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The mineralocorticoid system, comprising the renin-angiotensin-aldosterone system (RAAS) and associated receptors, is traditionally viewed as a regulator of sodium and fluid balance and blood pressure (BP), with the main mineralocorticoid hormone aldosterone acting via the mineralocorticoid receptor (MR) in distal renal tubules. Over the past few decades, there has been a wider understanding of the role of the mineralocorticoid system in regulating both classical BP-dependent and non-BP-dependent systemic effects. Mounting evidence indicates the novel role of the mineralocorticoid system in cardiometabolic health, with excess mineralocorticoid system activity being associated with adiposity, diabetes, insulin resistance and cardiovascular diseases independent of its effect on BP, and RAAS blockade and MR antagonists offering protection against cardiometabolic dysfunction. The metabolic manifestations of mineralocorticoid system overactivation are mainly mediated by their interactions with adipose tissue, which orchestrates energy, lipids, and glucose homeostasis via effects on the functions of brown and white adipocytes and immune cells. Adipose tissue can, in turn, influence mineralocorticoid system activity by harboring its own RAAS system and by releasing mineralocorticoid-secretory factors/adipokines, resulting in further progression of cardiometabolic dysfunction. This article discusses the interplay between the mineralocorticoid system and adipose tissue in the pathophysiology of cardiometabolic diseases. [ABSTRACT FROM AUTHOR]

Congenital adrenal hyperplasia (CAH) caused by 21‐hydroxylase deficiency accounts for 95% of all CAH cases and is one of the most common inborn metabolic conditions. The introduction of life‐saving glucocorticoid replacement therapy 70 years ago has changed the perception of CAH from a paediatric disorder into a lifelong, chronic condition affecting patients of all age groups. Alongside health problems that can develop during the time of paediatric care, there is an emerging body of evidence suggesting an increased risk of developing co‐morbidities during adult life in patients with CAH. The mechanisms that drive the negative long‐term outcomes associated with CAH are complex and involve supraphysiological replacement therapies (glucocorticoids and mineralocorticoids), excess adrenal androgens both in the intrauterine and postnatal life, elevated steroid precursors and adrenocorticotropic hormone levels. Alongside a review of mortality outcome, we discuss issues that need to be addressed when caring for the CAH patient including female and male fertility, cardio‐metabolic morbidity, bone health and other important long‐term outcomes of CAH. [ABSTRACT FROM AUTHOR]

Papillary thyroid cancer (PTC) is the 8th most common cancer among women overall. Licorice contains over 300 active compounds, many of them with anti-cancer properties. Glycyrrhetinic acid (GA) is a major component of licorice. The aim of this study was to investigate the potential anti-proliferative effects of licorice and GA on PTC cell cultures. Licorice extract (LE) was produced from the root and tested on BCPAP and K1 cell lines, as well as GA and aldosterone. We used the MTT test to investigate the anti-proliferative activity, the wound healing test for the migratory activity, and finally, we analyzed cell cycle distribution, apoptosis, and oxidative stress after LE, GA, or aldosterone incubation. Both LE and GA reduced cell viability at 48 h and cell migration at 24 h in both PTC cultures. Aldosterone reduced cell migration only in K1 cells. LE and GA induced cell cycle arrest in the G0/G1 phase in the BCPAP cell line, while LE and aldosterone induced it in the K1 culture. GA but not LE increased the apoptosis rate in both cell lines, whereas LE but not GA increased oxidative stress in both cultures. This study presents the first evidence of the in vitro anti-proliferative and anti-migratory activity of LE and GA on PTC. [ABSTRACT FROM AUTHOR]

Abstract This report describes the diagnosis and treatment of aldosterone resistance (AR) and acquired hyperkalemic type IV renal tubular acidosis (RTA) in 2 cats comparable to acquired pseudohypoaldosteronism in people. One cat developed AR from chronic kidney disease after an acute kidney injury and was treated with furosemide per os, which resolved the hyperkalemic RTA. The second cat developed transient AR secondary to a bacterial urinary tract infection associated with urethral catheterization, and treatment with antibiotics resolved the hyperkalemic RTA.

This report describes the diagnosis and treatment of aldosterone resistance (AR) and acquired hyperkalemic type IV renal tubular acidosis (RTA) in 2 cats comparable to acquired pseudohypoaldosteronism in people. One cat developed AR from chronic kidney disease after an acute kidney injury and was treated with furosemide per os, which resolved the hyperkalemic RTA. The second cat developed transient AR secondary to a bacterial urinary tract infection associated with urethral catheterization, and treatment with antibiotics resolved the hyperkalemic RTA. [ABSTRACT FROM AUTHOR]

Introduction: Congenital adrenal hyperplasia (CAH) is a group of diseases in which genetic defects occur that disturb the synthesis of cortisol. The most common variant of CAH (95%-99%) is caused by 21-hydroxylase deficiency as a result of mutations in the CYP21A2 gene and is one of the most common monogenic diseases. CAH is characterized by androgen overproduction along with variable degrees of cortisol and aldosterone deficiency. Age at diagnosis can provide some information about the underlying mutations, with those diagnosed at birth/early infancy being at greater risk of developing serious enzyme defects. Classic and non-classical forms of this disorder have been described in the literature. CAH diagnosis is based on the clinical presentation, hormonal panel, Adrenocorticotropic Hormone (ACTH) stimulation test, and genetic testing. The main goals of treatment for congenital adrenal hyperplasia are glucocorticoid/mineralcorticoid supplementation, control of high adrenal androgen levels, fertility control, genetic counseling, and optimization of patients’ quality of life. Purpose of the work: This study aims to review and characterize the clinical and pathophysiological aspects of congenital adrenal hyperplasia. Materials and methods: A comprehensive analysis of research papers available on PubMed, Google Scholar, Web of Science, Embase and Scopus was undertaken using the searchterms encompassing the following keywords: congenital adrenal hyperplasia, 21-hydroxylase deficiency, CYP21A2 Results: Congenital adrenal hyperplasia is a heterogeneous group of genetic disorders that can lead to serious and even fatal complications in the form of adrenal crisis. Therefore, screening tests and early diagnosis are crucial and can save the lives of newborns. Treatment should be individualized and allow patients to achieve normal growth, sexual development, fertility and a better quality of life.

