Mineralocorticoid Effects Research Articles

6664 A Case of Undistinguished Congenital Adrenal Hyperplasiain a Patient with Hypertensive Emergency and Hypokalemia

Abstract Disclosure: V.L. Del Signore: None. S.T. Kaufman: None. CAH is a group of autosomal recessive disorders resulting in alterations of adrenal steroid biosynthesis. With 95% of CAH cases due to 21-hydroxylase deficiency; other causes are rare. The metabolic, phenotypic, and physiologic derangements are specific to the altered enzymatic pathways, most of which are life threatening. Identifying the enzymatic defect is crucial to treat the patient. We present a case of undifferentiated CAH in an adult resulting in significant systemic illness. A 26-year-old well virilized male presented with chief complaint of shortness of breath, lower extremity swelling, and abdominal distension for 3 weeks. He was found to have acute decompensated heart failure with LVEF 20-25%, NSTEMI, atrial fibrillation, hypertensive emergency with BP of 224/102, and potassium (K+) of 2.7 (3.5-5mmol/L). PMH included hypertension and CAH diagnosed at birth. Patient was unsure of his CAH defect. Pediatric endocrinology prescribed glucocorticoids until age 17 at which point he was told steroids were no longer required. He had been lost to follow up for 9 years. Pediatric records were unattainable. Patient remained hypokalemic and hypertensive despite aggressive K+ repletion and multiple IV antihypertensives. Endocrine work up revealed renin 0.19 (0.25- 5.82ng/mL/hr), aldosterone 4 (< or = 21ng/dL), DHEAs 97 (74-617ug/dL), FSH <0.3 (1.4 - 18.1 m[IU]/mL), LH <0.3 (1.5 - 9.3 m[IU]/mL), total testosterone 306 (250-1,100 ng/dL), SHBG 32 (10-50nmol/L), progesterone 7 (0.2-1.4 ng/mL), ACTH 345 (6-50 pg/mL), AM cortisol 4.4 (5-23 ug/dL), 17 hydroxyprogesterone 311 (32-307 ng/dL), androstenedione 1,926 (50-220 ng/dL), 11-deoxycortisol >10,000 (< or = 119 ng/dL). Cosyntropin stimulation test: 30-minute cortisol 11.1 (>18 ug/dL) and 60-minute cortisol 10.4 (>18 ug/dL). Based on clinical and lab findings a diagnosis of 11-beta hydroxylase deficiency was made. Spironolactone was started to counteract the excessive mineralocorticoid effects of deoxycorticosterone and hydrocortisone to decrease ACTH production. With this treatment, patient’s potassium and blood pressure gradually improved. IV antihypertensives were weaned as he transitioned to oral agents. This case demonstrates the importance of understanding and identifying the underlying pathophysiology of CAH to treat patients appropriately. This patient had a mineralocorticoid excess state, but adequate cortisol precursors to prevent adrenal crisis. He requires glucocorticoid therapy to prevent excessive ACTH from driving their BP and metabolic derangements. With appropriate diagnosis of 11-beta hydroxylase deficiency, patient’s excess risk of morbidity and mortality due to the downstream effects of uncontrolled CAH can be minimized. Presentation: 6/3/2024

Licorice and liver function in patients with primary liver disease: A systematic review and meta-analysis of RCTs.

Licorice (Glycyrrhiza spp.) has been a cornerstone of traditional Chinese and Japanese medicine. This systematic review and meta-analysis aimed to evaluate the efficacy of licorice formulations, alone or in combination with other herbs, on liver function enzymes in patients with primary liver disease. We systematically searched MEDLINE, Embase, Scopus, Web of Science, and Cochrane Library up to April 2024. Randomized controlled trials (RCTs) comparing the effects of Glycyrrhiza spp. preparations versus placebo or standard of care controls were included. Standard Cochrane methods were used to extract data and appraise eligible studies. A total of 15 RCTs, involving 1367 participants, were included in the analysis. The studies varied widely in geographical location, duration, and licorice preparations used. Licorice significantly reduced alanine aminotransferase (ALT) by 15.63 U/L (95% CI: -25.08, -6.18; p = 0.001) and aspartate aminotransferase (AST) by 7.37 U/L (95% CI: -13.13, -1.61; p = 0.01) compared to control groups. Subgroup analyses revealed that purified glycyrrhizic acid compounds were particularly effective, showing greater reductions in ALT and AST without significant heterogeneity. Although licorice treatment did not significantly impact gamma-glutamyl transferase and total bilirubin (TBIL) levels overall, specific licorice-herb preparations did show a notable reduction in TBIL. The safety profile of licorice was consistent with known side effects, predominantly mild and related to its mineralocorticoid effects. Despite heterogeneity and potential language bias, the findings suggest that licorice can enhance liver function. Further studies should standardize licorice preparations and explore its role in multifaceted herbal formulations to better understand its hepatoprotective mechanisms.

