steroid hormones in the peripartum period of the bitch. Twenty-five healthy pregnant bitches presented for pregnancy monitoring and parturition assistance were included in the study. A blood sample was collected for routine progesterone assay, and serum was stored at -20°C. The day of parturition and the number of delivered puppies were registered. Concentrations of corticosteroids, androgens, progestogens, estrogens, for a total number of 17 different hormones, were measured using ultra-performance supercritical fluid chromatography-tandem mass spectrometry. Data were analyzed using a repeated measure, mixed-model approach, taking into account day (from day -4 to day +2 from parturition), age, parity (primiparous vs pluriparous), number of delivered puppies (<4 vs 4-8 vs > 8), and interactions between factors. Day related to parturition significantly affected the concentration of progesterone (P < 0.001), testosterone (P < 0.001), 17α-hydroxyprogesterone (P = 0.0002), and cortisone (P = 0.006). Estrogen concentration did not show any significant variation over time. Testosterone and androstenedione showed an abrupt decline on the day of parturition. The concentration of all glucocorticoids increased the day before parturition. Age or parity was not significantly associated with any of the steroids. Litter size significantly affected concentrations of aldosterone (P = 0.02) and etiocholanolone (P = 0.01). Aldosterone concentrations were higher in litters with 4 to 8 pups than in litters with more than 8 pups (P = 0.02). None of the steroids measured in our study, with the already known exception of progesterone, shows potential to be clinically useful in predicting the onset of parturition in the bitch., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The recent demonstration of the significant reduction in mortality in patients with septic shock treated with adjunctive glucocorticoids combined with fludrocortisone and the effectiveness of angiotensin II in treating vasodilatory shock have renewed interest in the role of the mineralocorticoid axis in critical illness. Glucocorticoids have variable interactions at the mineralocorticoid receptor. Similarly, mineralocorticoid receptor-aldosterone interactions differ from mineralocorticoid receptor-glucocorticoid interactions and predicate receptor-ligand interactions that differ with respect to cellular effects. Hyperreninemic hypoaldosteronism or selective hypoaldosteronism, an impaired adrenal response to increasing renin levels, occurs in a subgroup of hemodynamically unstable critically ill patients. The suggestion is that there is a defect at the level of the adrenal zona glomerulosa associated with a high mortality rate that may represent an adaptive response aimed at increasing cortisol levels. Furthermore, cross-talk exists between angiotensin II and aldosterone, which needs to be considered when employing therapeutic strategies.

Context: Estrogen-progestin combined oral contraceptive (COC) has been connected to mineralocorticoid receptor (MR) activation and adverse cardiometabolic events. We consequently hypothesised that insulin resistance (IR), hyperuricemia, and elevated circulating GSK-3 induced by COC is through activation of MR via mineralocorticoid and glucocorticoid pathways. Methods: Female Wistar rats aged 12 weeks received ( po ) vehicle and COC (1.0   μg ethinylestradiol plus 5.0   μg levonorgestrel) with or without MR blocker (0.25   mg/kg spironolactone; Spl), daily for eight   weeks. Results: Data showed that COC treatment led to increased IR, 1-hour postload glucose level, insulinemia, triglyceride/HDL-cholesterol ratio, total cholesterol/HDL-cholesterol ratio, uric acid, GSK-3, aldosterone, corticosterone values, impaired glucose tolerance and pancreatic β-cell function. However, MR blockade by Spl ameliorated all these alterations except that of aldosterone. Conclusion: The results demonstrate that COC induces IR, hyperuricemia and high GSK-3 levels through activation of MR via glucocorticoid dependent pathway.

Aims: We aimed to evaluate the associations of mineralocorticoids with type 2 diabetes mellitus (T2DM) and glucose homeostasis among rural Chinese adults., Methods: A total of 2713 participants were selected from the Henan Rural Cohort study. Serum mineralocorticoids were measured by liquid chromatography-tandem mass spectrometry. Logistic regression and restricted cubic splines were employed to evaluate the associations of mineralocorticoids with pre-diabetes and T2DM. Linear regression was implemented to assess the associations of aldosterone and 11-deoxycorticosterone with different markers of glucose homeostasis by different diabetes status., Results: Elevated aldosterone and 11-deoxycorticosterone were associated with an increased prevalence of pre-diabetes and T2DM (P < 0.05), with a nonlinear dose-response trend, but the association between 11-deoxycorticosterone and T2DM was no statistical significance after adjustment. A 100% increase in ln-aldosterone was associated with a 0.029 mg/dl higher fasting plasma glucose (FPG) and a 1.2% higher HOMA2-IR among those with normal glucose tolerance (NGT), and related to a 0.034 mg/dl lower FPG, a 1.1% higher HbA1c and a 1.3% higher HOMA2-β among individuals with pre-diabetes. A 100% increment in ln-11-deoxycorticosterone was associated with a 16% increase in HbA1c and a 5.6% decrease in HOMA2-β in participants with T2DM., Conclusions: Higher aldosterone and 11-deoxycorticosterone are associated with T2DM risk and glucose homeostasis disorder among different diabetes status., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Adrenal steroids are generated in the adrenal cortex and metabolized by various enzymes such as hydroxylases, dehydrogenases, and reductases. Determining the comprehensive metabolic signatures of adrenal steroids can provide insight into their metabolic functions and roles in the pathophysiology of adrenal diseases, including Cushing's syndrome (CS) and congenital adrenal hyperplasia (CAH). To this end, we developed an advanced quantitative profiling method of serum adrenal steroids with liquid chromatography-mass spectrometry (LC-MS) under molecular-specific scan modes. Twenty-seven steroids were separated on a 1.9-μm particle C18 column (50 × 2.1 mm) at a flow rate of 250 μL/min and quantified via triple-quadrupole MS with electrospray ionization. During validation, linearities ( r 2 ) were higher than 0.940 with a limit of quantification of 0.1-5.0 ng/mL, and precision (coefficient of variation) and accuracy (%bias) of 3.7-14.3 % and 96.3-113.1 %, respectively. In contrast with the significantly increased serum levels of mineralocorticoids (P <  0.001), the present LC-MS assay revealed remarkably decreased levels of all glucocorticoids and androgens in a patient diagnosed with 17α-hydroxylase deficiency CAH (P <  0.001) compared to those of age- and sex-matched healthy and CS subjects. In the CAH patient, the metabolic ratios for 17α-hydroxylase were significantly decreased, whereas there was no reduction in the metabolic ratio of 17-hydroxyprogesterone to androstenedione, indicating 17,20-lyase activity. In particular, both pregnenolone and dehydroepiandrosterone sulfates, and their metabolic ratio, were identified as potential biomarkers for 17α-hydroxylase deficiency (all P <  0.001), which were also distinct from those of CS patients. The devised LC-MS assay clearly revealed the metabolic signatures of 17α-hydroxylase deficiency, as a rare phenotype of CAH, compared to both healthy and CS subjects, indicating its utility for screening adrenal diseases., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: HLA-G is an immune checkpoint molecule, naturally expressed during pregnancy, playing a critical role in the tolerance of the fetal semi-allograft from the maternal immune system. While HLA-G expression levels are associated with progesterone, the influence of other hormones is still unclear. Congenital adrenal hyperplasia (CAH) represents an adequate model to study the hormonal influence on biomarkers as it leads to impaired cortisol biosynthesis and increased progesterone and androgens production due to 21-hydroxylase enzyme deficiency., Methods: In a cross-sectional study of CAH patients matched on sex and age with healthy control, the association between circulating levels of soluble HLA-G and hormones was assessed by use of non-parametric analyses tests. Multivariable linear regressions were performed on normalized data., Results: Overall, 83 CAH patients and 69 healthy controls were included. Among CAH patients, all were under glucocorticoid and 52 (62.6%) were under mineralocorticoid supplementation. Compared to controls, CAH patients had increased HLA-G levels (15 vs 8 ng/mL, P = 0.02). In controls, HLA-G level was independently associated with progesterone and estradiol (β = 0.44 (0.35-1.27) and -0.44 (-0.94, -0.26) respectively, both P values = 0.001). In CAH patients, HLA-G level was independently associated with mineralocorticoid supplementation dosage (β = 0.25 (0.04-0.41), P = 0.001) and estradiol (β = -0.22 (-0.57, -0.02), P < 0.001)., Conclusion: CAH patients had higher HLA-G levels than healthy controls. HLA-G level was positively associated with progesterone and corticosteroid supplementation, and negatively with estradiol. The association between mineralocorticoid, renin and HLA-G levels may suggest a role of the renin-angiotensin system in the expression of soluble HLA-G.

