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The hypothalamus-pituitary-adrenal axis (HPA axis) and the sympathetic-adrenal-medullary system (SAM system), two neuroendocrine systems associated with the stress response, have often been implicated to modulate decision-making in various domains. This systematic review summarizes the scientific evidence on the effects of pharmacological HPA axis and SAM system modulation on decision-making. We found 6375 references, of which 17 studies fulfilled our inclusion criteria. We quantified the risk of bias in our results with respect to missing outcome data, measurements, and selection of the reported results. The included studies administered hydrocortisone, fludrocortisone (HPA axis stimulants), yohimbine, reboxetine (SAM system stimulants), and/or propranolol (SAM system inhibitor). Integrating the evidence, we found that SAM system stimulation had no impact on risk aversion, loss aversion or intertemporal choice, while SAM system inhibition showed a tentative reduction in sensitivity to losses. HPA axis stimulation had no effect on loss aversion or reward anticipation but likely a time-dependent effect on decision under risk. Lastly, combined stimulation of both systems exhibited inconsistent results that could be explained by dose differences (loss aversion) and sex differences (risk aversion). Future research should address time-, dose-, and sex-dependencies of pharmacological effects on decision-making., (© The Author(s) 2024. Published by Oxford University Press.)

A 78-year-old man was admitted to the hospital with a 4-day history of fever and confusion. Physical examination revealed oral dryness and decreased skin turgor. Blood tests showed hyponatremia (121.5 ‍mEq/l), and cerebrospinal fluid examination revealed positivity for herpes simplex virus 1 (HSV-1) via polymerase chain reaction. He was diagnosed with herpes simplex encephalitis and initiated acyclovir treatment. The hyponatremia was diagnosed as cerebral salt wasting syndrome (CSWS) and treated with hypertonic saline infusion and fludrocortisone. The cerebrospinal fluid HSV-1 DNA became negative, and the serum sodium levels normalized. Hyponatremia complicated with encephalitis is often caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), whereas CSWS is rare, mostly observed in tuberculous meningitis. Differentiating between the SIADH and CSWS is important as they require distinct therapeutic strategies.

Addison´s disease can form part of type 2 autoimmune polyglandular syndrome. The article reports the case of a 41-year-old female patient with hypothyroidism and vitiligo, who came to the emergency department complaining of asthenia that had worsened in recent months, as well as anorexia, nausea, and weight loss (6 kg in a year). Cutaneous hyperpigmentation was the main finding on physical examination, together with vitiligo lesions on the face, hands, and armpits. Further study revealed a low serum cortisol level, normal urine-free cortisol, and an elevated adrenocorticotropic hormone (ACTH). Antiperoxidase antibodies and 17-alpha-hidroxylase antibodies were both positive. Treatment was started with prednisolone and fludrocortisone, and a good clinical response was obtained. This case report aims to draw attention to the high level of clinical suspicion required to diagnose Addison´s disease and the need to screen actively for other potentially associated autoimmune diseases that may be associated., Competing Interests: The authors declare no competing interests., (Copyright: Gabriela Venade et al.)