Association and mediation analyses among multiple metal exposure, mineralocorticoid levels, and serum ion balance in residents of northwest China

Toxic metals are vital risk factors affecting serum ion balance; however, the effect of their co-exposure on serum ions and the underlying mechanism remain unclear. We assessed the correlations of single metal and mixed metals with serum ion levels, and the mediating effects of mineralocorticoids by investigating toxic metal concentrations in the blood, as well as the levels of representative mineralocorticoids, such as deoxycorticosterone (DOC), and serum ions in 471 participants from the Dongdagou–Xinglong cohort. In the single-exposure model, sodium and chloride levels were positively correlated with arsenic, selenium, cadmium, and lead levels and negatively correlated with zinc levels, whereas potassium and iron levels and the anion gap were positively correlated with zinc levels and negatively correlated with selenium, cadmium and lead levels (all P < 0.05). Similar results were obtained in the mixed exposure models considering all metals, and the major contributions of cadmium, lead, arsenic, and selenium were highlighted. Significant dose–response relationships were detected between levels of serum DOC and toxic metals and serum ions. Mediation analysis showed that serum DOC partially mediated the relationship of metals (especially mixed metals) with serum iron and anion gap by 8.3% and 8.6%, respectively. These findings suggest that single and mixed metal exposure interferes with the homeostasis of serum mineralocorticoids, which is also related to altered serum ion levels. Furthermore, serum DOC may remarkably affect toxic metal-related serum ion disturbances, providing clues for further study of health risks associated with these toxic metals.

Refractory Hypokalemia Revealing Cushing’s Syndrome and Persisting after Bilateral Adrenalectomy: A Case Report and Review of the Literature

Cushing's syndrome (CS), a rare endocrine disorder, is characterized by a diverse range of clinical manifestations due to prolonged exposure to excess glucocorticoids. CS can be divided into ACTH-dependent and ACTH-independent types, with varying degrees of clinical severity. Biochemical abnormalities, such as hypokalemia, are associated with CS, potentially resulting from the mineralocorticoid effects of cortisol. We present a unique case of Cushing's disease with a prominent and persistent feature of hypokalemia, even after a successful bilateral adrenalectomy. The patient's clinical presentation included sudden abdominal obesity, lumbago, polyuria, polydipsia, chronic constipation, muscle cramps, and profound weakness. Early diagnostic evaluation revealed severe hypokalemia requiring treatment. Despite bilateral adrenalectomy, hypokalemia persisted postoperatively, necessitating ongoing potassium supplementation. This case highlights the complex interplay of hormones in CS and the need for comprehensive clinical and biochemical assessments. Hypokalemia is prevalent in Cushing's syndrome (CS), typically resulting from renal potassium loss, influenced by cortisol's mineralocorticoid-like effects. Additionally, ACTH might inhibit 11β-HSD2, allowing cortisol to act as a mineralocorticoid. Persistent hypokalemia in our ACTH-dependent CS case, even after bilateral adrenalectomy, raises questions about the role of ACTH and 11β-HSD2. Further research is needed to clarify these mechanisms and their relationship with CS.

Single-cell transcriptomics and chromatin accessibility profiling elucidate the kidney-protective mechanism of mineralocorticoid receptor antagonists.