Background Hypertrophic cardiomyopathy (HCM) in childhood is a rare diagnosis, and associations with adrenocortical tumors (ACTs) have been rarely reported in the pediatric literature. Case presentation We present a case of a 5-month-old who presented with HCM and during the evaluation for hypertension was found to have elevated glucocorticoids, mineralocorticoids, androgens and urine metanephrines. During preoperative evaluation, he developed shock followed by cardiogenic collapse requiring extracorporeal membrane oxygenation (ECMO); however, he did not survive. Pathology revealed an ACT with hormone production that contributed to his demise. Conclusions Adrenocortical tumors associated with hypertrophic cardiomyopathy can be life-threatening. We discuss the complex interplay of unrestricted cortical hormone production in the setting of hypertrophic cardiomyopathy that may lead to rapid decline and poor clinical outcomes.

Estrogen deficiency has been associated with increased incidence of cardiovascular diseases , and recent clinical trials of standard formulations of hormonal therapies have not demonstrated consistent beneficial effects. Estrogen-progestin therapy has been used as exogenous estrogen to normalize depressed estrogen level during menopause. Ovariectomized rodents mimic an estrogen-deficient state in that they develop cardiometabolic dysfunction, including insulin resistance (IR). We therefore hypothesized that hormonal therapy with combined oral contraceptive steroids, ethinylestradiol-levonorgestrel (EEL), improves IR, obesity, and glycogen synthase kinase-3 (GSK-3) through reduction of circulating mineralocorticoid in ovariectomized rats. Twelve-week-old female Wistar rats were divided into 4 groups: sham-operated (SHM) and ovariectomized (OVX) rats were treated with or without EEL (1.0 μg ethinylestradiol and 5.0 μg levonorgestrel) daily for 8 weeks. Results showed that OVX or SHM + EEL treated rats had increased HOMA-IR (homeostatic model assessment of IR), 1 h postload glucose, HOMA-β, triglycerides (TG), total cholesterol (TC), TC/HDL cholesterol, TG/HDL cholesterol, plasma insulin, GSK-3, corticosterone, and aldosterone. On the other hand, OVX + EEL treatment ameliorated all these effects except that of aldosterone. Taken together, the results demonstrate that oral hormonal replacement with EEL improves IR and pancreatic β-cell function and suppresses GSK-3 and glucocorticoid independent of circulating aldosterone, suggesting a positive cardiometabolic effect of oral EEL therapy in estrogen-deficient rats.

Context: Mineralocorticoid (MC) replacement therapy in patients with primary adrenal insufficiency (PAI) was introduced more than 60 years ago. Still, there are limited data on how MC substitution should be optimized, because MC dosing regimens have only been systematically investigated in a few studies. We review the management of current standard MC replacement therapy in PAI and its plausible impact on outcome., Design: Using PubMed, we conducted a systematic review of the literature from 1939 to 2017, with the following keywords: adrenal insufficiency, MC deficiency, aldosterone, cardiovascular disease, hypertension, and heart failure., Results: The current standard treatment consists of fludrocortisone (FC) given once daily in the morning, aiming at normotension, normokalemia, and plasma renin activity in the upper normal range. Available data suggest that patients with PAI may be underreplaced with FC as symptoms and signs indicating chronic MC underreplacement, such as salt craving and postural dizziness persist, in many treated patients with PAI. Data acquired from large registry-based studies show that glucocorticoid doses for replacement in PAI are higher than those estimated from endogenous production. Glucocorticoid overreplacement may reduce the need of MC replacement but may also be a consequence of inadequate MC replacement., Conclusions: The commonly used MC replacement in PAI may not be adequate in some patients. Insufficient MC substitution may be responsible for poor cardiometabolic outcome and the failure to restore well-being adequately in patients with PAI. Well-designed studies oriented at optimizing MC replacement therapy are urgently needed., (Copyright © 2017 Endocrine Society)

Competing Interests: Competing interests All authors have completed the Unified Competing Interest form (available on request from the corresponding author) and declare no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, and no other relationships or activities that could appear to have influenced the submitted work.