Rationale: The use of hydrocortisone in adult patients with septic shock is controversial, and the effectiveness of adding fludrocortisone to hydrocortisone remains uncertain. Objectives: To assess the comparative effectiveness and safety of fludrocortisone plus hydrocortisone, hydrocortisone alone, and placebo or usual care in adults with septic shock. Methods: A systematic review and a Bayesian network meta-analysis of peer-reviewed randomized trials were conducted. The primary outcome was all-cause mortality at last follow-up. Treatment effects are presented as relative risks (RRs) with 95% credible intervals (CrIs). Placebo or usual care was the reference treatment. Measurements and Main Results: Among 7,553 references, we included 17 trials (7,688 patients). All-cause mortality at last follow-up was lowest with fludrocortisone plus hydrocortisone (RR, 0.85; 95% CrI, 0.72-0.99; 98.3% probability of superiority, moderate-certainty evidence), followed by hydrocortisone alone (RR, 0.97; 95% CrI, 0.87-1.07; 73.1% probability of superiority, low-certainty evidence). The comparison of fludrocortisone plus hydrocortisone versus hydrocortisone alone was based primarily on indirect evidence (only two trials with direct evidence). Fludrocortisone plus hydrocortisone was associated with a 12% lower risk of all-cause mortality compared with hydrocortisone alone (RR, 0.88; 95% CrI, 0.74-1.03; 94.2% probability of superiority, moderate-certainty evidence). Conclusions: In adult patients with septic shock, fludrocortisone plus hydrocortisone was associated with lower risk of all-cause mortality at last follow-up than placebo and hydrocortisone alone. The scarcity of head-to-head trials comparing fludrocortisone plus hydrocortisone versus hydrocortisone alone led our network meta-analysis to rely primarily on indirect evidence for this comparison. Although we undertook several sensitivity analyses and assessments, these findings should be considered while also acknowledging the heterogeneity of included trials.

Objectives: This systematic review and Bayesian network meta-analysis evaluated the efficacy and safety of hydrocortisone combined with fludrocortisone or hydrocortisone alone, compared with placebo in adult patients with septic shock., Data Sources: By extending a prior Cochrane review, databases, including PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov , along with other relevant websites, were searched until August 31, 2023., Study Selection: Randomized controlled trials (RCTs) and observational studies using target trial emulation were included., Data Extraction: The primary outcome was short-term mortality with an emphasis on 28- or 30-day mortality as the main measure and in-hospital or ICU mortality as the nearest surrogate of this measure. Three of the most common adverse events, namely, gastroduodenal bleeding, superinfection, and hyperglycemia, were also considered., Data Synthesis: A total of 19 studies involving 95,841 patients were included. Hydrocortisone plus fludrocortisone showed the lowest short-term mortality versus placebo (odds ratio [OR]: 0.79; 95% credible interval [CrI], 0.64-0.99; number needed to treat [NNT]: 21, range: 12-500; low certainty of evidence) in terms of informative priors. The surface under the cumulative ranking curve values for hydrocortisone plus fludrocortisone, hydrocortisone alone, and placebo were 0.9469, 0.4542, and 0.0989, respectively. Consistent results were observed in RCTs alone and those using a daily 200-mg dose of hydrocortisone. Although gastroduodenal bleeding or superinfection showed no clear increase, hyperglycemia risk increased. The ORs were 0.53 for placebo versus hydrocortisone plus fludrocortisone and 0.64 for placebo versus hydrocortisone alone, with very low certainty of evidence., Conclusions: In adults with septic shock, hydrocortisone plus fludrocortisone improved short-term survival with minimal adverse events compared with hydrocortisone alone or placebo. However, these findings are not definitive due to the limited certainty of evidence and wide NNT range. Additional large-scale, placebo-controlled RCTs are needed to provide conclusive evidence., Competing Interests: Dr. Huang received support for article research from the National Cheng Kung University Hospital, Tainan, Taiwan (NCKUH-11209002). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Tuberculosis remains an important public health problem globally. Addison's disease due to bilateral adrenal Tuberculosis as the primary manifestation of Extrapulmonary Tuberculosis is a very rare clinical entity. Previously healthy 52 years old male presented with increasing darkening of the skin, dizziness, loss of weight, loss of appetite, generalized weakness for one year and diarrhoea, vomiting for 3 months. Patient did not have any history of exposure to Tuberculosis. Physical examination revealed a hyposthenic man with generalized hyperpigmentation especially on the face, oral mucosa, palmer crease, and knuckles. Investigations revealed high erythrocyte sedimentation rate, persistent hyponatremia, and strongly positive mantoux test. Short Synacthen test confirmed the adrenal insufficiency. Ultrasound scan of the abdomen found to have bilaterally enlarged adrenal glands. Contrast-Enhanced Computed Tomography of abdomen confirmed the bilaterally enlarged adrenal glands. Magnetic resonance imaging brain has done, it was normal with no evidence of pituitary masses. Then Computed Tomography guided biopsy has done from left adrenal gland. Histology of biopsy report was compatible with Tuberculosis. With the evidence of above finding this patient diagnosed to have Addison's disease due to tuberculosis of bilateral adrenal glands. Anti-Tuberculosis Treatment started and continued for six months. Hydrocortisone and Fludrocortisone started. When there is an adrenal insufficiency, it should be always considered the possibility of existence of TB even failure to isolate bacillus Mycobacterium, failure to identify epidemiological exposure., Competing Interests: Conflicts of interest All authors have none to declare., (Copyright © 2020 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.)