Mineralocorticoid excess commonly leads to hypertension (HTN) and kidney disease. In our study, we used single-cell expression and chromatin accessibility tools to characterize the mineralocorticoid target genes and cell types. We demonstrated that mineralocorticoid effects were established through open chromatin and target gene expression, primarily in principal and connecting tubule cells and, to a lesser extent, in segments of the distal convoluted tubule cells. We examined the kidney-protective effects of steroidal and nonsteroidal mineralocorticoid antagonists (MRAs), as well as of amiloride, an epithelial sodium channel inhibitor, in a rat model of deoxycorticosterone acetate, unilateral nephrectomy, and high-salt consumption-induced HTN and cardiorenal damage. All antihypertensive therapies protected against cardiorenal damage. However, finerenone was particularly effective in reducing albuminuria and improving gene expression changes in podocytes and proximal tubule cells, even with an equivalent reduction in blood pressure. We noted a strong correlation between the accumulation of injured/profibrotic tubule cells expressing secreted posphoprotein 1 (Spp1), Il34, and platelet-derived growth factor subunit b (Pdgfb) and the degree of fibrosis in rat kidneys. This gene signature also showed a potential for classifying human kidney samples. Our multiomics approach provides fresh insights into the possible mechanisms underlying HTN-associated kidney disease, the target cell types, the protective effects of steroidal and nonsteroidal MRAs, and amiloride.

A case of chronic licorice intoxication-induced apparent mineralocorticoid excess syndrome

Licorice is a perennial herb belonging to the legume family that mainly grows in northeastern China, Mongolia, Siberia, and other regions. It is used in traditional medicine in the form of dried roots in the East and the West. The main active component of licorice, glycyrrhizin, is known to produce mineralocorticoid effects when consumed chronically, which can lead to apparent mineralocorticoid excess syndrome. Herein, we present the case of a 72-year-old woman who was admitted to the emergency room with severe generalized weakness and difficulty keeping her neck upright, which had developed after daily consumption of licorice-infused water for the past 2 months. Blood tests revealed metabolic alkalosis and severe hypokalemia, and an electrocardiogram showed ventricular bigeminy. The patient was treated with daily potassium and spironolactone supplements, leading to a significant improvement in muscle strength after a week. One week later, the patient was discharged, showing rare ventricular premature contractions on electrocardiography, but with no specific complaints. Chronic licorice ingestion leading to hypokalemia and muscle weakness can be life-threatening, necessitating the discontinuation of the causative agent, close monitoring, and cautious supplementation of potassium and spironolactone as treatment.

A Chinese girl with delayed puberty due to 17α-hydroxylase deficiency: the diagnosis, treatment and monitoring approach.

17α-hydroxylase deficiency (17α-OHD) is a rare form of congenital adrenal hyperplasia. We report the case of a teenage girl with 17α-OHD who presented with delayed puberty, hypergonadotropic hypogonadism and hypertension. We illustrate the clinical approach in workup, the subsequent management and monitoring of this rare condition. 17α-hydroxylase deficiency (17α-OHD) should be considered as a rare yet important differential diagnosis of girls with delayed puberty and elevated gonadotropins. Urine steroid profile, plasma aldosterone and renin levels should be assessed in adolescent girls with hypergonadotropic hypogonadism, after the exclusion of more common conditions, e.g. Turner syndrome. Inhibiting deoxycorticosterone (DOC) release by partial glucocorticoid replacement, counteracting DOC's mineralocorticoid effects by antagonists (such as eplerenone or spironolactone) as well as sex hormone replacements constitute the major backbone in the management of 17α-OHD.

Effect of Dexamethasone on Abiraterone Pharmacokinetics in Mice: Determined by LC/MS Analysis

Background: Abiraterone acetate is a cytochrome P450 17A1 (CYP17A1) inhibitor that is indicated for use in both castration-resistant and castration-sensitive prostate cancer patients. To manage the mineralocorticoid effects of CYP17A1 inhibition, a glucocorticoid such as dexamethasone is co-administered with abiraterone. The goal of the present study was to understand the effect of dexamethasone on the disposition of abiraterone. Methods: Adult male CD-1 mice were treated with either dexamethasone (80 mg/kg/day) or vehicle for three consecutive days, followed by the administration of a single dose of abiraterone acetate (180 mg/kg) as an oral gavage. Blood samples were collected by tail bleeding at timepoints between 0 to 24 h. Subsequently, abiraterone was extracted from the mouse serum using a neutral pH condition and serum abiraterone levels were determined using a liquid chromatography-mass spectrometry assay. Results: Our results demonstrated that dexamethasone lowered the maximum plasma concentration and area under the curve parameters by approximately five- and ten-fold, respectively. Similar effects were also observed on the plasma half-life and oral clearance parameters. This is the first report of dexamethasone effect on abiraterone disposition in vivo. Conclusions: We conclude that dexamethasone has the potential to reduce the plasma abiraterone level and thus compromise its CYP17A1 inhibitory ability in the procancerous androgen biosynthesis pathway. Thus, use of a higher abiraterone dose may be warranted when used alongside dexamethasone.