Objective: The aim of this study was to investigate the serum aldosterone level and abnormal levels of mineral corticoid in patients with the central serous chorioretinopathy (CSC)., Patients and Methods: All recruited patients with CSC received fundus fluorescein angiography (FFA), enhanced depth imaging spectral-domain optical coherence tomography (EDI-OCT) and serum aldosterone assay. The patients were classified into spontaneously resolved group and unresolved group according to a 3-months follow-up of Optical Coherence Tomography (OCT) examination. Patients from unresolved group were recruited to receive treatment with 40 mg spironolactone orally for 2 months. After the treatment, the EDI-OCT and best corrected visual acuity (BCVA) were performed again to assess the treatment efficacy., Results: The study included 61 patients (72 eyes) with 34 patients in the unresolved group and 27 patients in the resolved group. The aldosterone level was significantly associated with the subfoveal choroidal thickness (SFCT) of revolved CSC eyes (r=0.342, p<0.05) as well as the SFCT of unresolved CSC eyes (r=0.348, p<0.05). And the aldosterone level in the unresolved CSC group was greater than that in the spontaneously resolved group (161.8 ± 50.1 ng/dl vs. 122.5 ± 50.5 ng/dl, p<0.05). The central macular thickness and SFCT were decreased significantly (p<0.05) after the treatment with 40 mg/d spironolactone for two months., Conclusions: The unresolved CSC patients were characterized by high level of aldosterone and thickened SFCT. Spironolactone treatment was associated with the improvement of chronic CSC. Besides, the side effect of spironolactone treatment was rare.

Serum steroid assays are major tools in the clinical evaluation of adrenal disorders. The main adrenal steroids are routinely measured with immunoassays. However, chromatographic methods are known to offer better specificity. We report a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for simultaneous quantification of 15 adrenal steroids targeting the mineralo- and gluco-corticosteroid pathways. Serum steroids combined with deuterated internal standards were extracted using successive protein precipitation and solid phase extraction steps. Cortisol, cortisone, 11-deoxycortisol, 17-hydroxyprogesterone, 21-deoxycortisol, progesterone, 11-deoxycorticosterone, corticosterone, 11-dehydrocorticosterone, 18-hydroxycorticosterone, 18-hydroxy-11-deoxycorticosterone, aldosterone, dehydroepiandrosterone sulfate, testosterone and androstenedione were resolved in fourteen minutes using a BEH C18 column coupled to a methanol-ammonium formate gradient. Detection was performed using multiple reaction monitoring quantitation. Routinely determined steroid levels by immunoassays were compared to those measured by LC-MS/MS. This method was applied to assess steroid profiles in congenital adrenal hyperplasia (CAH) patients with 21-hydroxylase deficiency. Low quantification limits depending on each steroid (ranging from 0.015ng/mL for aldosterone to 20ng/mL for DHEAS) are adapted to the clinical use. Recoveries of steroids range from 64% for 21-deoxycortisol to 101% for cortisol and are fully corrected by internal standards. A good linearity with R>0.989 is obtained for each compound. The inter-day variation coefficients ranged from 4.7% for cortisol to 16.3% for 11-deoxycorticosterone. The immunoassay for cortisol (Immulite 2000, Siemens) showed acceptable agreement with LC-MS/MS (bias +7.2%). However, Bland-Altman plots revealed large negative bias for aldosterone (-33.4%, AldoCT, CisBio international), for 17-hydroxyprogesterone at concentrations below 2ng/mL (-74.1%, OHP-CT MP Biomedical), for androstenedione (-80.3%, RIA D4, Beckman Coulter) and for 11-deoxycortisol (-125.3%, Diasource Immunoassays). Finally, the analysis of samples from 21-hydroxylase defective patients demonstrated the potential usefulness of multiplexed steroid profiling for the diagnosis and/or monitoring of different forms of congenital adrenal hyperplasia. This LC-MS/MS method provides highly sensitive and specific assessments of mineralo- and glucocorticoids pathways from a small volume sample and is therefore a promising potent tool for clinical and experimental endocrine studies., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Events during foetal or early extrauterine life may affect bodily structure and/or functions and even pave the way for adult diseases., Aims: To find whether extremely low birth weight (ELBW) infants differ from healthy controls regarding the excretion of steroid metabolites., Methods: The study compared 17 female and 10 male ELBW infants, all prepubertal, aged 8-11 years, birth weight <1,000 g, with 27 age- and sex-matched controls. All were healthy at the time of the study. Height, weight and BMI did not differ between the groups. Results were adjusted according to body surface area. 36 urinary steroid metabolites were quantified by gas chromatography-mass spectrometry., Results: In the ELBW girls 33/36 steroid metabolites were higher (19 significantly) than in the controls. All 36 steroid metabolites were higher in the ELBW boys (9 significantly) than in the controls. Sums of mineralocorticoid precursors, metabolites descriptive for cortisol and parameters of adrenal androgen production were significantly higher in ELBW infants (both sexes). Only the sum of the metabolites known to be illustrative for adrenal 11β-hydroxysteroid dehydrogenase activity was not different., Conclusion: Prepubertal ELBW children have an augmented urinary excretion of adrenal androgens, cortisol and mineralocorticoid precursors. These findings corroborate and help to explain the link between early-life adversity and subsequent adrenocortical function., (© 2015 S. Karger AG, Basel.)

Adrenal incidentalomas are found in approximately 2-3% of abdominal CT-scan examinations. A key issue is to determine whether the incidentaloma is neoplastic or responsible for endocrine hypersecretion, two situations in which surgical excision is recommended. Candidate incidentalomas for surgery include hypersecreting tumors (pheochromocytomas, Cushing's adenoma, Conn's adenoma) and adrenocortical carcinomas. The majority of adrenal incidentalomas are non-secreting cortical adenomas and lesions to remove account for less than 5% of adrenal incidentalomes. The pathological consequences of "subclinical" cortisol-secreting adenomas responsible for mild hypercortisolism and whether or not these tumors should be removed remain debatable., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Objective: In most cases of primary aldosteronism (PA), An adrenal aldosterone-secreting tumor cannot be reasonably proven, so these patients undergo medical treatment. Controversial data exist about the evolution of PA after medical therapy: long-term treatment with mineralocorticoid antagonists has been reported to normalize aldosterone levels but other authors failed to find remission of mineralocorticoid hypersecretion. Thus, we planned to retest aldosterone secretion in patients with medically treated PA diagnosed at least 3 years before., Design: Retrospective, cross-sectional study., Methods: The same workup for PA as at diagnosis (basal aldosterone to renin activity ratio (ARR) and aldosterone suppression test) was performed after stopping interfering drugs and low-salt diet, in 34 subjects with PA diagnosed between 3 and 15 years earlier, by case finding from subgroups of hypertensive patients at high risk for PA. Criteria for persistence of PA were the same as at diagnosis (ARR (pg/ml per ng per ml per h) >400, aldosterone >150 pg/ml basally, and >100 pg/ml after saline infusion) or less restrictive., Results: PA was not confirmed in 26 (76%) of the patients and also not in 20 (59%) using the least restrictive criteria suggested by international guidelines. Unconfirmed PA was positively associated with female sex, higher potassium levels, longer duration of hypertension, and follow-up, but not with adrenal mass, aldosterone levels at diagnosis, and treatment with mineralocorticoid antagonists., Conclusions: This study suggests that mineralocorticoid hyperfunction in patients with PA after medical treatment may decline spontaneously. Higher potassium concentration and duration of treatment seem to increase the probability of this event.