Objective: Despite published guidelines no unified approach to hormone replacement in congenital adrenal hyperplasia (CAH) exists. We aimed to explore geographical and temporal variations in the treatment with glucocorticoids and mineralocorticoids in CAH., Design: This retrospective multi-center study, including 31 centers (16 countries), analyzed data from the International-CAH Registry., Methods: Data were collected from 461 patients aged 0-18 years with classic 21-hydroxylase deficiency (54.9% females) under follow-up between 1982 and 2018. Type, dose and timing of glucocorticoid and mineralocorticoid replacement were analyzed from 4174 patient visits., Results: The most frequently used glucocorticoid was hydrocortisone (87.6%). Overall, there were significant differences between age groups with regards to daily hydrocortisone-equivalent dose for body surface, with the lowest dose (median with interquartile range) of 12.0 (10.0-14.5) mg/m2/day at age 1-8 years and the highest dose of 14.0 (11.6-17.4) mg/m2/day at age 12-18 years. Glucocorticoid doses decreased after 2010 in patients 0-8 years (P < 0.001) and remained unchanged in patients aged 8-18 years. Fludrocortisone was used in 92% of patients, with relative doses decreasing with age. A wide variation was observed among countries with regards to all aspects of steroid hormone replacement., Conclusions: Data from the I-CAH Registry suggests international variations in hormone replacement therapy, with a tendency to treatment with high doses in children.

Purpose: The impact of patient's characteristics on glucocorticoid (GC) replacement therapy in adrenal insufficiency (AI) is poorly evaluated. Aims of this study were to assess the influence of sex and body weight on GC dosing and to describe the choice of GC in AI of different etiologies., Methods: We retrospectively evaluated hydrocortisone (HC) equivalent total daily dose (HC-TDD) and per-kg-daily dose (HC-KDD) in 203 patients (104 primary AI [pAI], 99 secondary AI [sAI]) followed up for ≥ 12 months. They were treated with HC, modified-release HC (MRHC) or cortisone acetate (CA) and fludrocortisone acetate (FCA) in pAI., Results: At baseline, CA was preferred both in pAI and sAI; at last visit, MRHC was most used in pAI (49%) and CA in sAI (73.7%). Comparing the last visit with baseline, in pAI, HC-TDD and HC-KDD were significantly lower (p = 0.04 and p = 0.006, respectively), while FCA doses increased during follow-up (p = 0.02). The reduction of HC-TDD and HC-KDD was particularly relevant for pAI women (p = 0.04 and p = 0.002, respectively). In sAI patients, no change of HC-KDD and HC-TDD was observed, and we found a correlation between weight and HC-TDD in males (r 0.35, p = 0.02)., Conclusions: Our real-life study demonstrated the influence of etiology of AI on the type of GC used, a weight-based tailoring in sAI, a likely overdosage of GC treatment in pAI women at the start of treatment and the possibility to successfully increase FCA avoiding GC over-treatment. These observations could inform the usual clinical practice.