Presentation, Diagnosis, and Follow-Up Characteristics of 17α-Hydroxylase Deficiency Cases with Exon 1–6 Deletion (Founder Mutation) in the CYP17A1Gene: 20-Year Single-Center Experience

Context: 17α-Hydroxylase/17,20-lyase deficiency (17OHD) is characterized by decreased sex steroids and cortisol synthesis, as well as an increased mineralocorticoid effect. Aim: This study aimed to evaluate the clinical, biochemical, and molecular characteristics of patients with 17OHD and to discuss the diagnosis, treatment, and follow-up process. Methods: Age, symptoms, anthropometric measurements, blood pressure, and hormonal, biochemical, and chromosomal analysis results of 13 patients diagnosed with 17OHD between 2003 and 2022 were recorded at admission and during follow-up. Whole gene next-generation sequencing was performed for the CYP17A1 gene. Multiplex ligation-dependent probe amplification was used to detect deletions in patients without point mutations in CYP17A1. Results: The median age at diagnosis was 14.0 (3.5–16.8) years. Nine of 13 patients (69.2%) had 46,XY karyotypes. All patients were phenotypically female and were raised as girls. The most common reasons for admission were the absence of puberty and amenorrhea (n = 8, 61.5%), followed by hypertension (n = 3, 23.0%), and family screening (n = 2, 15.3%). At the time of diagnosis, hypertension was detected in 10 (76.9%) patients, and 11 (84.6%) patients had hypokalemia. Conclusions: 17OHD should be considered in patients with pubertal delay/primary amenorrhea, hypertension, and hypokalemia. Adrenal function should be included in the clinical study of hypergonadotropic hypogonadism, after excluding Turner syndrome, in all 46,XX females. Deletion in the CYP17A1 gene, including exons 1–6, is the founder mutation for Turkey’s east and southeast regions.

LBODP010 A Case of Glucocorticoid Resistance Syndrome

Abstract Case presentation A 55 yr old female presented with persistent mild elevation of cortisol for the previous 7 years. Four years prior to presentation, she was incidentally noted to have a small left sided adrenal nodule on CT scan of the abdomen. Biochemical evaluation of the nodule showed 24 hour urine cortisol of 176(0-50), morning cortisol of 36 ug/dl(6.2-19.4), ACTH 18 pg/ml(7.3-66.3), two out of three salivary samples with elevated cortisol. High dose dexamethasone suppressed ACTH to &amp;lt;1.1 from 13.8, cortisol from 30 to 3.3. She did not have signs and symptoms of Cushing's syndrome, mineralocorticoid excess nor androgen excess. Serum testosterone and DHEA were normal. DEXA revealed normal bone density. MRI brain demonstrated normal pituitary . She had no family history of pituitary or adrenal tumors nor endocrine syndromes. She underwent laparoscopic left adrenalectomy with pathology demonstrating benign adrenal adenoma, although the pathologist was unable to exclude nodular hyperplasia due to fragmented specimen. Elevation of 24 hour urine cortisol, serum cortisol and ACTH have persisted after surgery, without any clinical features of Cushing's. Gene sequencing with copy number analysis revealed heterozygous variant in the NR3C1 gene c.2239A&amp;gt;T(p. Ile747Phe), suspicious for autosomal dominant hereditary primary glucocorticoid resistance syndrome also known as Chrousos syndrome. Discussion Glucocorticoid resistance syndrome is rare, may be familial or sporadic, and is characterized by end organ insensitivity to glucocorticoids. Glucocorticoids are steroid hormones synthesized and secreted by adrenal cortex. The actions of glucocorticoids are mediated by the glucocorticoid receptor, which belongs to nuclear receptor family of ligand-dependent transcription factors. Affected individuals have elevations in circulating cortisol and ACTH, but no clinical evidence of hypercortisolism. Excess ACTH can result in increased mineralocorticoid and/or androgenic activity resulting in HTN and/or hypokalemic alkalosis and acne/hirsutism/infertility/male pattern hair loss. Asymptomatic, normotensive patients with primary glucocorticoid resistance do not require any treatment. Aim of treatment is to suppress excess ACTH to decrease mineralocorticoid and androgen effects. Treatment involves high doses of dexamethasone(1-3 mg/day), which activate the mutated and/or wild type hGR alpha and suppresses endogenous secretion of ACTH. Conclusion Mutations in human GR gene impair one or more molecular mechanisms of glucocorticoid action affecting signal transduction and altering tissue sensitivity to these hormones. Recognition of this condition avoids unnecessary adrenal surgery and informs appropriate treatment and long term follow up of patients and family members. Presentation: No date and time listed