Multiple hormonal factors play a major role in the functional and structural abnormalities of hypertension (HT). At present, the kidneys and, in particular, renal Na(+) retention are thought to constitute a primary and sustaining mechanism in the development of HT. However, the precise renal and hormonal mechanisms leading to increased Na(+) reabsorption and HT remain unknown. Because the vast majority of HT is primary, this article focuses on the major endocrine systems, the RAS, aldosterone, and the SNS, that play a prominent role in the pathogenesis of HT., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose of Review: Inherited forms of mineralocorticoid hypertension are a group of monogenic disorders that, although rare, have enlightened our understanding of normal physiology, and subsequent processes implicated in the pathogenesis of 'essential' hypertension. They often present in early life and can be a cause of major morbidity and mortality that can be effectively treated with simple but targeted pharmacological therapy. Interestingly, all the conditions centre on the regulation of sodium transport through its epithelial channel, either directly or through mediators that act via the mineralocorticoid receptor., Recent Findings: In recent years, molecular mechanisms of these conditions and their functional consequences have been elucidated. Diagnosis has been facilitated by plasma and urinary biomarkers., Summary: We provide an overview and diagnostic approach to apparent mineralocorticoid excess, glucocorticoid remediable aldosteronism, familial hyperaldosteronism type 2, Liddle's syndrome, Gordon's syndrome, activating mutations of the mineralocorticoid receptor, generalized glucocorticoid resistance and hypertensive forms of congenital adrenal hyperplasia.

It is suggested to use the aldosterone-to-renin ratio (ARR) as a first test in the screening for primary aldosteronism (PA). However, many groups rather rely on the determination of urinary tetrahydroaldosterone secretion; others calculate a ratio of urinary aldosterone to plasma renin activity. The aim of the present study was to evaluate the usefulness of different parameters of aldosterone excess in the case finding of PA. The study included 28 patients with PA and 33 subjects with essential hypertension. Clinical data, which included the hormonal parameters, serum aldosterone, plasma renin concentration, urinary free aldosterone and metabolites and serum and urinary electrolyte levels were analyzed. These indices of aldosterone excess, the ARR, serum sodium to urinary sodium to (serum potassium)(2) to urinary potassium (SUSPPUP) ratio and combinations of these parameters were compared between the groups. Receiver-operating curve analysis revealed that the ARR multiplied by the SUSPPUP ratio (ARR x SUSPPUP) is the most reliable screening test, with a sensitivity of 92.3% and a specificity of 93.9% (cutoff point 199.2 (mmol l(-1))(-1)). The combination of ARR x SUSPPUP ratio with urinary free aldosterone divided by the plasma renin concentration rendered a specificity of 100%. Less useful was the correction of urinary free aldosterone and its metabolites for sodium excretion. Although the ARR and urinary free aldosterone divided by renin are good tests in the screening for PA, the combination of ARR with SUSPPUP ratio is a better indicator of an aldosterone excess and aldosterone action in patients with ongoing antihypertensive medication. Antihypertensive drugs only marginally interfere with the SUSPPUP ratio, but they may influence the ARR, whereby the effects in PA patients seem to be negligible.

In the neonatal period, the human kidney is characterized by an impaired ability to regulate water and sodium homeostasis, resembling partial aldosterone resistance. The aim of our study was to assess this hormonal insensitivity in newborn infants and to determine its relationship with neonatal sodium handling. We conducted a prospective study in 48 healthy newborns and their mothers. Aldosterone, renin, and electrolyte concentrations were measured in umbilical cords and in maternal plasma. Urinary aldosterone concentrations and sodium excretion were determined at urination within 24 h after birth. A significant difference was observed between aldosterone and renin levels in newborn infants compared with their mothers (817 +/- 73 versus 575 +/- 55 pg/mL and 79 +/- 10 versus 15 +/- 2 pg/mL, respectively, p < 0.001). This hyperactivation of the renin-angiotensin-aldosterone system was associated with hyponatremia and hyperkalemia in the newborn infants, and high urinary sodium loss, consistent with a partial aldosterone resistance at birth. Unlike plasma aldosterone, urinary aldosterone concentration was found highly correlated with plasma potassium concentrations, thus representing the best index for accurate evaluation of mineralocorticoid sensitivity. Our study represents a comprehensive characterization of the renin-aldosterone axis in newborn infants and provides evidence for physiologic partial aldosterone resistance in the neonatal period.

Patients with congenital adrenal hyperplasia arising from mutations of 11beta-hydroxylase, the final enzyme in the glucocorticoid biosynthetic pathway, exhibit glucocorticoid deficiency, adrenal hyperplasia driven by unsuppressed hypothalamo-pituitary-adrenal activity, and excess mineralocorticoid activity caused by the accumulation of deoxycorticosterone. A mouse model, in which exons 3-7 of Cyp11b1 (the gene encoding 11beta-hydroxylase) were replaced with cDNA encoding enhanced cyan fluorescent protein, was generated to investigate the underlying disease mechanisms. Enhanced cyan fluorescent protein was expressed appropriately in the zona fasciculata of the adrenal gland, and targeted knock-out was confirmed by urinary steroid profiles and, immunocytochemically, by the absence of 11beta-hydroxylase. The null mice exhibited glucocorticoid deficiency, mineralocorticoid excess, adrenal hyperplasia, mild hypertension, and hypokalemia. They also displayed glucose intolerance. Because rodents do not synthesize adrenal androgens, changes in reproductive function such as genital virilization of females were not anticipated. However, adult homozygote females were infertile, their ovaries showing an absence of corpora lutea and a central proliferation of disorganized steroidogenic tissue. Null females responded normally to superovulation, suggesting that raised systemic progesterone levels also contribute to infertility problems. The model reveals previously unrecognized phenotypic subtleties of congenital adrenal hyperplasia.