Abstract Introduction Proteinuria is a modifiable risk factor for chronic kidney disease (CKD) progression in children. Finerenone, a selective, non-steroidal, mineralocorticoid receptor antagonist (MRA) has been approved to treat adults with CKD associated with type 2 diabetes mellitus (T2DM) following results from the phase III clinical trials FIDELIO-DKD (NCT02540993) and FIGARO-DKD (NCT02545049). In a pre-specified pooled analysis of both studies (N = 13,026), finerenone was shown to have an acceptable safety profile and was efficacious in decreasing the risk of adverse kidney and cardiovascular outcomes and of proteinuria. Objective FIONA and the associated open-label extension (OLE) study aim to demonstrate that combining finerenone with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) is safe, well-tolerated, and effective in sustainably reducing urinary protein excretion in children with CKD and proteinuria. Design FIONA (NCT05196035; Eudra-CT: 2021–002071-19) is a randomized (2:1), double-blind, placebo-controlled, multicenter, phase III study of 6 months’ duration in approximately 219 pediatric patients. Patients must have a clinical diagnosis of CKD (an eGFR ≥ 30 mL/min/1.73 m2 if ≥ 1 to

Isolated aldosterone synthase deficiency is a rare autosomal recessive disorder caused by pathogenic variants in CYP11B2, resulting in impaired aldosterone synthesis. We report on a neonate with isolated aldosterone synthase deficiency caused by a novel homozygous CYP11B2 variant Chr8: NM_000498.3: c.400G>A p.(Gly134Arg). The patient presented shortly after birth with severe signs of aldosterone deficiency. Interestingly, segregation analysis revealed that the patient's asymptomatic father was also homozygous for the CYP11B2 variant. Biochemical evaluation of the father indicated subclinical enzyme impairment, characterized by elevated aldosterone precursors. Apparently, this homozygous variant led to different clinical phenotypes in two affected relatives. In this manuscript we elaborate on the biochemical and genetic work-up performed and describe potential pitfalls in CYP11B2 sequencing due to its homology to CYP11B1.

Background The pathobiology of heart failure with preserved ejection fraction (HFpEF) is still poorly understood, and effective therapies remain limited. Diabetes and mineralocorticoid excess are common and important pathophysiological factors that may synergistically promote HFpEF. The authors aimed to develop a novel animal model of HFpEF that recapitulates key aspects of the complex human phenotype with multiorgan impairments. Methods and Results The authors created a novel HFpEF model combining leptin receptor-deficient db/db mice with a 4-week period of aldosterone infusion. The HFpEF phenotype was assessed using morphometry, echocardiography, Ca2+ handling, and electrophysiology. The sodium-glucose cotransporter-2 inhibitor empagliflozin was then tested for reversing the arrhythmogenic cardiomyocyte phenotype. Continuous aldosterone infusion for 4 weeks in db/db mice induced marked diastolic dysfunction with preserved ejection fraction, cardiac hypertrophy, high levels of B-type natriuretic peptide, and significant extracardiac comorbidities (including severe obesity, diabetes with marked hyperglycemia, pulmonary edema, and vascular dysfunction). Aldosterone or db/db alone induced only a mild diastolic dysfunction without congestion. At the cellular level, cardiomyocyte hypertrophy, prolonged Ca2+ transient decay, and arrhythmogenic action potential remodeling (prolongation, increased short-term variability, delayed afterdepolarizations), and enhanced late Na+ current were observed in aldosterone-treated db/db mice. All of these arrhythmogenic changes were reversed by empagliflozin pretreatment of HFpEF cardiomyocytes. Conclusions The authors conclude that the db/db+aldosterone model may represent a distinct clinical subgroup of HFpEF that has marked hyperglycemia, obesity, and increased arrhythmia risk. This novel HFpEF model can be useful in future therapeutic testing and should provide unique opportunities to better understand disease pathobiology.

Background: The 2021 Surviving Sepsis Campaign Guidelines recommend the use of hydrocortisone in patients who remain hemodynamically unstable despite adequate fluid resuscitation and vasopressor therapy. Fludrocortisone has been used concomitantly with hydrocortisone in some studies without a clearly defined role or known clinical benefit. The purpose of this study was to assess the impact of fludrocortisone added to hydrocortisone on shock-free days for septic shock. Methods: A single-center, retrospective propensity score-weighted study was conducted to compare hydrocortisone versus hydrocortisone plus fludrocortisone for septic shock. Adults admitted to the medical intensive care unit (ICU) from 2015 to 2020 were included in the study. All patients received =200 mg/day hydrocortisone for at least 24 h ± fludrocortisone initiated within 72 h of vasopressors. The primary outcome was shock-free days by day 14. The secondary outcomes included duration of shock, change in Sequential Organ Failure Assessment (SOFA) score, hospital and ICU length of stay, and all-cause inhospital mortality. Results: A total of 228 patients met inclusion criteria with 212 patients retained after propensity score weighting. There was no difference between groups in 14-day shock-free days (6.3 vs. 6.1 days; P = 0.781). Furthermore, no significant differences were observed for the secondary outcomes of ICU/hospital length of stay, duration of shock, change in SOFA score, and all-cause inhospital mortality. Conclusion: The addition of fludrocortisone to hydrocortisone in septic shock did not increase shock-free days by day 14. These results suggest that the use of hydrocortisone alone may be an adequate adjunctive therapy in septic shock. A prospective randomized controlled trial is needed to confirm results. [ABSTRACT FROM AUTHOR]

Introduction: Proteinuria is a modifiable risk factor for chronic kidney disease (CKD) progression in children. Finerenone, a selective, non-steroidal, mineralocorticoid receptor antagonist (MRA) has been approved to treat adults with CKD associated with type 2 diabetes mellitus (T2DM) following results from the phase III clinical trials FIDELIO-DKD (NCT02540993) and FIGARO-DKD (NCT02545049). In a pre-specified pooled analysis of both studies (N = 13,026), finerenone was shown to have an acceptable safety profile and was efficacious in decreasing the risk of adverse kidney and cardiovascular outcomes and of proteinuria. Objective: FIONA and the associated open-label extension (OLE) study aim to demonstrate that combining finerenone with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) is safe, well-tolerated, and effective in sustainably reducing urinary protein excretion in children with CKD and proteinuria. Design: FIONA (NCT05196035; Eudra-CT: 2021–002071-19) is a randomized (2:1), double-blind, placebo-controlled, multicenter, phase III study of 6 months’ duration in approximately 219 pediatric patients. Patients must have a clinical diagnosis of CKD (an eGFR ≥ 30 mL/min/1.73 m2 if ≥ 1 to < 18 years or a serum creatinine level ≤ 0.40 mg/dL for infants 6 months to < 1 year) with significant proteinuria despite ACEi or ARB usage. The primary objective is to demonstrate that finerenone, added to an ACEi or ARB, is superior to placebo in reducing urinary protein excretion. FIONA OLE (NCT05457283; Eudra-CT: 2021–002905-89) is a single-arm, open-label study, enrolling participants who have completed FIONA. The primary objective of FIONA OLE is to provide long-term safety data. FIONA has two primary endpoints: urinary protein-to-creatinine ratio (UPCR) reduction of ≥ 30% from baseline to day 180 and percent change in UPCR from baseline to day 180. A sample size of 198 participants (aged 2 to < 18 years) in FIONA will provide at least 80% power to reject the null hypothesis of either of the two primary endpoints. Conclusion: FIONA is evaluating the use of finerenone in children with CKD and proteinuria. Should safety, tolerability, and efficacy be demonstrated, finerenone could become a useful additional therapeutic agent in managing proteinuria and improving kidney outcomes in children with CKD. Trial registration: ClinicalTrials.gov NCT05196035. Registered on 19 January 2022. [ABSTRACT FROM AUTHOR]