ODP442 Posaconazole-induced Pseudohyperaldosteronism (PIPH) in Patient Treated for Acute Myeloid Leukemia

Abstract Case summary A 62-year-old Caucasian female presented to our institute with mechanical fall complicated by cervical spine fracture. She had known history of essential hypertension and recently diagnosed acute myeloid leukemia with myelodysplasia related changes (AML-MRC). She had undergone induction chemotherapy with combination of daunorubicin and cytarabine, resulting in chemotherapy induced prolonged pancytopenia. She was initially started on primary prophylaxis with fluconazole, but was switched to voriconazole due to persistent neutropenia. Patient then developed bilateral upper and lower extremity erythematous popular rash on voriconazole. Decision at that time was to switch to Posaconazole 300 mg orally daily. Three months after initiating Posaconazole, patient presented with severe hypokalemia (2.1 mmol/L) and hypertension. Previously her blood pressure was under control with amlodipine, lisinopril and nadolol. Hypokalemia persisted despite aggressive oral and intermittent intravenous potassium replacement therapy. No sources of potassium loss were identified on clinical history. She had persistently elevated blood pressure (systolic blood pressure of 150-180 mmHg) despite being on her home anti-hypertensive regimen. Further work up showed undetectable plasma aldosterone of less than 1 ng/dL (normal &amp;lt; 28 ng/dL) and plasma renin activity level was suppressed to 0.14 ng/mL/h (normal 0.25–5.82 ng/mL/h) with concurrent potassium of 2.9 mmol/L (normal 3.5-5.3 mmol/l). Diagnosis of pseudohyperaldosteronism was made at this time. Posaconazole gradually stopped and eplerenone 25 mg daily was commenced to selectively block mineralocorticoids receptors to control blood pressure. Subsequently hypokalemia resolved after stopping posaconazole and blood pressure normalized with her original home anti-hypertensive regimen. Eplerenone was eventually stopped. Her potassium level and blood pressure remained normal 2 weeks after discharge. Discussion Recent studies have shown the presentation of hypokalemia and hypertension in nearly a quarter of patients on Posaconazole. The clinical presentation of hypokalemia and hypertension with apparent mineralocorticoid excess was evident in our patient and was consistent with posaconazole-induced pseudohyperaldosteronism (PIPH). Posaconazole interference with the steroid synthesis pathway has been described in various literature. Both cortisol and aldosterone activate aldosterone receptors. In the case of posaconazole, excess mineralocorticoid effect is due to relative selectivity of posaconazole for 11ΒHSD2 inhibition. 11ΒHSD2 inhibition causes increased serum cortisol level by preventing the conversion to inactive cortisone. The high cortisol level cross-reacts with the mineralocorticoid receptor leading to apparent mineralocorticoid excess with low serum aldosterone level and low plasma renin activity. The degree of pseudohyperaldosterone effect on systolic blood pressure and hypokalemia has been strongly associated with serum posaconazole level in some studies. Our patient had resolution of uncontrolled hypertension and hypokalemia after withholding the posaconazole and short term treatment with selective mineralocorticoid receptor blocker. Conclusion Early diagnosis and to allow for early intervention with cessation of the offending agent or treatment with mineralocorticoid antagonists, such as spironolactone and eplerenone is necessary in PIPH. Presentation: No date and time listed

Ectopic-Adrenocorticotropic Hormone secretion in adolescents and young adult patients with neuroendocrine neoplasm: a challenge for clinical and social management