It has long been held that cortisol, acting through a single receptor, carries out both glucocorticoid and mineralocorticoid actions in teleost fish. The recent finding that fish express a gene with high sequence similarity to the mammalian mineralocorticoid receptor (MR) suggests the possibility that a hormone other than cortisol carries out some mineralocorticoid functions in fish. To test for this possibility, we examined the effect of in vivo cortisol, 11-deoxycorticosterone (DOC) and aldosterone on salinity tolerance, gill Na(+),K(+)-ATPase (NKA) activity and mRNA levels of NKA alpha 1a and alpha 1b in Atlantic salmon. Cortisol treatment for 6-14 days resulted in increased, physiological levels of cortisol, increased gill NKA activity and improved salinity tolerance (lower plasma chloride after a 24h seawater challenge), whereas DOC and aldosterone had no effect on either NKA activity or salinity tolerance. NKA alpha 1a and alpha 1b mRNA levels, which increase in response to fresh water and seawater acclimation, respectively, were both upregulated by cortisol, whereas DOC and aldosterone were without effect. Cortisol, DOC and aldosterone had no effect on gill glucocorticoid receptor GR1, GR2 and MR mRNA levels, although there was some indication of possible upregulation of GR1 by cortisol (p=0.07). The putative GR blocker RU486 inhibited cortisol-induced increases in salinity tolerance, NKA activity and NKA alpha 1a and alpha 1b transcription, whereas the putative MR blocker spironolactone had no effect. The results provide support that cortisol, and not DOC or aldosterone, is involved in regulating the mineralocorticoid functions of ion uptake and salt secretion in teleost fish.

Background: The hormone deficiencies in Addison's disease (primary adrenal insufficiency) are conventionally treated with oral glucocorticoid and mineralocorticoid replacement but the available therapies do not restore the physiological hormone levels and biorhythm. Despite such treatment these patients self-report impaired health-related quality of life (HRQoL) and recent research has indicated increased mortality., Objective/methods: We review the literature and recent developments in replacement therapy., Results/conclusion: Patients with Addison's disease require mineralocorticoid replacement, i.e., fludrocortisone 0.05 - 0.20 mg once daily. Starting doses of glucocorticoids should be 15 - 20 mg for hydrocortisone or 20 - 30 mg for cortisone acetate, divided into two or three doses, and preferentially weight-adjusted. There are indications that the synthetic glucocorticoids have undesirable metabolic long-term effects, which make them less suitable as first-line treatment. Timed-release hydrocortisone tablets and continuous subcutaneous hydrocortisone infusion are promising new treatment modalities. Studies of replacement with the adrenal androgen dehydroepiandrosterone (DHEA) in adrenal failure have shown inconsistent benefit on HRQoL. DHEA, or possibly testosterone replacement is likely to be beneficial for selected groups of patients with Addison's disease but this remains to be shown. We here give our opinion of the best treatment and future direction of research in this area.

A 75-year-old woman had a low circulating level of aldosterone, despite the mineralocorticoid excess state. These abnormalities were improved by spironolactone administration. The distinct elevation of urinary cortisol/cortisone ratio revealed 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) impairment. Moreover, slight but distinct elevation of the ratio was found in a 95-year-old woman with normotension and normopotassemia. The mineralocorticoid excess state with reduced aldosterone level appeared following with vomiting and diarrhea, exaggerating asymptomatic impairment of 11beta-HSD2 to induce apparent mineralocorticoid excess (AME)-like condition.

Objective: To present a case of concomitant secretion of cortisol, androgens, and 11-deoxycorticosterone (DOC) by an adrenocortical carcinoma and review the literature in an attempt to identify similar cases., Methods: The patient's medical history, physical examination, laboratory data, computed tomographic scan, and histopathologic results were analyzed and summarized in a case report, and an extensive review of the literature was performed., Results: Endocrinologic data showed excess cortisol production, substantially elevated testosterone and androstenedione levels, and profoundly increased DOC in the setting of suppressed aldosterone. An abdominal computed tomographic scan showed a left adrenal tumor. A left adrenalectomy was performed, and the histopathologic diagnosis was stage II adrenocortical carcinoma. The review of the pertinent literature revealed the absence of any identical cases in the past., Conclusion: Our patient presented with a rare case of cosecretion of cortisol, testosterone, androstenedione, and DOC by an adrenocortical carcinoma, resulting in a clinical picture consistent with Cushing's syndrome, hyperandrogenism, and primary hypermineralocorticoidism. We recommend the routine performance of a DOC assay in the setting of mineralocorticoid excess in association with low plasma aldosterone levels.

Mineralocorticoid hypertension is hypertension associated with the presence of hypokalemia, metabolic alkalosis, and suppression of plasma renin. Mineralocorticoid hypertension represents only 10% of patients with essential hypertension. However, its recognition is important because it is a potentially reversible cause of hypertension. Primary hyperaldosteronism is the most common form of mineralocorticoid hypertension. It is current clinical practice to use the plasma aldosterone-renin ratio and the absolute plasma aldosterone level as screening tests. Confirmatory suppression tests and adrenal imaging are performed in appropriate patients. Three monogenic forms of mineralocorticoid hypertension have been identified including Liddle's syndrome, glucocorticoid-remediable hypertension, and apparent mineralocorticoid excess. In a number of patients with mineralocorticoid hypertension, hypokalemia can be a variable finding. This review highlights mineralocorticoid biology and important features of primary hyperaldosteronism and monogenic hypertension.

Aldosterone hormone is a mineralocorticoid secreted by adrenal gland cortex and controls serum sodium (Na(+)) and potassium (K(+)) levels. Aldosterone has a stimulatory effect on expression of sodium-potassium ATPase (Na, K-ATPase) and sodium-potassium-chloride cotransporter (NKCC) in cell membranes. In the present investigation, the relation between serum aldosterone levels and age-related hearing loss (presbycusis) and the correlation between these levels versus the degree of presbycusis in humans were examined. Serum aldosterone concentrations were compared between normal hearing and presbycusic groups. Pure-tone audiometry, transient evoked otoacoustic emissions (TEOAE), hearing in noise test (HINT) and gap detection were tested for each subject and compared to the serum aldosterone levels. A highly significant difference between groups in serum aldosterone concentrations was found (p = 0.0003, t = 3.95, df = 45). Highly significant correlations between pure-tone thresholds in both right and left ears, and HINT scores versus serum aldosterone levels were also discovered. On the contrary, no significant correlations were seen in the case of TEOAEs and gap detection. We conclude that aldosterone hormone may have a protective effect on hearing in old age. This effect is more peripheral than central, appearing to affect inner hair cells more than outer hair cells.