Isolated aldosterone synthase deficiency is a rare autosomal recessive disorder caused by pathogenic variants in CYP11B2, resulting in impaired aldosterone synthesis. We report on a neonate with isolated aldosterone synthase deficiency caused by a novel homozygous CYP11B2 variant Chr8:NM_000498.3:c.400G>A p.(Gly134Arg). The patient presented shortly after birth with severe signs of aldosterone deficiency. Interestingly, segregation analysis revealed that the patient's asymptomatic father was also homozygous for the CYP11B2 variant. Biochemical evaluation of the father indicated subclinical enzyme impairment, characterized by elevated aldosterone precursors. Apparently, this homozygous variant led to different clinical phenotypes in two affected relatives. In this manuscript we elaborate on the biochemical and genetic work-up performed and describe potential pitfalls in CYP11B2 sequencing due to its homology to CYP11B1. [ABSTRACT FROM AUTHOR]

Context: The prevalence of cardiovascular and metabolic complications among adults with 21-hydroxylase deficiency (21OHD) is unknown. Objective: We sought to determine the prevalence of cardiovascular and metabolic morbidities among adults with 21OHD and to identify clinical factors and biomarkers associated with cardiovascular outcomes. Methods: A 10-year retrospective cross-sectional analysis was conducted on adult patients with confirmed 21OHD, aged 18 to 70 years, who had at least one clinical visit for assessment at the University of Michigan. The presence of cardiovascular diseases (CVDs) and other metabolic comorbidities was extracted from medical records based on International Classification of Diseases (ICD) codes. Medical treatments, glucocorticoid (GC) and mineralocorticoid doses, as well as specific biomarkers of disease control since age 18, were collected for analysis. Results: A total of 254 patients with 21OHD, median age of 35 years (interquartile range, 28.25-46 y), were included in the analysis. The prevalence of CVDs in the entire cohort was 7.5%. An increase in prevalence was seen from early adulthood, reaching 25% in patients older than 60 years. Increasing age (adjusted odds ratio [OR], 1.05; 95% CI, 1.01-1.09), hypertension (OR, 4.27; 95% CI, 1.41-12.92), and higher GC doses (OR, 1.51; 95% CI, 1.11-2.06) were significantly associated with prevalent CVDs. Higher plasma renin activity was significantly associated with CVDs (OR, 1.07; 95% CI, 1.01-1.15) but not other biochemical markers of disease. Conclusion: Cardiometabolic morbidities are prevalent among adults with 21OHD. Hypertension, age, and GC exposure are the main predictive factors of established CVDs in our cohort. [ABSTRACT FROM AUTHOR]

Aldosterone (Aldo) exerts its action through binding with the mineralocorticoid receptor (MR). Clinically, a link between primary aldosteronism (PA) and thyroid diseases has been hypothesised. However, the presence and activity of MR on the thyroid have not yet been demonstrated. We investigated the gene/protein expression and activation of MR in primary thyroid cell cultures (normal rat thyroid [FRTL-5] and human papillary thyroid cancer [PTC] cell lines, BCPAP and K1) through qRT-PCR analysis, immunofluorescence, and confocal microscopy. We also studied the effects of Aldo on thyroid-specific and inflammation genes in vitro. Paired human normal and neoplastic thyroid tissues were also studied. We demonstrated both gene and protein expression and activation of MR in normal rat thyroid and human PTC lines. Incubation with Aldo induced an acute increase in IL-6 expression in both the FRTL-5 and BCPAP lines, which was antagonised by spironolactone, and an acute and late upregulation of thyroid-specific genes in FRTL-5. MR was also expressed at both gene and protein levels in normal human thyroid tissues and in PTC, with a progressive decline during neoplastic tumourigenesis, particularly in more aggressive histotypes. We present the first evidence of MR gene and protein expression in both normal and pathological thyroid cells and tissues. We have shown that MR is present and functionally activated in thyroid tissue. Binding of Aldo to MR induces the expression of inflammatory and thyroid-specific genes, and the thyroid may thus be considered a novel mineralocorticoid target tissue. [ABSTRACT FROM AUTHOR]

11‐beta‐hydroxysteroid dehydrogenases (11β‐HSDs) catalyse the conversion of active 11‐hydroxy glucocorticoids (cortisol, corticosterone) and their inert 11‐keto forms (cortisone, 11‐dehydrocorticosterone). They were first reported in the body and brain 70 years ago, but only recently have they become of interest. 11β‐HSD2 is a dehydrogenase, potently inactivating glucocorticoids. In the kidney, 11β‐HSD2 generates the aldosterone‐specificity of intrinsically non‐selective mineralocorticoid receptors. 11β‐HSD2 also protects the developing foetal brain and body from premature glucocorticoid exposure, which otherwise engenders the programming of neuropsychiatric and cardio‐metabolic disease risks. In the adult CNS, 11β‐HSD2 is confined to a part of the brain stem where it generates aldosterone‐specific central control of salt appetite and perhaps blood pressure. 11β‐HSD1 is a reductase, amplifying active glucocorticoid levels within brain cells, notably in the cortex, hippocampus and amygdala, paralleling its metabolic functions in peripheral tissues. 11β‐HSD1 is elevated in the ageing rodent and, less certainly, human forebrain. Transgenic models show this rise contributes to age‐related cognitive decline, at least in mice. 11β‐HSD1 inhibition robustly improves memory in healthy and pathological ageing rodent models and is showing initial promising results in phase II studies of healthy elderly people. Larger trials are needed to confirm and clarify the magnitude of effect and define target populations. The next decade will be crucial in determining how this tale ends – in new treatments or disappointment. [ABSTRACT FROM AUTHOR]

This review paper presents a review of the evolution of this disease throughout the centuries, describes and summarizes the pathophysiologic mechanisms, briefly discusses the mechanism of action of diuretics, presents their role in decongesting heart failure in patients, and reveals the data behind ultrafiltration in the management of acutely or chronically decompensated heart failure (ADHF), focusing on all the available data and advancements in this field. Acutely decompensated heart failure (ADHF) presents a critical clinical condition characterized by worsening symptoms and signs of heart failure, necessitating prompt intervention to alleviate congestion and improve cardiac function. Diuretics have traditionally been the mainstay for managing fluid overload in ADHF. Mounting evidence suggests that due to numerous causes, such as coexisting renal failure or chronic use of loop diuretics, an increasing rate of diuretic resistance is noticed and needs to be addressed. There has been a series of trials that combined diuretics of different categories without the expected results. Emerging evidence suggests that ultrafiltration may offer an alternative or adjunctive approach. [ABSTRACT FROM AUTHOR]