Background/aim: Aldosterone is a mineralocorticoid that secreted from adrenal glands and a known factor to increase magnesium excretion by direct and indirect effects on renal tubular cells. Although the frequency of hypomagnesemia was found to be approximately 5% in adult studies, there is no study in the literature investigating the frequency of hypomagnesemia in children by using fludrocortisone, which has a mineralocorticoid activity., Materials and Methods: A multi-center retrospective study was conducted, including children who were under fludrocortisone treatment for primary adrenal insufficiency and applied to participant pediatric endocrinology outpatient clinics., Results: Forty-three patients (58.1% male, 41.9% prepubertal) included in the study, whose median age was 9.18 (0.61-19) years, and the most common diagnosis among the patients was a salt-wasting form of congenital adrenal hyperplasia (67.4%). Mean serum magnesium level was 2.05 (±0.13) mg/dL, and hypomagnesemia was not observed in any of the patients treated with fludrocortisone. None of the patients had increased urinary excretion of magnesium., Conclusion: Unlike the studies performed in adults, we could not find any evidence of magnesium wasting effect of fludrocortisone treatment with normal or even high doses in children and adolescents., Competing Interests: Authors declared no conflict of interest and received no funding., (This work is licensed under a Creative Commons Attribution 4.0 International License.)

Background: The effects of hyperandrogenism and steroid treatment on bone mineral density (BMD) in patients with congenital adrenal hyperplasia (CAH) are controversial., Objectives: The objectives of this study were to characterize BMD and fractures in patients with CAH and to identify whether there is an association between alterations in BMD, nutritional status, and variables related to the disease., Methods: A cross-sectional descriptive study was conducted to explore clinical, hormonal, dairy consumption, physical activity, and BMD variables in patients with CAH due to 21-hydroxylase deficiency and controls matched by age, gender, skin color, body mass index, and Tanner scale., Results: Fifty subjects (CAH n = 25; females n = 42 [84%]) with a mean age of 15.9 ± 5.8 years were included in the study. White skin color predominated in 34 subjects (68%), mestizo in 11 (22%), and black in 5 (10%). In patients with CAH, BMD lumbar spine was decreased compared to that in controls (0.83 ± 0.23 vs. 0.98 ± 0.26 g/cm3, p = 0.004). BMD femur was also decreased in patients with CAH; however, this was not significant (0.95 ± 0.20 vs. 1.04 ± 0.24 g/cm3, p = 0.17). There was a positive relationship between age at diagnosis, age of initiation of glucocorticoid treatment, and testosterone levels with all measurements of BMD. The daily glucocorticoid dose was negatively related to BMD. No fractures were found., Conclusions: Patients with CAH had decreased BMD, especially in lumbar spine. Increased androgen exposure seemed to improve, while increased glucocorticoid dose impaired BMD., (© 2021 S. Karger AG, Basel.)