Pregnancy-induced hypertension (PIH) is a frequent cause of maternal and neonatal morbidity and mortality. 19-Noraldosterone, which was shown to be synthesized in the human adrenal gland, exhibits potent mineralocorticoid and hypertensive activity. To examine the role of mineralocorticoids in the pathophysiology of PIH, we studied urinary 19-noraldosterone, tetrahydroaldosterone, free cortisol, and cortisone concentrations and mineralocorticoid receptor levels in peripheral blood mononuclear leukocytes, from 17 women with PIH and 16 normal pregnant women as controls. Sequence analysis of the mineralocorticoid receptor gene in PIH patients was also done. The 24-h urinary excretion of 19-noraldosterone was significantly lower in PIH (120 +/- 38 pmol/day) than in controls (358 +/- 55 pmol/day) (P < 0.05). Urinary tetrahydroaldosterone was also decreased in PIH compared with controls. Ratios of urinary free cortisol to cortisone (a measure of 11beta-hydroxysteroid dehydrogenase 2 activity) did not differ significantly between groups. Mineralocorticoid receptor density was significantly (P < 0.05) decreased in the PIH group (133 +/- 15 binding sites/cell) compared with controls (255 +/- 21 binding sites/cell). No mutations were found in the coding region of the mineralocorticoid receptor gene in PIH. These results suggest that circulating aldosterone, 19-noraldosterone, and renal 11beta-hydroxysteroid dehydrogenase2 do not contribute to the pathogenesis of PIH. Regulatory factors that cause the down-regulation of the mineralocorticoid receptor in PIH should be clarified.

Unlabelled: The two-phase restorative proctocolectomy is the treatment of choice for surgical therapy of the familial adenomatous polyposis (FAP) and also for the ulcerative colitis (UC). Besides the well-known complications the entire removal of the colorectum leads to an impairment of fluid and electrolyte resorption., Patients and Methods: Over a time period of two years we observed 320 proctocolectomized patients with ileal pouch-anal anastomosis (IPAA). All patients with high pouch output but without organic malfunction were identified. The organic reasons were excluded with the help of pouchoscopy, radiography or MR imaging. We evaluated routine parameters, the kidney function, the electrolyte changes, the acid-base balance and the urine pH, as well as the hormonal changes of the suprarenal glands. We identified seven patients with 'high pouch output' out of 320 patients observed. The control group consisted of 14 proctocolectomized patients without hints of complications in the endoscopic, radiographic and routine laboratory diagnostics., Results: Neither group showed any significant differences in the analysis of the routine parameters. A significant drop of the urine sodium concentration of 40.5 +/- 18.7 mmol/l (control group 98 +/- 43.4 mmol/l) was observed in the group with 'high pouch output'. In this group the plasma aldosterone values were strongly increased with an average of 42.6 +/- 28.9 ng/dl (control group 13.2 +/- 6.8 ng/dl) as well as the plasma 18-hydroxycorticosterone with an average of 153.7 +/- 121.1 ng/dl (control group 153.7 +/- 121.1 ng/dl). Neither group of patients showed increased activity of free corticosterone and free cortisol. Only free 11-desoxycorticosterone was elevated in the group with 'high pouch output'., Conclusion: Our results prove that the mineralocorticoid adrenal activity plays a central role in order to preserve the volume and electrolyte homeostasis. The low frequency of 'high-pouch-output'-complications in realms of the restorative proctocolectomy proves the excellent compensation of the removal of the colon mucosa. Plasma aldosterone seems to be a diagnostic marker encapsulating the reabsorption problems of intestinal salt and volume losses after proctocolectomy.

Objective: The conversion of cortisol, which binds avidly to the mineralocorticoid receptor, to cortisone, which no longer has mineralocorticoid function, is predominantly catalyzed by the 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD 2). It was the objective of the present study to examine the impact of different forms of glucocorticoid excess on the cortisol/cortisone ratio and to differentiate their role in the genesis of hypertension., Design and Methods: Plasma cortisol and cortisone levels were determined in 12 adults with Cushing's disease, 12 adults with hypercortisolism due to an adrenal tumor, and 20 healthy volunteers before and after an intravenous ACTH test, using specific radioimmunoassays after automated Sephadex LH 20 chromatography., Results: The cortisol/cortisone ratios were significantly higher in patients with Cushing's disease (13.9 +/- 1.1), adrenal tumors (11.5 +/- 2.3), and in healthy volunteers after ACTH stimulation (14.1 +/- 2.0) than in untreated controls (6.0 +/- 0.5) (P < 0.001, P < 0.05, and P < 0.001, respectively). Similar differences were seen for cortisol plasma concentrations, whereas cortisone concentrations did not differ among the groups., Conclusions: Our data suggest that the excessive mineralocorticoid effects in patients with hypercortisolism are inflicted by elevated cortisol/cortisone ratios possibly due to an insufficient conversion of cortisol to cortisone by 11beta-HSD 2. This may provide a possible explanation for the occurrence of hypertension. This effect seems to be independent of the role of ACTH in the mechanism of hypercortisolism.

This study tests the hypothesis that a history of common stressful experiences further promotes the cognitive deficit of apolipoprotein E (apoE)-knockout mice, an animal model to study aspects of Alzheimer's disease. In experiment 1, apoE-knockout and wild-type mice were repeatedly subjected to an environmental challenge (i.e. exposure to rats) and the effect was monitored on Morris water maze performance. Naive apoE-knockout mice were impaired, but surprisingly after rat stress their water maze performance improved and switched to a goal-directed search strategy. Rat stress induced in wild-type mice spatial learning deficits and an inefficient search strategy. Swim ability was not affected by rat stress and under basal conditions measures for locomotion and anxiety were similar for both genotypes. In experiments 2 and 3, we found that the rat stress paradigm attenuated the elevation of basal and stress-induced corticosterone concentrations in the apoE-knockout mice towards concentrations observed in wild-type mice. The expression of hippocampal mineralocorticoid and glucocorticoid receptor mRNA was similar in both genotypes, but in response to rat stress, the level of glucocorticoid receptor mRNA increased selectively in the CA1 pyramidal field. In conclusion, repeated exposure to a common environmental experience did abolish and reverse the difference in cognitive performance and corticosterone concentrations of apoE-knockout and wild-type mice.