Primary aldosteronism is an endocrine disorder caused by excessive production of aldosterone by the adrenal glands, and is recognized as the most important cause of endocrine hypertension. With specific therapy, this type of hypertension is potentially curable. In the general population, high salt intake increases the risk for cardiovascular diseases like stroke. In populations with aldosterone excess, observational and experimental data suggest that aldosterone-induced organ damage requires a combination of high dietary salt intake and high plasma aldosterone, i.e., plasma aldosterone levels inappropriately high for salt status. Therefore, understanding the relationship between plasma aldosterone levels and dietary salt intake and the nature of their combined effects is crucial for developing effective prevention and treatment strategies. In this review, we present an update on findings about primary aldosteronism and salt intake and the underlying mechanisms governing their interaction. [ABSTRACT FROM AUTHOR]

An Addisonian Crisis (AC) is an endocrinological emergency associated with high mortality, resulting from an acute deficit of hormones from the adrenal glands. It can occur either in a patient with known Adrenal Insufficiency (AI) or as the initial presentation of the disease. Primary Adrenal Insufficiency (PAI), which can be caused by autoimmune adrenalitis or tubercular adrenalitis, is the most common cause worldwide and particularly prevalent in developing countries like India. Other causes of PAI include infiltrative pathology, drugs, haemorrhage, or, rarely, malignancy. Secondary Adrenal Insufficiency (SAI) often occurs due to abrupt steroid withdrawal or defects at the level of the pituitary or hypothalamus. The present case series highlights three cases (three male patients) in which patients presented with adrenal crisis despite no prior history of AI. Subsequently, they were diagnosed with bilateral adrenal masses of different aetiologies, including primary adrenal malignancy and granulomatous infiltration of the adrenals due to Tuberculosis (TB). One case involved bilateral primary adrenal malignancy with left perirenal and pararenal space infiltration, while the other two patients were diagnosed with disseminated TB with adrenal gland infiltration. The presentation of all three cases was characterised by non specific symptoms. Initial management for all three patients involved mineralocorticoid and glucocorticoid replacement, and they were discharged with corticosteroid supplements. However, the patient with bilateral adrenal malignancy was referred to the surgery and oncology department for further evaluation and management, whereas the remaining two patients were started on Antitubercular (ATT) drugs for definite treatment.

Central serous chorioretinopathy (CSCR) belongs to the pachychoroid spectrum, a pathological phenotype of the choroidal vasculature, in which blood flow is under the choroidal nervous system (ChNS) regulation. The pathogenesis of CSCR is multifactorial, with the most recognised risk factor being intake of glucocorticoids, which activate both the gluco- and the mineralocorticoid (MR) receptors. As MR over-activation is pathogenic in the retina and choroid, it could mediate the pathogenic effects of glucocorticoids in CSCR. But the role of MR signalling in pachychoroid is unknown and whether it affects the ChNS has not been explored. Using anatomo-neurochemical characterisation of the ChNS in rodents and humans, we discovered that beside innervation of arteries, choroidal veins and choriocapillaris are also innervated, suggesting that the entire choroidal vasculature is under neural control. The numerous synapses together with calcitonin gene-related peptide (CGRP) vesicles juxtaposed to choroidal macrophages indicate a neuro-immune crosstalk. Using ultrastructural approaches, we show that transgenic mice overexpressing human MR, display a pachychoroid-like phenotype, with signs of choroidal neuropathy including myelin abnormalities, accumulation and enlargement of mitochondria and nerves vacuolization. Transcriptomic analysis of the RPE/choroid complex in the transgenic mice reveals regulation of corticoids target genes, known to intervene in nerve pathophysiology, such as Lcn2, rdas1/dexras1, S100a8 and S100a9, rabphilin 3a (Rph3a), secretogranin (Scg2) and Kinesin Family Member 5A (Kif5a). Genes belonging to pathways related to vasculature development, hypoxia, epithelial cell apoptosis, epithelial mesenchymal transition, and inflammation, support the pachychoroid phenotype and highlight downstream molecular targets. Hypotheses on the imaging phenotype of pachychoroid in humans are put forward in the light of these new data. Our results provide evidence that MR overactivation causes a choroidal neuropathy that could explain the pachychoroid phenotype found in transgenic mice overexpressing human MR. In patients with pachychoroid and CSCR in which systemic dysautonomia has been demonstrated, MR-induced choroidal neuropathy could be the missing link between corticoids and pachychoroid. [ABSTRACT FROM AUTHOR]

Congenital forms of endocrine hypertension are rare and potentially life-threatening disorders, primarily caused by genetic defects affecting adrenal steroid synthesis and activation pathways. These conditions exhibit diverse clinical manifestations, which can be distinguished by their unique molecular mechanisms and steroid profiles. Timely diagnosis and customized management approach are crucial to mitigate unfavorable outcomes associated with uncontrolled hypertension and other related conditions. Treatment options for these disorders depend on the distinct underlying pathophysiology, which involves specific pharmacological therapies or surgical adrenalectomy in some instances. This review article summarizes the current state of knowledge on the therapeutic management of congenital forms of endocrine hypertension, focusing on familial hyperaldosteronism (FH), congenital adrenal hyperplasia, apparent mineralocorticoid excess, and Liddle syndrome. We provide an overview of the genetic and molecular pathogenesis underlying each disorder, describe the clinical features, and discuss the various therapeutic approaches available and their risk of adverse effects, aiming to improve outcomes in patients with these rare and complex conditions. [ABSTRACT FROM AUTHOR]

Stress induces changes in nervous system function on different signaling levels, from molecular signaling to synaptic transmission to neural circuits to behavior—and on different time scales, from rapid onset and transient to delayed and long-lasting. The principal effectors of stress plasticity are glucocorticoids, steroid hormones that act with a broad range of signaling competency due to the expression of multiple nuclear and membrane receptor subtypes in virtually every tissue of the organism. Glucocorticoid and mineralocorticoid receptors are localized to each of the cellular compartments of the receptor-expressing cells—the membrane, cytosol, and nucleus. In this review, we cover the neuroendocrine effects of stress, focusing mainly on the rapid actions of acute stress–induced glucocorticoids that effect changes in synaptic transmission and neuronal excitability by modulating synaptic and intrinsic neuronal properties via activation of presumed membrane glucocorticoid and mineralocorticoid receptors. We describe the synaptic plasticity that occurs in 4 stress-associated brain structures, the hypothalamus, hippocampus, amygdala, and prefrontal cortex, in response to single or short-term stress exposure. The rapid transformative impact of glucocorticoids makes this stress signal a particularly potent effector of acute neuronal plasticity. [ABSTRACT FROM AUTHOR]