Importance: The survival benefit of corticosteroids in septic shock remains uncertain., Objective: To estimate the individual treatment effect (ITE) of corticosteroids in adults with septic shock in intensive care units using machine learning and to evaluate the net benefit of corticosteroids when the decision to treat is based on the individual estimated absolute treatment effect., Design, Setting, and Participants: This cohort study used individual patient data from 4 trials on steroid supplementation in adults with septic shock as a training cohort to model the ITE using an ensemble machine learning approach. Data from a double-blinded, placebo-controlled randomized clinical trial comparing hydrocortisone with placebo were used for external validation. Data analysis was conducted from September 2019 to February 2020., Exposures: Intravenous hydrocortisone 50 mg dose every 6 hours for 5 to 7 days with or without enteral 50 μg of fludrocortisone daily for 7 days. The control was either the placebo or usual care., Main Outcomes and Measures: All-cause 90-day mortality., Results: A total of 2548 participants were included in the development cohort, with median (interquartile range [IQR]) age of 66 (55-76) years and 1656 (65.0%) men. The median (IQR) Simplified Acute Physiology Score (SAPS II) was 55 [42-69], and median (IQR) Sepsis-related Organ Failure Assessment score on day 1 was 11 (9-13). The crude pooled relative risk (RR) of death at 90 days was 0.89 (95% CI, 0.83 to 0.96) in favor of corticosteroids. According to the optimal individual model, the estimated median absolute risk reduction was of 2.90% (95% CI, 2.79% to 3.01%). In the external validation cohort of 75 patients, the area under the curve of the optimal individual model was 0.77 (95% CI, 0.59 to 0.92). For any number willing to treat (NWT; defined as the acceptable number of people to treat to avoid 1 additional outcome considering the risk of harm associated with the treatment) less than 25, the net benefit of treating all patients vs treating nobody was negative. When the NWT was 25, the net benefit was 0.01 for the treat all with hydrocortisone strategy, -0.01 for treat all with hydrocortisone and fludrocortisone strategy, 0.06 for the treat by SAPS II strategy, and 0.31 for the treat by optimal individual model strategy. The net benefit of the SAPS II and the optimal individual model treatment strategies converged to zero for a smaller number willing to treat, but the individual model was consistently superior than model based on the SAPS II score., Conclusions and Relevance: These findings suggest that an individualized treatment strategy to decide which patient with septic shock to treat with corticosteroids yielded positive net benefit regardless of potential corticosteroid-associated side effects.

Context: Appropriate management of adrenal insufficiency (AI) in pregnancy can be challenging due to the rarity of the disease and lack of evidence-based recommendations to guide glucocorticoid and mineralocorticoid dosage adjustment., Objective: Multicenter survey on current clinical approaches in managing AI during pregnancy., Design: Retrospective anonymized data collection from 19 international centers from 2013 to 2019., Setting and Patients: 128 pregnancies in 113 women with different causes of AI: Addison disease (44%), secondary AI (25%), congenital adrenal hyperplasia (25%), and acquired AI due to bilateral adrenalectomy (6%)., Results: Hydrocortisone (HC) was the most commonly used glucocorticoid in 83% (97/117) of pregnancies. Glucocorticoid dosage was increased at any time during pregnancy in 73/128 (57%) of cases. In these cases, the difference in the daily dose of HC equivalent between baseline and the third trimester was 8.6 ± 5.4 (range 1-30) mg. Fludrocortisone dosage was increased in fewer cases (7/54 during the first trimester, 9/64 during the second trimester, and 9/62 cases during the third trimester). Overall, an adrenal crisis was reported in 9/128 (7%) pregnancies. Cesarean section was the most frequent mode of delivery at 58% (69/118). Fetal complications were reported in 3/120 (3%) and minor maternal complications in 15/120 (13%) pregnancies without fatal outcomes., Conclusions: This survey confirms good maternal and fetal outcome in women with AI managed in specialized endocrine centers. An emphasis on careful endocrine follow-up and repeated patient education is likely to have reduced the risk of adrenal crisis and resulted in positive outcomes., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Renal tubular acidosis (RTA) is a rare disease caused by a defect of urinary acidification. The ammonium chloride loading test is the gold standard method for determining the type of RTA. However, because this test has some side effects (e.g., nausea, vomiting, and stomach discomfort), applying this test for pediatric cases is difficult. Recently, a loading test with the combination of furosemide and fludrocortisone was reported to be an alternative to the ammonium chloride loading test, with 100% sensitivity and specificity in adult's cases. We report the first pediatric case of distal RTA in a patient who was successfully diagnosed by a drug loading test with the combination of furosemide and fludrocortisone without any side effects. We also performed genetic analysis and detected a known pathogenic variant in the SLC4A1 gene. The combination loading test of furosemide and fludrocortisone is a useful and safe diagnostic tool for pediatric cases of RTA.