Well and poorly differentiated neuroendocrine neoplasms (NENs) may be associated with an ectopic production of Adrenocorticotropic Hormone (ACTH) [1] that leads to a paraneoplastic Cushing Syndrome (CS). This heterogeneous clinical pattern is the result of a hypercortisolism [2] due to an uncontrolled and continuous hyperstimulation of the adrenal cortex, which escapes the negative feedback of the Hypothalamus-Hypophysis axis [3]. Among NENs, ectopic-ACTH secretion (EAS) has been historically associated with small-cell lung cancers (SCLCs), but the improvement of the knowledge and diagnostic techniques led to a broadening of the causes also to NENs with different morphologies and from other sites [4]. According to the previous published data, EAS by gastro-entero-pancreatic (GEP) NENs occurs in almost 13% of cases. Irrespective of the NENs site of origin and the biology (which means morphology and proliferation index), the CS may represent a life-threatening condition for the patients due the consequences of the mineralocorticoid effect of persistent high levels of cortisol. These patients may experience a plethora of different symptoms which includes diffuse oedema, overweight/obesity of the trunk and striae rubrae, but also severe hypokalemia and hypertension, that represent medical emergencies and tumor fatal consequences even without a progression disease [1]. EAS may initially occur with non-specific clinical manifestations, as psychiatric complaints, recurrent orthopedic issues, sexual and reproductive disfunctions [3] that are not easily related to a tumoral cause and lead the patient presents to many specialists before being referred to an endocrinology / oncology Center. For all these reasons, CS diagnosis is often delayed. In a very small pool of cases [5], EAS may occur in the peculiar category of the adolescents and young adults (AYA) patients, worldwide defined as the cancerpopulation between 15 and 39 years of age [6]. Generally, the cancer diagnosis in AYA population is delayed, on one hand due to the sense of invulnerability and the minimizing of the symptoms of AYA patients and, on the other, the trend of the providers to a low suspicion of cancer in AYA population. Therefore, the features of the AYA category together with the equivocal clinical patterns of CS may lead to a delay of the diagnosis and management of EAS by extra-pituitary NENs [3, 7]. Here we reported the case of a NEN AYA patient with CS by EAS and a review of the literature on this topic in this peculiar population.

Syndromes of Pseudo-Hyperaldosteronism.

Syndromes of Pseudo-Hyperaldosteronism.

Abstract 45: Sex Differences Of Renal11β-hsd1 And 11β-hsd2 Expression In A Doca-salt Model Of Hypertension.

The balance between hydroxysteroid dehydrogenase 1 (11β-HSD1) and hydroxysteroid dehydrogenase 2 (11β-HSD2) have been implicated in the regulation of mineralocorticoid effects. We have previously shown in the DOCA-salt model of hypertension that males have a more pro-inflammatory immune profile and higher BP than females. The current study tested the hypothesis that males have a higher ratio of 11β -HSD1 to 11β -HSD2 and that preventing DOCA-salt induced increases in BP significantly shifts that ratio.At 10 wks of age, male and female Sprague-Dawley rats were anesthetized and a right uni-nephrectomy (UNX) was performed. After one week of recovery, rats were randomized to the following groups: 1) UNX controls, 2) DOCA-salt (200 mg) with 0.9% saline to drink, or 3) DOCA-salt with saline + hydrochlorothiazide (HCTZ; 55 mg/kg/day) and reserpine (RES; 4.5 mg/kg/day. After 3 weeks of treatment, the remaining kidney was isolated to measure mRNA expression of 11β-HSD1 and 11β-HSD2 via RT-qPCR.Control UNX males had a higher 11β-HSD1:11β-HSD2 ratio than females (0.9 ± 0.15 vs 0.3 ± 0.04; P=0.02). After DOCA-salt, 11β-HSD1 increased in both males and females (2.5 ± 0.1 vs. 1.3 ± 0.08; P treatment &lt;0.0001). Males maintained a higher 11β-HSD1:11β-HSD2 ratio as well has had a higher increase in 11β-HSD1 to 11β-HSD2 ratio than females (P sex =0.04; P interaction =0.04) after DOCA-salt. With HCTZ/RES treatment, 11β-HSD1 to 11β-HSD2 ratios significantly decreased in both males and females (1.9 ± 0.5 vs. 0.8 ± 0.09; P treatment =0.002), but males maintained a higher 11β-HSD1:11β-HSD2 ratio vs females (P sex =0.002; P interaction =0.54). Our data suggests that there are sex differences in the balance of renal mRNA expression of 11β-HSD1 and 11β-HSD2, with males having a greater 11β-HSD1:11β-HSD2 ratio compared to females. Preventing DOCA-salt induced increases in BP significantly shifts this ratio through an upregulation of 11β-HSD2 in both sexes.

A comparison of intravenous methylprednisolone and hydrocortisone for the treatment of acute inflammatory bowel disease.