Background: The Ileo-Pouch-Anal-Anastomosis (IPAA) is the standard restorative procedure for Ulcerative Colitis and Familial Adenomatous Polyposis (FAP). IPAA may lead to considerable losses of fluids, especially in association with a protective loop ileostomy., Aim: The aim of this study was to investigate adrenal mechanisms in the regulation of volume homeostasis immediately after IPAA and protective ileostomy., Methods: For that purpose, 20 patients out of our patient population with elective IPAA with ileostomy participated in this study between 1993 and 1997. In all patients, routine laboratory tests and gluco- and minealocorticoid hormone measurements were performed preoperatively and 10 days after operation., Results: These blood analyses indicated functional hyperaldosteronism immediately after IPAA. Significantly elevated levels of Aldosterone (36.4 +/- 25.1 ng/dl) and 18-OH-Corticosterone ( 173 +/- 11.3 ng/dl) were found. Among hormones with glucocorticoid effects, blood levels of Cortisol (10.4 +/- 4.8 microg/dl) were significantly elevated, while 11-Desoxycortiosterone (13.9 +/- 8.4 ng/dl) and Corticosterone (0.8 +/- 0.6 microg/dl) were not significantly elevated. Serum electrolytes remained unchanged., Conclusions: Our results indicate that hormones with mineralocorticoid effects play a predominant role in the compensation of ileostomy losses after IPAA.

A 14-year-old Native American girl from the Iroquois Nation was referred as a potential patient with the syndrome of Apparent Mineralocorticoid Excess. Instead, her evaluation revealed resistance to glucocorticoids, mineralocorticoids, and androgens. She lacked Cushingoid features in spite of significantly high cortisol levels. Menstruation was regular and there was no clinical evidence of masculinization despite high serum androgen levels in the male range. The patient's sister had similar clinical features. Partial resistance to exogenous glucocorticoid and mineralocorticoid administration was well demonstrated in both patients. It is proposed that these patients represent the first cases of partial resistance to multiple steroids, possibly owing to a coactivator defect.

We present an in vivo and in vitro study of congenital adrenal hyperplasia in a patient with 11beta-hydroxylase deficiency. Sequencing of the CYP11B1 gene showed two new base substitutions, a conservative 954 G-->C transversion at the last base of exon 5 (T318T), and a IVS8 + 4A-->G transition in intron 8. In addition, two polymorphisms were found in exons 1 and 2. The genetically female patient was raised as a male because of severe pseudohermaphroditism. Glucocorticoid-suppressive treatment encountered difficulties in equilibration and compliance, resulting in uncontrolled hypertension with pronounced hypertrophic cardiomyopathy. At 42 yr of age the occurrence of central retinal vein occlusion with permanent loss of left eye vision led to the decision to perform bilateral laparoscopic adrenalectomy. Surgery was followed by normalization of blood pressure and good compliance with glucocorticoid and androgen substitutive therapies. In vitro, adrenal cells in culture and isolated mitochondria showed extremely low 11beta-hydroxylase activity. Analysis of adrenal CYP11B1 messenger ribonucleic acid (mRNA) by RT-PCR and sequencing showed the expression of a shorter mRNA that lacked exon 8 and did not contain either the exon 5 mutation or the exon 1 and 2 polymorphisms. This suggested that one CYP11B1 allele carried the intron 8 mutation, responsible for skipping exon 8. The other allele carried the exon 5 mutation, and its mRNA was not detectable. Western blot analysis showed weak expression of a shorter CYP11B immunoreactive band of 43 kDa, consistent with truncation of exon 8. Thus, bilateral adrenalectomy in this patient allowed effective treatment of severe hypertension and helped in understanding the mechanisms and physiopathological consequences of two novel mutations of CYP11B1.

Preovulatory cervical mucous of normal cycles was checked in 8 women for the presence of deoxycorticosterone (DOC), corticosterone and aldosterone. Cervical mucous DOC varied from lower to higher levels, and corticosterone concentration was several fold lower than in the blood serum. No aldosternone was detected in the cervical mucous. High cervical mucous DOC levels may indicate its synthesis by glandular cells of the cervix. Low corticosterone cervical mucous levels may indicate its transfer from the blood.

The effects on the pituitary-adrenocortical functions of the prolonged (7-day) blockade of endogenous bradykinin (BK) synthesis, obtained by the administration of the kallikrein inhibitor (K-I) cyclohexylacetyl-Phe-Arg-Ser-Val-Gln amide, were investigated in the rat. K-I treatment did not cause significant changes in the (i) body and adrenal weights; (ii) basal plasma levels of ACTH, aldosterone and corticosterone; and (iii) average volume of adrenocortical cells and their basal secretory capacity. Conversely, K-I administration induced a significant magnification of the in vivo mineralo- and glucocorticoid responses to the intraperitoneal (i.p.) bolus injection of ACTH. Moreover, K-I-treated rats, but not control ones, displayed a moderate and short-term adrenal secretory response to the mild stress evoked by the placebo i.p. injection. Collectively, these findings rule out the possibility that endogenous BK plays a relevant role in the control of adrenocortical function under basal conditions. However, they suggest that endogenous BK may be involved in quenching exceedingly high adrenocortical responses to ACTH and stresses.

Exposure of pregnant rats to morphine, from day 11 to day 18 of gestation, was previously reported to induce both an adrenal atrophy and hypoactivity of the glucocorticoid function in newborns at term, but did not affect, in vitro, the responsiveness of those glands to adrenocorticotrophin hormone (ACTH) concerning corticosterone release. Moreover, these effects were mediated by maternal hormones from the adrenal glands. In the present work, we investigated the effects of a prenatal morphine exposure on the mineralocorticoid activity of the adrenals in neonates. The first aim of the present study was to determine in these newborns 1) the adrenal and plasma aldosterone concentrations at birth time and during the early postnatal period 2) the plasma levels of Na+ and K+ at birth time, 3) the in vitro responsiveness of the newborn adrenals to angiotensin II (A(II)) and ACTH. The second aim of our study was to investigate the mineralocorticoid activity of the adrenals in newborns from adrenalectomized mothers treated with morphine during gestation. According to present data morphine given to intact mothers induced in newborns a severe adrenal atrophy but increased adrenal aldosterone content and plasma aldosterone level. However, prenatal morphine was unable to affect significantly Na+/K+ ratio in both mothers and newborns. In vitro, the adrenals of neonates from morphine-treated mothers were unresponsive to An and ACTH for promoting aldosterone release; in contrast, aldosterone secretion was significantly stimulated by high potassium levels (55 mEq). Maternal adrenalectomy performed one day before the beginning of morphine treatment prevented morphine-induced adrenal atrophy but was unable to affect significantly the adrenal mineralocorticoid function of the offspring. Such data suggest that a prenatal morphine exposure stimulated both aldosterone synthesis and release in neonates. However, this basal hyperfunction did not appear to be coupled with an enhanced adrenal responsivity to AII or ACTH. Prenatal morphine-induced hyperactivity of the mineralocorticoid function of the newborn adrenals, which drastically contrast with hypoactivity of the glucocorticoid one, was independent of adrenal factors from maternal origin.