Background and Objectives: Metabolic acidosis is a frequent manifestation of sickle cell disease but the mechanisms and determinants of this disorder are unknown. Our aim was to characterize urinary acidification capacity in adults with sickle cell disease and to identify potential factors associated with decreased capacity to acidify urine., Design, Setting, Participants, & Measurements: Among 25 adults with sickle cell disease and an eGFR of ≥60 ml/min per 1.73 m 2 from a single center in France, we performed an acute acidification test after simultaneous administration of furosemide and fludrocortisone. A normal response was defined as a decrease in urinary pH <5.3 and an increase in urinary ammonium excretion ≥33 µ Eq/min at one or more of the six time points after furosemide and fludrocortisone administration., Results: Of the participants (median [interquartile range] age of 36 [24-43] years old, 17 women), 12 had a normal and 13 had an abnormal response to the test. Among these 13 participants, nine had normal baseline plasma bicarbonate concentration. Plasma aldosterone was within the normal range for all 13 participants with an abnormal response, making the diagnosis of type 4 tubular acidosis unlikely. The participants with an abnormal response to the test were significantly older, more frequently treated with oral bicarbonate, had a higher plasma uric acid concentration, higher hemolysis activity, lower eGFR, lower baseline plasma bicarbonate concentration, higher urine pH, lower urine ammonium ion excretion, and lower fasting urine osmolality than those with a normal response. Considering both groups, the maximum urinary ammonium ion excretion was positively correlated with fasting urine osmolality ( r 2 =0.34, P =0.002), suggesting that participants with sickle cell disease and lower urine concentration capacity have lower urine acidification capacity., Conclusions: Among adults with sickle cell disease, impaired urinary acidification capacity attributable to distal tubular dysfunction is common and associated with the severity of hyposthenuria., Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019&#95;12&#95;10&#95;CJN07830719.mp3., (Copyright © 2020 by the American Society of Nephrology.)

Background: Addison's disease is an uncommon condition encountered during pregnancy; however, pregnant patients with Addison's disease are at higher risk for multiple pregnancy related complications. Treatment during pregnancy involves steroid replacement therapy., Case Report: A 34-year-old previously healthy G2P1001 presented with lethargy, skin hyperpigmentation, polyuria, and salt craving. Laboratory evaluation showed hyperkalemia, hyponatremia, elevated ACTH, and low cortisol. The patient terminated the pregnancy due to her symptoms. She was then placed on a regimen of hydrocortisone and fludrocortisone, leading to symptom resolution. On second presentation as a G5P1031, her Addison's disease was managed with hydrocortisone and fludrocortisone. When Addison's symptoms recurred, ACTH levels were checked to determine if her current medications could be optimized. She ultimately delivered a healthy male infant vaginally. For her third presentation as a G6P2032, her pregnancy was managed in a similar manner to the previous pregnancy., Conclusion: There is currently minimal cohesive literature on the management of Addison's disease during pregnancy. Patients can be managed successfully by monitoring for recurrence of Addison's symptoms and adjusting medication dosing as needed.

Congenital Adrenal Hyperplasia is a group of autosomal recessive disorders due to deficiencies of enzymes involved in steroidogenesis. The most common form is a 21-hydroxylase deficiency which can be classical or non-classical. The severe form also called Classical Congenital Adrenal Hyperplasia is usually detected after birth to infant period. If Congenital Adrenal Hyperplasia is not diagnosed and treated early, neonates are susceptible to sudden death in the early weeks of life. We report a case of thirty-five days male with a salt-wasting variant of congenital adrenal hyperplasia. The diagnosis was based on an elevated level of 17-hydroxyprogesterone. He was managed and life long oral Prednisolone and Fludrocortisone were prescribed. Keywords: 21-hydroxylase, congenital adrenal hyperplasia, case report.