BACKGROUND: Renin suppression in primary aldosteronism indicates mineralocorticoid receptor activation via excessive aldosterone secretion, inducing renal damage. We investigated whether the reversal of renin suppression after the initiation of mineralocorticoid receptor antagonist therapy was associated with long-term renal outcomes in medically treated patients with primary aldosteronism. METHODS: This retrospective cohort study included 318 patients with primary aldosteronism treated with mineralocorticoid receptor antagonist between 2008 and 2020 at the Yokohama Rosai Hospital in Japan. The posttreatment renin status was defined as unsuppressed (ie, reversal of renin suppression) when individual plasma renin activity after the initiation of mineralocorticoid receptor antagonist (post-plasma renin activity) was ≥1.0 ng/mL per hour; otherwise, it was defined as suppressed. We analyzed the association of posttreatment renin status with subsequent longitudinal estimated glomerular filtration rate changes using linear mixed-effects models for repeated measurements, adjusting for potential confounders. RESULTS: The posttreatment renin status of 119 patients was unsuppressed (median post-plasma renin activity, 1.7 ng/mL per hour) and that of 199 patients was suppressed (median post-PRA, 0.5 ng/mL per hour). Through the median follow-up period of 3.1 years, the decline in estimated glomerular filtration rate was milder among patients with the unsuppressed posttreatment renin (-0.46 [95% CI, -0.63 to -0.28] mL/min per 1.73 m² per year) than those with suppressed posttreatment renin (-1.41 [95% CI, -1.56 to -1.27] mL/min per 1.73 m² per year; difference, 0.96 [95% CI, 0.72-1.20] mL/min per 1.73 m² per year). CONCLUSIONS: Our findings may highlight the importance of reversing renin suppression with optimal mineralocorticoid receptor antagonist titration in medically treated primary aldosteronism, which could mitigate adverse renal outcomes. [ABSTRACT FROM AUTHOR]

BACKGROUND: The expression of NGAL/lcn2 (neutrophil gelatinase-associated lipocalin) is directly modulated by mineralocorticoid receptor activation but its role in blood pressure control is unclear. METHODS: a potential relationship between NGAL plasma levels, systolic blood pressure and urinary Na excretion was assessed in the STANISLAS cohort. The specific role of NGAL/lcn2 in salt-sensitive hypertension was studied using lcn2- knockout mice (lcn2 KO) fed with low-Na diet (0Na). RESULTS: we show that NGAL plasma levels positively correlate with systolic blood pressure, whereas they negatively correlate with urinary Na excretion in subjects of the STANISLAS cohort. Prolonged feeding of lcn2 KO mice with a 0Na diet induced lower systolic blood pressure than that of the control group (wildtype), suggesting a role for NGAL/lcn2 in Na-balance homeostasis. Short-term or prolonged 0Na increased Na-Cl cotransporter (NCC) phosphorylation in the cortex of wildtype mice, which was prevented in lcn2 KO mice. Recombinant mouse lcn2 injections in lcn2 KO mice induced NCC phosphorylation in the kidney cortex, associated with decreased urinary Na excretion. Ex vivo experiments using kidney slices from lcn2 KO mice showed increased NCC phosphorylation by recombinant murine lcn2. In addition, recombinant murine lcn2 induced activation of CamK2ß (calcium/calmodulin-dependent protein kinase II ß subunit) phosphorylation in lcn2 KO mice and in kidney slices, providing an underlying mechanism involved in lcn2-induced NCC phosphorylation. Indeed, the inhibition of CamK2ß prevented NCC phosphorylation induced by recombinant lcn2 in kidney slices. CONCLUSIONS: we highlight a novel role of NGAL/lcn2 as a modulator of the activity of the renal sodium transporter NCC affecting salt-sensitive blood pressure. [ABSTRACT FROM AUTHOR]

Disorders of Sex Development (DSD) associated with adrenal dysfunction occur due to different defects in the proteins involved in gonadal and adrenal steroidogenesis. The deficiencies in 21-hydroxylase and 11β-hydroxylase lead to DSD in 46,XX patients, defects in StAR, P450scc, 17α-hydroxylase and 17,20-lyase lead to 46,XY DSD, and 3β-HSD2 and POR deficiencies cause both 46,XX and 46,XY DSD. Challenges in diagnosis arise from the low prevalence and the variability in serum steroid profiles. Replacement therapy with hydrocortisone and fludrocortisone helps to minimize life-threatening adrenal crises; however, availability is still an unresolved problem in many countries. Adverse health outcomes, due to the disease or its treatment, are common and include adult short stature, hypertension, osteoporosis, obesity, cardiometabolic risk, and reproductive health issues. Potential biomarkers to improve monitoring and novel treatment options that have been developed with the primary aim to decrease adrenal androgen production are promising tools to help improve the health and quality of life of these patients. Steroid profiling by mass spectrometry and next-generation sequencing technologies represent useful tools for establishing an etiologic diagnosis and drive personalized management. Nonetheless, access to health care still remains an issue requiring urgent solutions in many resource-limited settings. [ABSTRACT FROM AUTHOR]

Abstract Background Primary aldosteronism (PA) is an adrenal gland disease, that induces increased secretion of the mineralocorticoid, aldosterone, resulting in symptoms such as hypertension. This study reports a patient with agoraphobia and panic attacks, associated with PA. This patient’s psychiatric symptoms improved after treatment with eplerenone, a mineralocorticoid receptor antagonist. Case presentation The patient was a 40-year-old female with agoraphobia, which refers to the irrational fear of situations that may cause anxiety, and panic attacks characterized by profuse sweating, palpitations, and generalized weakness. She was diagnosed with hypertension from PA. Subsequently, she received treatment with eplerenone, which improved her agoraphobia and panic attacks. Conclusions There have been no previous reports on PA associated with agoraphobia and panic attacks that improved with pharmacotherapy. Patients with agoraphobia and panic attacks should be evaluated for PA. In patients with PA, pharmacotherapy with eplerenone should be considered.

[Figure: see text].