Corticosterone and Brain-Derived Neurotrophic Factor (BDNF) have both been shown to be involved in spatial memory formation in rats. In the present study we have investigated the effect of corticosterone on hippocampal BDNF mRNA expression after training in the Morris water maze in young adult Wistar rats. Therefore, we first studied BDNF mRNA levels in the hippocampus in relation to corticosterone levels at several time points after 4 training trials in the Morris water maze. Corticosterone levels were significantly increased after this procedure, and hippocampal BDNF mRNA levels only displayed a minor change: an increase in CA1 at 1 hr after training. However, in a previous study we observed dramatically decreased hippocampal BDNF mRNA levels in dentate gyrus and CA1 at 3 hr after injection of corticosterone. In order to analyze this discrepancy, we subsequently investigated if hippocampal BDNF mRNA expression is affected by corticosterone at 3 hr after water maze training. Therefore, we incorporated ADX animals and ADX animals which were injected with corticosterone in our study. ADX animals which were subjected to water maze training displayed similar hippocampal BDNF mRNA levels 3 hr after training compared to control ADX animals. Furthermore, ADX animals which were injected with corticosterone showed decreased BDNF mRNA levels in all hippocampal regions compared to control ADX animals. Water maze training did not alter this effect. Thus, the increased corticosterone levels during water maze training do not affect hippocampal BDNF mRNA expression, although exogenous corticosterone is effective under these conditions. Hence, our results suggest that in this situation BDNF is resistant to regulation by endogenous corticosterone, which may be important for learning and memory processes.

Blacks appear, on average, to retain more Na than whites. A higher production rate of mineralocorticoids could explain the greater Na retention in blacks. Although production of aldosterone has been shown to be lower in blacks, the level of another mineralocorticoid may be increased. Plasma levels of deoxycorticosterone and cortisol were measured in young whites (n=23; age=16.4+/-3.1[SD] years) and young blacks (n=25; age=13.8+/-1.3 years). Blacks had lower plasma levels of renin activity and aldosterone and lower urinary aldosterone excretion rates; thus, they appeared to be representative of blacks that retain additional Na. Plasma deoxycorticosterone levels were lower in blacks than in whites both at baseline (247+/-161 versus 381+/-270 pmol/L, P=0.048) and after stimulation with adrenocorticotropic hormone (822+/-294 versus 1127+/-628 pmol/L at 30 minutes, P=0.047; 925+/-366 versus 1440+/-834 pmol/L at 60 minutes, P=0.013). Cortisol levels were also lower in blacks at baseline (P=0.014) but were not significantly different from levels in whites after stimulation with adrenocorticotropic hormone. In a larger cohort of 407 whites (age=12.0+/-2.9 years) and 247 blacks (age=12.9+/-3.1 years), 18-hydroxycortisol excretion rates were also lower in blacks (P=0. 021). In conclusion, increased Na retention in blacks does not appear to be secondary to increased production of either aldosterone, deoxycorticosterone, cortisol, or 18-hydroxycortisol. A primary renal mechanism may mediate the increase in Na reabsorption in blacks.

Our understanding of Na(+) transport defects has exploded in the past several years, and has provided unique insights into epithelial transport processes, and unusual clinical syndromes resulting from mutations of specific ion transporters. These genetic disorders affect Na(+) balance, with both Na(+) retaining and Na(+) wasting conditions being the consequence. A major focus of these studies has been the epithelial sodium channel (ENaC), which can be directly affected by mutations (eg, Liddle syndrome, autosomal recessive pseudohypoaldosteronism, type I) or by changes in the response to (autosomal recessive pseudohypoaldosteronism, type I), or production of mineralocorticoids (apparent mineralocorticoid excess syndrome, glucocorticoid-remediable aldosteronism). As a result, we now have clearly defined syndromes in which ENaC activity is dysregulated with subsequent development of disorders of systemic blood pressure that can be attributed to a primary renal mechanism.

The importance of sodium in the pathophysiology of hypertension has been revealed by several sources, including large epidemiological analyses, interventional trials, and a large body of experimental and clinical evidence. According to Guyton's hypothesis, a shift of the pressure-natriuresis curve has been described in all forms of hypertension, suggesting that the ability of the kidney to excrete sodium must be altered in hypertension. Yet, the intrarenal mechanism responsible for the abnormal salt excretion remains unknown. In recent years, the discovery of the molecular mechanisms involved in the pathogenesis of some rare forms of hypertension, i.e. , Liddle's syndrome, glucocorticoid-remediable hypertension, and apparent mineralocorticoid excess, has revived the interest in salt-induced hypertension, since the reported genetic defects decrease the ability of the kidneys to excrete sodium. This review presents the pathogenic mechanisms revealed by these rare disorders and discusses the possible implication of these discoveries for the understanding of the pathophysiology of essential hypertension.

Background: Patients with Cushing's syndrome exhibit a bimodal distribution of maximal rates of the erythrocyte amiloride-sensitive Na+/H+ exchange (NHE). Enhanced erythrocyte NHE has recently been found in patients with primary aldosteronism., Objective: To test the hypothesis that occult hypermineralocorticoidism in a subset of patients with Cushing's syndrome is responsible for the greater than normal NHE., Methods: NHE was measured as maximal initial rate (Vmax) of amiloride-inhibited efflux of H+ into an alkaline Na+-containing medium, for 47 patients with hypercortisolism (20 with pituitary adenomas, 18 with adrenal adenomas, and nine with ectopic production of adrenocorticotropin). Clinical appearance, blood pressure levels, plasma aldosterone and deoxycorticosterone levels, serum electrolytes, and urine (tetrahydrocortisol plus 5-alpha-tetrahydrocortisol) : tetrahydrocortisone ratios were assessed for all patients. Twenty patients (10 with greater than normal NHE and 10 with low-to-normal NHE) were randomly selected from 47 patients with hypercortisolism, and treated with 200 mg/day spironolactone for 7 days. NHE in these patients was assessed before starting the treatment and 2 days after its cessation., Results: Greater than normal NHE (Vmax) was associated with peripheral edema, high diastolic blood pressure, hypokalemia, and high urine (tetrahydrocortisol plus 5-alpha-tetrahydrocortisol) : tetrahydrocortisone ratios. The enhanced NHE was rapidly normalized by treatment with spironolactone., Conclusion: Erythrocyte NHE in patients with hypercortisolism and functional hypermineralocorticoidism is greater than normal due to incomplete peripheral conversion of cortisol (which binds to mineralocorticoid receptors) into metabolically inactive cortisone.