Patients with primary adrenal insufficiency (PAI) require increased doses of glucocorticoids and mineralocorticoids during stressors, such as surgery, trauma, and sepsis. Although current guidelines exist for dose adjustments in these situations, there is no accepted dosing regimen for patients with PAI participating in intensive endurance exercise. Given the extensive physiologic stress of events, such as marathons, triathlons, and similar events, it is likely that a "stress-dose" of adrenal replacement therapy will not only prevent adrenal crisis, but also improve performance. A 50-year-old male endurance athlete with known PAI reported severe fatigue, nausea, and malaise after competing in prior marathons and intensive endurance exercise. After supplementing with glucocorticoids and mineralocorticoids before competition, he experienced decreased symptoms and improved performance. To better care for these patients, further studies should be conducted to provide safe and effective glucocorticoid and mineralocorticoid dose adjustments before intensive endurance exercise.

A 45-year-old man presented with a 3-month history of involuntary weight loss, anorexia, postural dizziness and intermittent fever. On investigation, he was found to have parathyroid hormone (PTH)-independent hypercalcaemia, with negative workup for 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D excess, thyrotoxicosis, multiple myeloma and bony metastases. On further evaluation, he was detected to have primary hypoadrenalism with bilateral adrenal enlargement, secondary to adrenal histoplasmosis. Hypercalcaemia improved with hydration and physiological steroid replacement even before initiation of antifungal therapy, confirming adrenal insufficiency as the cause for hypercalcaemia. Hypercalcaemia resulting from hypoadrenalism secondary to adrenal histoplasmosis is rare and should be suspected whenever evaluating a patient with PTH-independent hypercalcaemia., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

We report a case of cerebral salt-wasting syndrome in a 12-year-old boy with severe traumatic brain injury. The child developed refractory intracranial hypertension at the time of injury, which required decompressive craniectomy on the 7th day after injury. Infusion of hypertonic sodium chloride solutions performed at the intensive care unit resulted in hypernatremia on the 5th day and polyuria and hypovolemia on the 11th day, which was regarded as manifestations of central diabetes insipidus. Persistent hyponatremia developed on the 17th day after injury; on the next day, the therapy was supplemented with Fludrocortisone at a dose of 100 µg/day, followed by an increase in the dose to 150 µg/day, which had no significant effect. Fludrocortisone was discontinued on the 30th day of therapy, but it was re-used at a dose of 400 µg/day from the 54th day. During this treatment, polyuria gradually decreased to 4 to 5 l/day, and the plasma sodium concentration remained within the reference values. The dose of Fludrocortisone was increased to 600 µg/day since the 66th day. The child was transferred to a specialized department on the 67th day after injury. At the Department of Neurosurgery, the dose of Cortineff was gradually reduced starting with the 94th day and completely discontinued on the 122nd day after injury. On day 132th of the post-traumatic period, the patient was transferred to another hospital for rehabilitation therapy.

Hyponatraemia is a common electrolyte disturbance with multiple causes. We present a case of a 49-year-old Caucasian female with cholangiocarcinoma, who had a hyponatraemia which was initially assumed to be based on a syndrome of inappropriate antidiuretic hormone secretion as paraneoplastic phenomenon. At physical examination, hyperpigmentation was seen and multiple episodes with syncope were reported. Subsequent endocrine assessment with a synthetic adrenocorticotropin hormone (ACTH) stimulation test and measurement of ACTH levels revealed primary adrenal insufficiency also known as Morbus Addison. We started hydrocortisone and fludrocortisone replacement therapy, resulting in resolving of symptoms, hyponatraemia and hyperpigmentation., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction:: AZD9977 is a novel mineralocorticoid receptor (MR) modulator, which in preclinical studies demonstrated organ protection without affecting aldosterone-regulated urinary electrolyte excretion. However, when tested in humans, using fludrocortisone as an MR agonist, AZD9977 exhibited similar effects on urinary Na + /K + ratio as eplerenone. The aim of this study is to understand whether the contradictory results seen in rats and humans are due to the mineralocorticoid used., Materials and Methods:: Rats were treated with single doses of AZD9977 or eplerenone in combination with either aldosterone or fludrocortisone. Urine was collected for five to six hours and total amounts excreted Na + and K + were assessed., Results:: AZD9977 dose-dependently increased urinary Na + /K + ratio in rats when tested against fludrocortisone, but not when tested against aldosterone. Eplerenone dose-dependently increased urinary Na + /K + ratio when tested against fludrocortisone as well as aldosterone., Conclusions:: The data suggest that the contrasting effects of AZD9977 on urinary electrolyte excretion observed in rats and humans are due to the use of the synthetic mineralocorticoid fludrocortisone. Future clinical studies are required to confirm the reduced electrolyte effects of AZD9977 and the subsequent lower predicted hyperkalemia risk.