Despite widespread recommendations and use of intravenous corticosteroids (IVCS) for the treatment of acute flares of ulcerative colitis and Crohn's disease, limited evidence exists comparing outcomes of the two most common regimens, intravenous methylprednisolone (IVMP) and intravenous hydrocortisone (IVHC). IVHC has stronger mineralocorticoid effects compared with IVMP and may cause higher rates of hypokalemia. We aimed to determine differences in clinical outcomes including requirement for inpatient rescue therapy, bowel resection, and rates of hypokalemia. We conducted a multicenter cohort study of all adult patients admitted with an acute flare of inflammatory bowel disease (IBD) to the three tertiary hospitals in Auckland, New Zealand, where the protocol at each institution is either IVMP 60mg daily or IVHC 100mg four times daily. All patients requiring IVCS between 20 June 2016 and 30 June 2018 were included. The IVCS protocol was then changed at one hospital, where further data were collected for a further 12months from 30 January 2019 until 30 December 2019. There were 359 patients, including 129 (35.9%) patients receiving IVMP and 230 (64.1%) patients receiving IVHC. IVMP treatment was associated with a greater requirement for rescue therapy than IVHC (36.4% vs 19.6%, P=0.001; odds ratio [OR]=2.79; 95% confidence interval [CI], 1.64-4.75, P<0.001), but also reduced rates of hypokalemia (55.8% vs 67.0%, P=0.04; OR=0.49; 95% CI, 0.30-0.81, P=0.005). There was no difference between treatment groups for the median length of admission (5days, interquartile range [IQR] 3-8), median duration of IVCS treatment (3days, IQR 2-5), or bowel resection within 30days of admission (12.4% vs 11.7%; OR=1.04). For the treatment of an acute flare of IBD, treatment with IVMP results in significantly more requirement for inpatient rescue biologic or cyclosporin. In addition, it causes statistically significant less hypokalemia than IVHC, although in practice differences are negligible.

Direct Mineralocorticoid Receptor (MR) Activation, Independent of Increases in Blood Pressure, Drive Sex Differences in Tregs in DOCA‐salt rats

Our lab has previously shown that greater T regulatory cells (Tregs) in females attenuate deoxycorticosterone acetate salt (DOCA)-induced increases in blood pressure (BP). Tregs do not contribute to BP control in male rats with DOCA hypertension. DOCA is a mineralocorticoid model of hypertension, and mineralocorticoid receptor activation alone can significantly increase fibrosis, oxidative stress, and inflammation, independent of an effect on BP. The goal of the current study was to test the hypothesis that direct mineralocorticoid effects, independent of increases in BP, drives sex differences in Tregs in DOCA-salt rats. At 10 wks of age, male and female Sprague-Dawley rats were anesthetized, a right uni-nephrectomy was performed, and a telemeter was implanted for continuous BP measurement. After one week of recovery, all rats received a subcutaneous 21-day slow-release DOCA pellet (200 mg) with 0.9% saline water to drink. To separate the effects of MR activation and increases in BP on DOCA-salt-induced alterations in renal Tregs, rats were randomized to the following groups: 1) BP lowering drugs hydrochlorothiazide (HCTZ; 55 mg/kg/day) and reserpine (RES; 4.5 mg/kg/day; N=9-12/group) or vehicle control (DOCA-salt only) or 2) MR blocker spironolactone (15 mg/kg/day; N=6/group) or vehicle control (DOCA-salt only). After 21 days, the remaining kidney was isolated for flow cytometric analysis of Tregs (CD3+CD4+FoxP3+). Treatment with HCTZ/RES prevented DOCA-induced increases in BP in both males (179 ± 3 mmHg vs 110 ± 5 mmHg; Ptreatment<0.0001) and females (157 ± 4 mmHg vs 101 ± 5 mmHg; Ptreatment<0.0001). Preventing DOCA-induced increases in BP did not alter sex differences in renal Tregs (Table) as females maintained more Tregs than males (Psex<0.0001; Ptreatment=0.11; Pinteraction=0.38). In contrast, treatment with spironolactone did not significantly alter BP in either male (180 ± 2 vs 178 ± 2 mmHg; Ptreatment=0.73) or female DOCA rats (170 ± 6 vs 162 ± 4 mmHg; Ptreatment=0.10). However, blocking the direct effects of MR activation with spironolactone abolished sex differences in renal Tregs by increasing Tregs (Table) in males (Psex=0.07; Ptreatment<0.0001; Pinteraction=0.04). Our data suggests that direct mineralocorticoid effects, independent of BP, drives sex differences in Tregs in DOCA-salt rats. Future studies will be designed to determine the specific mechanisms by which MR activation regulates Tregs in a sex-specific manner.