Abstract Background Primary hypoadrenocorticism (PH) is rare in cats and knowledge about treatment is sparse. Objective To describe cats with PH with a focus on long‐term treatment. Animals Eleven cats with naturally occurring PH. Methods Descriptive case series with data on signalment, clinicopathological findings, adrenal width, and doses of desoxycorticosterone pivalate (DOCP) and prednisolone during a follow‐up period of >12 months. Results Cats ranged from 2 to 10 years (median 6.5); 6 cats were British Shorthair. Most common signs were reduced general condition and lethargy, anorexia, dehydration, obstipation, weakness, weight loss, and hypothermia. Adrenal glands on ultrasonography were judged small in 6. Eight cats could be followed for 14 to 70 months (median: 28). Two were started on DOCP doses ≥2.2 mg/kg (2.2; 2.5) and 6

Background: Different lines of evidence imply that metformin could alter steroid hormone homeostasis and thereby improve social impairment. Here, we tried to correlate the impact of metformin treatment on alterations in steroid hormones and autism spectrum traits before versus after treatment with metformin. Material & methods: Urine steroid hormones were measured using gas chromatography mass spectrometry in 12 male subjects (54.2 ± 9.1 years, 177.3 ± 4.1 cm, 80 ± 10.4 kg) and 7 female subjects (64.14 ± 18.0 years, 162.7 ± 4.1 cm, 76.1 ± 10.4 kg). Furthermore, a questionnaire on autism spectrum traits (Autism Spectrum Questionnaire]) was administered prior to and after metformin treatment. Results: Overall, a decrease of steroid hormones were detected, which were most pronounced in the metabolites of corticosterone, deoxycortisol, cortisol, as well as androgens. These remained after Bonferroni correction (three classes: glucocorticoid, mineralocorticoid, androgens). No effect on autism spectrum traits (social skills, attention switching skills, attention to detail skills, communication skills, imagination skills), was identified pre versus post metformin treatment. Discussion: The decreased steroid hormone levels are based on different mechanisms; one effect is likely via mitochondria, another effect via activated protein kinase prior to post treatment. The finding on autistic traits must be taxed as negative and do not directly provide an argument for using metformin in the treatment of autism.

• Dorsal horn (DH) neurons express glucocorticoid and mineralocorticoid receptors. • Corticosterone (CORT) acutely modulates synaptic signaling in the adolescent DH. • Prolonged CORT exposure shapes synaptic transmission in a sex-dependent manner. • CORT fails to significantly alter the intrinsic firing of adolescent DH neurons. Stress evokes age-dependent effects on pain sensitivity and commonly occurs during adolescence. However, the mechanisms linking adolescent stress and pain remain poorly understood, in part due to a lack of information regarding how stress hormones modulate the function of nociceptive circuits in the adolescent CNS. Here we investigate the short- and long-term effects of corticosterone (CORT) on the excitability of GABAergic and presumed glutamatergic neurons of the spinal superficial dorsal horn (SDH) in Gad1 -GFP mice at postnatal days (P)21-P34. In situ hybridization revealed that glutamatergic SDH neurons expressed significantly higher mRNA levels of both glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) compared to adjacent GABAergic neurons. The incubation of spinal cord slices with CORT (90 min) evoked select long-term changes in spontaneous synaptic transmission across both cell types in a sex-dependent manner, without altering the intrinsic firing of either Gad1 -GFP+ or GFP− neurons. Meanwhile, the acute bath application of CORT significantly decreased the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs), as well as the frequency of miniature inhibitory postsynaptic currents (mIPSCs), in both cell types leading to a net reduction in the balance of spontaneous excitation vs. inhibition (E:I ratio). This CORT-induced reduction in the E:I ratio was not prevented by selective antagonists of either GR (mifepristone) or MR (eplerenone), although eplerenone blocked the effect on mEPSC amplitude. Collectively, these data suggest that corticosterone modulates synaptic function within the adolescent SDH which could influence the overall excitability and output of the spinal nociceptive network. [ABSTRACT FROM AUTHOR]

BackgroundMineralocorticoid receptor antagonists (MRA) are an underutilized therapy for heart failure with a reduced ejection fraction (HFrEF), but the current impact of hospitalization on MRA use is not well characterized. The objective of this study was to describe contemporary MRA prescription for heart failure patients before and after the full scope of hospitalizations and the association between MRA discharge prescription and post-hospitalization outcomes.MethodsWe conducted a retrospective cohort study at an academic hospital system in 2013-2016. Among 1500 included hospitalizations of 1009 unique patients with HFrEF and without MRA contraindication, the mean age was 71.9 ± 13.6 years and 443 (29.5%) were female. We compared MRA prescription before and after hospitalizations with McNemar's test and between patients with principal and secondary diagnoses of HFrEF with the chi-square test, and association of MRA discharge prescription with 30-day and 180-day mortality and readmissions using generalized estimating equations.ResultsMRA prescriptions increased from 303 (20.2%) to 375 (25.0%) at discharge (+4.8%, p

Autoimmune Addison’s disease (AAD) is defined as primary adrenal insufficiency due to immune-mediated destruction of the adrenal cortex. This destruction of steroid-producing cells has historically been thought of as an irreversible process, with linear progression from an ACTH-driven compensated phase to overt adrenal insufficie ncy requiring lifelong glucocorticoid replacement. However, a growing body of evidence suggests that this process may be more heterogeneous than previously thought, with potential for complete or partial recovery of glucocorticoid secretion. Although patients with persistent mineralocorticoid deficiency despite preserved or recovered glucocorticoid function are anecdotally mentioned, few well-documented cases have been reported to date. We present three patients in the United Kingdom who further challenge the long-standing hypothesis that AAD is a progressive, irreversible disease process. We describe one patient with a 4-year history of mineralocorticoid-only Addison’s disease, a patient with spontaneous recovery of adrenal function and one patient with clinical features of adrenal insufficiency despite significant residual cortisol function. All three patients show varying degrees of mineralocorticoid deficiency, suggesting that recovery of zona fasciculata function in the adrenal cortex may occur independently to that of the zona glomerulosa. We outline the current evidence for heterogeneity in the natural history of AAD and discuss possible mechanisms for the recovery of adrenal function.

Aldosterone, as a mineralocorticoid of adrenal origin, has effects that are not limited to the urinary tract. As an important regulator in Vasoactive hormone pathways, aldosterone may play an effect in the pathogenesis of diabetic retinopathy (DR) through the regulation of oxidative stress, vascular regulation, and inflammatory mechanisms. This implies that mineralocorticoids, including aldosterone, have great potential and value for the diagnosis and treatment of DR. Because early studies did not focus on the intrinsic association between mineralocorticoids and DR, targeted research is still in its infancy and there are still many obstacles to its application in the clinical setting. Recent studies have improved the understanding of the effects of aldosterone on DR, and we review them with the aim of exploring possible mechanisms for the treatment and prevention of DR. [ABSTRACT FROM AUTHOR]

Background: Primary hypoadrenocorticism (PH) is rare in cats and knowledge about treatment is sparse. Objective: To describe cats with PH with a focus on long‐term treatment. Animals: Eleven cats with naturally occurring PH. Methods: Descriptive case series with data on signalment, clinicopathological findings, adrenal width, and doses of desoxycorticosterone pivalate (DOCP) and prednisolone during a follow‐up period of >12 months. Results: Cats ranged from 2 to 10 years (median 6.5); 6 cats were British Shorthair. Most common signs were reduced general condition and lethargy, anorexia, dehydration, obstipation, weakness, weight loss, and hypothermia. Adrenal glands on ultrasonography were judged small in 6. Eight cats could be followed for 14 to 70 months (median: 28). Two were started on DOCP doses ≥2.2 mg/kg (2.2; 2.5) and 6 < 2.2 mg/kg (1.5‐2.0 mg/kg, median 1.8) q28 days. Both high‐dose cats and 4 low‐dose cats needed a dose increase. Desoxycorticosterone pivalate and prednisolone doses at the end of the follow‐up period were 1.3 to 3.0 mg/kg (median: 2.3) and 0.08 to 0.5 mg/kg/day (median: 0.3), respectively. Conclusions and Clinical Importance: Desoxycorticosterone pivalate and prednisolone requirements in cats were higher than what is currently used in dogs; thus, a DOCP starting dose of 2.2 mg/kg q28 days and a prednisolone maintenance dose of 0.3 mg/kg/day titrated to the individual need seems warranted. Small adrenal glands (width < 2.7 mm) on ultrasonography in a cat suspected of hypoadrenocorticism can be suggestive of the disease. The apparent predilection of British Shorthaired cats for PH should be further evaluated. [ABSTRACT FROM AUTHOR]

Marijuana has long been used both for recreational and medicinal purposes. Most of the available forms of marijuana contain additives such as liquorice to enhance its flavour. Liquorice increases the amounts of cortisol in the body and produces metabolic abnormalities seen in primary hyperaldosteronism. Liquorice extracts are mixed with marijuana in the same way as for tobacco. We describe a case of apparent mineralocorticoid excess due to excessive smoking of liquorice-laced marijuana. To our knowledge, this is the first reported case of apparent mineralocorticoid excess caused by marijuana use.

Background: Primary aldosteronism (PA) is an adrenal gland disease, that induces increased secretion of the mineralocorticoid, aldosterone, resulting in symptoms such as hypertension. This study reports a patient with agoraphobia and panic attacks, associated with PA. This patient's psychiatric symptoms improved after treatment with eplerenone, a mineralocorticoid receptor antagonist. Case presentation: The patient was a 40-year-old female with agoraphobia, which refers to the irrational fear of situations that may cause anxiety, and panic attacks characterized by profuse sweating, palpitations, and generalized weakness. She was diagnosed with hypertension from PA. Subsequently, she received treatment with eplerenone, which improved her agoraphobia and panic attacks. Conclusions: There have been no previous reports on PA associated with agoraphobia and panic attacks that improved with pharmacotherapy. Patients with agoraphobia and panic attacks should be evaluated for PA. In patients with PA, pharmacotherapy with eplerenone should be considered. [ABSTRACT FROM AUTHOR]

We performed a comprehensive assessment of rare inherited variation in autism spectrum disorder (ASD) by analyzing whole-genome sequences of 2,308 individuals from families with multiple affected children. We implicate 69 genes in ASD risk, including 24 passing genome-wide Bonferroni correction and 16 new ASD risk genes, most supported by rare inherited variants, a substantial extension of previous findings. Biological pathways enriched for genes harboring inherited variants represent cytoskeletal organization and ion transport, which are distinct from pathways implicated in previous studies. Nevertheless, the de novo and inherited genes contribute to a common protein-protein interaction network. We also identified structural variants (SVs) affecting non-coding regions, implicating recurrent deletions in the promoters of DLG2 and NR3C2. Loss of nr3c2 function in zebrafish disrupts sleep and social function, overlapping with human ASD-related phenotypes. These data support the utility of studying multiplex families in ASD and are available through the Hartwell Autism Research and Technology portal.

Background and Purpose: Delayed wound healing is among the deleterious consequences of over‐activation of the mineralocorticoid receptor (MR) induced by topical dermocorticoids. The role of dermal inflammation and angiogenesis in the benefits of MR blockade is unknown. Experimental Approach: Skin wounds were made on C57Bl6 mice after topical pretreatment with the dermocorticoid clobetasol. The impact of topical MR blockade by canrenoate on inflammation, angiogenesis, and the wound macrophage phenotype was analysed 5 days post‐wounding. Similar experiments were conducted on mice with genetic deletion of the MR in myeloid cells. Key Results: Topical inhibition of the MR with canrenoate improved delayed wound healing through the resolution of prolonged inflammation in glucocorticoid‐pretreated mouse skin. This effect was associated with a higher ratio of anti‐inflammatory macrophages versus pro‐inflammatory macrophages in wounds treated by canrenoate. Furthermore, MR blockade led to upregulated expression of pro‐angiogenic factors and improved impaired angiogenesis in wounds of glucocorticoid‐pretreated skin. Finally, deletion of MR expression by myeloid cells reproduced the benefits of topical pharmacological MR blockade. Conclusion and Implications: Topical MR antagonism facilitates the switching of macrophages towards an anti‐inflammatory phenotype, which improves prolonged inflammation and induces angiogenesis to accelerate wound healing delayed by glucocorticoid treatment. [ABSTRACT FROM AUTHOR]

Several agents are emerging from five different novel classes of antihypertensive medications. We will focus on endothelin antagonists and non-steroidal mineralocorticoid receptor antagonists. While several agents exist in this later class, only a couple have demonstrated superior efficacy in resistant hypertension management. Endothelin receptor antagonists are effective therapy for primary and resistant hypertension, but they are not widely used. This is due to side effects demonstrated in large clinical trials, specifically increased peripheral edema and worsening heart failure in some cases, as well as the availability of many alternative agents to manage blood pressure effectively. However, the relationship between endothelin and its close ties to hypertension is evolving. Recent pre-clinical work explores new applications of more selective endothelin receptor antagonists. They suggest that specific subtypes of hypertension may benefit more from endothelin receptor blockade than simply those with primary hypertension. We review this topic and other related data. Lastly, we also provide a brief overview of non-steroidal mineralocorticoid receptor antagonists as some in the class show promise as antihypertensive agents. [ABSTRACT FROM AUTHOR]

Glucocorticoid (GC) hormones act on the brain to regulate diverse functions, from behavior and homeostasis to the activity of the hypothalamic-pituitary-adrenal axis. Local regeneration and metabolism of GCs can occur in target tissues through the actions of the 11β-hydroxysteroid dehydrogenases [11 beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and 11 beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2), respectively] to regulate access to GC receptors. Songbirds have become especially important model organisms for studies of stress hormone action; however, there has been little focus on neural GC metabolism. Therefore, we tested the hypothesis that 11β-HSD1 and 11β-HSD2 are expressed in GC-sensitive regions of the songbird brain. Localization of 11β-HSD expression in these regions could provide precise temporal and spatial control over GC actions. We quantified GC sensitivity in zebra finch (Taeniopygia guttata) brain by measuring glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) expression across six regions, followed by quantification of 11β-HSD1 and 11β-HSD2 expression. We detected GR, MR, and 11β-HSD2 mRNA expression throughout the adult brain. Whereas 11β-HSD1 expression was undetectable in the adult brain, we detected low levels of expression in the brain of developing finches. Across several adult brain regions, expression of 11β-HSD2 covaried with GR and MR, with the exception of the cerebellum and hippocampus. It is possible that receptors in these latter two regions require direct access to systemic GC levels. Overall, these results suggest that 11β-HSD2 expression protects the adult songbird brain by rapid metabolism of GCs in a context and region-specific manner.