Examination of the association of steroids with fluid accumulation in critically ill patients, considering the possibility of biases

Glucocorticoids might have significant influence on positive fluid balance, mostly due to their mineralocorticoid effect. We assessed the association between glucocorticoid therapy and fluid balance in septic patients, in the intensive care unit (ICU). We considered two definitions of exposure: daily exposure to glucocorticoids and glucocorticoid treatment at any time. Of 945 patients, 375 were treated with glucocorticoids in the ICU. We applied four regression models. In the first, fluid balance did not differ during days with and without glucocorticoid treatment, among patients treated and not treated with glucocorticoids in the ICU. In our second model, daily fluid balance was increased in patients who were ever treated with glucocorticoids during their ICU stay compared to untreated patients. In the third model, which included only patients treated with glucocorticoids during their ICU stay, glucocorticoid treatment days were not associated with daily fluid balance. In the last model, on "steroid-free days", patients who received glucocorticoid treatment during their ICU stay had a positive fluid balance compared to those who were never treated with steroids. Despite their known mineralocorticoid activity, glucocorticoids themselves appear not to contribute substantially to fluid retention. This work highlights the importance of precise selection of variables to mitigate biases.

Antifungal therapy with azoles and the syndrome of acquired mineralocorticoid excess

The syndromes of mineralocorticoid excess describe a heterogeneous group of clinical manifestations leading to endocrine hypertension, typically either through direct activation of mineralocorticoid receptors or indirectly by impaired pre-receptor enzymatic regulation or through disturbed renal sodium homeostasis. The phenotypes of these disorders can be caused by inherited gene variants and somatic mutations or may be acquired upon exposures to exogenous substances. Regarding the latter, the symptoms of an acquired mineralocorticoid excess have been reported during treatment with azole antifungal drugs. The current review describes the occurrence of mineralocorticoid excess particularly during the therapy with posaconazole and itraconazole, addresses the underlying mechanisms as well as inter- and intra-individual differences, and proposes a therapeutic drug monitoring strategy for these two azole antifungals. Moreover, other therapeutically used azole antifungals and ongoing efforts to avoid adverse mineralocorticoid effects of azole compounds are shortly discussed.

Protocolo de evaluación y manejo de efectos adversos del tratamiento esteroideo

The use of corticosteroids is becoming more and more widespread in clinical practice. They are synthetic analogs of steroid hormones and show a mineralocorticoid and glucocorticoid effect varying in duration and intensity. Its side effects are frequent and of clinical relevance and depend on the dose and cumulative duration of the corticosteroid administered. In patients treated with corticosteroids, two aspects have to be evaluated: side effects of corticosteroids and the state of the adrenal axis. Both procedures require specific study protocols. Being the use of corticosteroids a frequent practice in clinical activity, close monitoring of the patients by expert professionals to identify both the activity of the adrenal axis and the presence of side effects is required.

A noninvasive method to study the evolution of extracellular fluid volume in mice using time-domain nuclear magnetic resonance.

Maintaining water homeostasis is fundamental for cellular function. Many diseases and drugs affect water balance and plasma osmolality. Water homeostasis studies in small animals require the use of invasive or terminal methods that make intracellular fluid volume and extracellular fluid volume (ECF) monitoring over time stressful and time consuming. We examined the feasibility of monitoring mouse ECF by a noninvasive method using time-domain nuclear magnetic resonance (TD-NMR). This technique allows differentiation of protons in a liquid environment (free fluid) from protons in soft tissues containing a majority of either small molecules (lean) or large molecules (fat). Moreover, this apparatus enables rapid, noninvasive, and repeated measurements on the same animal. We assessed the feasibility of coupling TD-NMR analysis to a longitudinal metabolic cage study by monitoring mice daily. We determined the effect of 24-h water deprivation on mouse body parameters and detected a sequential and overlapping decrease in free fluid and lean mass during water deprivation. Finally, we studied the effect of mineralocorticoids that are known to induce a transient increase in ECF but for which no direct measurements have been performed in mice. We showed, for the first time, that mineralocorticoids induced a transient ~15% increase in free fluid in conscious mice. TD-NMR is, therefore, the first method to allow direct measurement of discrete changes in ECF in conscious small animals. This method allows analysis of kinetic changes to stimuli before investigating with terminal methods and will allow further understanding of fluid disorders.