Background The pathobiology of heart failure with preserved ejection fraction (HFpEF) is still poorly understood, and effective therapies remain limited. Diabetes and mineralocorticoid excess are common and important pathophysiological factors that may synergistically promote HFpEF. The authors aimed to develop a novel animal model of HFpEF that recapitulates key aspects of the complex human phenotype with multiorgan impairments. Methods and Results The authors created a novel HFpEF model combining leptin receptor–deficient db/db mice with a 4‐week period of aldosterone infusion. The HFpEF phenotype was assessed using morphometry, echocardiography, Ca2+ handling, and electrophysiology. The sodium‐glucose cotransporter‐2 inhibitor empagliflozin was then tested for reversing the arrhythmogenic cardiomyocyte phenotype. Continuous aldosterone infusion for 4 weeks in db/db mice induced marked diastolic dysfunction with preserved ejection fraction, cardiac hypertrophy, high levels of B‐type natriuretic peptide, and significant extracardiac comorbidities (including severe obesity, diabetes with marked hyperglycemia, pulmonary edema, and vascular dysfunction). Aldosterone or db/db alone induced only a mild diastolic dysfunction without congestion. At the cellular level, cardiomyocyte hypertrophy, prolonged Ca2+ transient decay, and arrhythmogenic action potential remodeling (prolongation, increased short‐term variability, delayed afterdepolarizations), and enhanced late Na+ current were observed in aldosterone‐treated db/db mice. All of these arrhythmogenic changes were reversed by empagliflozin pretreatment of HFpEF cardiomyocytes. Conclusions The authors conclude that the db/db+aldosterone model may represent a distinct clinical subgroup of HFpEF that has marked hyperglycemia, obesity, and increased arrhythmia risk. This novel HFpEF model can be useful in future therapeutic testing and should provide unique opportunities to better understand disease pathobiology.

Background: The retinal pigment epithelium (RPE), a layer of pigmented cells that lies between the neurosensory retina and the underlying choroid, plays a critical role in maintaining the functional integrity of photoreceptor cells and in mediating communication between the neurosensory retina and choroid. Prior studies have demonstrated neurotrophic effects of select steroids that mitigate the development and progression of retinal degenerative diseases via an array of distinct mechanisms of action.Methods: Here, we identified major steroid hormone signaling pathways and their key functional protein constituents controlling steroid hormone signaling, which are potentially involved in the mitigation or propagation of retinal degenerative processes, from human proteome datasets with respect to their relative abundances in the retinal periphery, macula, and fovea.Results: Androgen, glucocorticoid, and progesterone signaling networks were identified and displayed differential distribution patterns within these three anatomically distinct regions of the choroid-retinal pigment epithelial complex. Classical and non-classical estrogen and mineralocorticoid receptors were not identified.Conclusion: Identified differential distribution patterns suggest both selective susceptibility to chronic neurodegenerative disease processes, as well as potential substrates for drug target discovery and novel drug development focused on steroid signaling pathways in the choroid-RPE. [ABSTRACT FROM AUTHOR]

Aldosterone exerts some of its effects not by binding to mineralocorticoid receptors, but rather by acting via G protein-coupled estrogen receptors (GPER). To determine if aldosterone binds directly to GPER, we studied the ability of aldosterone to compete for the binding of [³H] 2-methoxyestradiol ([³H] 2-ME), a high potency GPER-selective agonist. We used GPER gene transfer to engineer Sf9-cultured insect cells to express GPER. We chose insect cells to avoid interactions with any intrinsic mammalian receptors for aldosterone. [³H] 2-ME binding was saturable and reversible to a high-affinity population of receptors with Kd = 3.7 nM and Bmax = 2.2 pmol/mg. Consistent with agonist binding to G Protein-coupled receptors, [³H] 2-ME high- affinity state binding was reduced in the presence of the hydrolysis-resistant GTP analog, GppNHp. [³H] 2-ME binding was competed for by the GPER agonist G1, the GPER antagonist G15, estradiol (E2), as well as aldosterone (Aldo). The order of potency for competing for [³H] 2-ME binding, namely 2ME > Aldo > E2 ≥ G1, paralleled the orders of potency for inhibition of cell proliferation and inhibition of ERK phosphorylation by ligands acting at GPER. These data confirm the ability of aldosterone to interact with the GPER, consistent with the interpretation that aldosterone likely mediates its GPER-dependent effects by direct binding to the GPER. Significance statement: Despite the growing evidence for aldosterone's actions via G protein-coupled estrogen receptors (GPER), there remains significant skepticism that aldosterone can directly interact with GPER. The current studies are the first to demonstrate directly that aldosterone indeed is capable of binding to the GPER and thus likely mediates its GPER-dependent effects by direct binding to the receptor. [ABSTRACT FROM AUTHOR]

Purpose: The topical administration of spironolactone, a mineralocorticoid receptor antagonist (MRA) improves dry eye symptoms in patients with ocular graft-versus-host disease (GVHD); however, the detailed mechanism remains unclear. This study aimed to investigate the effects of spironolactone eyedrops on the ocular surface using a chronic GVHD (cGVHD) mouse model and to determine the expression of the mineralocorticoid receptor (MR)., Methods: A cGVHD mouse model was established by allogeneic bone marrow transplantation (BMT) from B10.D2 mice to BALB/c mice. Subsequently, cGVHD mice were treated with either 0.005 % spironolactone or vehicle eyedrops. The eyelids, cornea and conjunctiva of the recipients were analyzed at 4-week intervals post-BMT in both groups., Results: Signs of ocular GVHD, such as corneal epithelial damage, depletion of meibomian glands, and inflammatory cell infiltration onto the ocular surface, were significantly decreased in cGVHD mice treated with spironolactone eyedrops. The expression of the MR NR3C2 in the corneal and conjunctival epithelia was significantly increased in cGVHD mice. HSP47 + NR3C2 + MR-expressing fibroblasts, CD45 + NR3C2 + MR-expressing leukocytes, and CD4 + NR3C2 + MR-expressing T cells infiltrated the ocular surface tissue of cGVHD mice significantly more than that of syngeneic controls., Conclusions: MR expression is increased in epithelial cells, fibroblasts, and T cells in a murine cGVHD model, whereas MRA and spironolactone eyedrops could attenuate the severity of ocular GVHD. These findings suggest that MR signaling partially contributes to the development of ocular GVHD in this mouse model., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)