Importance: Tuberculous meningitis is associated with high frequency of cerebral salt wasting. There is a paucity of objective information regarding the best method of treatment of this condition., Objective: To evaluate the efficacy and safety of fludrocortisone in the treatment of cerebral salt wasting in patients with tuberculous meningitis., Design, Setting, and Participants: This is a single-center, open-label, randomized clinical trial conducted from October 2015 to April 2017 in India. Patients were randomized in a 1:1 ratio to arms receiving saline only or saline plus fludrocortisone, in addition to a standard treatment of 4 antitubercular drugs, prednisolone, and aspirin. The 2 arms were matched for demographic, clinical, and magnetic resonance imaging findings. The patients were followed up for at least 6 months., Interventions: Patients were randomized to a 0.9% solution of intravenous saline with 5 to 12 g per day of oral salt supplementation, with or without the addition of 0.1 to 0.4 mg of fludrocortisone per day., Main Outcomes and Measures: The primary end point was the time needed to correct serum sodium levels; secondary end points were in-hospital deaths, disability at 3 months, disability at 6 months, occurence of stroke, and serious adverse reactions., Results: Ninety-three patients with suspected tuberculous meningitis were recruited; 12 did not meet the inclusion criteria, including 4 with alternate diagnoses. A total of 37 patients with cerebral salt wasting were eligible for the study. One refused to participate, and therefore 36 patients were included, with 18 randomized to each group. The median (range) age was 30 (20-46) years, and 19 were male (52.8%). Those receiving fludrocortisone regained normal serum sodium levels after 4 days, significantly earlier than those receiving saline only (15 days; P = .004). In an intention-to-treat analysis, hospital mortality, disability at 3 months, and disability at 6 months did not differ significantly, but fewer infarcts occurred in the deep border zone in the group receiving fludrocortisone (1 of 18 [6%]) vs those in the control arm (6 of 18 [33%]; P = .04). Fludrocortisone was associated with severe hypokalemia and hypertension in 2 patients each, and pulmonary edema occurred in 1 patient. These adverse reactions necessitated discontinuation of fludrocortisone in 2 patients., Conclusions and Relevance: Fludrocortisone results in earlier normalization of serum sodium levels, but did not affect outcomes at 6 months. Fludrocortisone had to be withdrawn in 2 patients because of severe adverse effects. This study provides class II evidence on the role of fludrocortisone in treatment of hyponatremia associated with cerebral salt wasting in patients with tuberculous meningitis., Trial Registration: Clinical Trials Registry of India (ctri.nic.in) Identifier: CTRI/2017/10/010255.

Context: Failure of plasma aldosterone suppression during fludrocortisone suppression testing (FST) or saline suppression testing (SST) confirms primary aldosteronism (PA). Aldosterone is often higher upright than recumbent in PA; upright levels are used during FST. In a pilot study (24 patients with PA), seated saline suppression testing (SSST) was more sensitive than recumbent saline suppression testing (RSST)., Objective, Design, and Patients: The current validation study involved 100 patients who underwent FST, RSST, and SSST, eight before and after unilateral adrenalectomy. Of the 108 FSTs, 73 confirmed and 18 excluded PA. Four patients with inconclusive FST lateralized on adrenal venous sampling, making a total of 77 with PA., Results: The area under the receiver operating characteristic (ROC) curve was greater for SSST than RSST (0.96 vs. 0.80; P < 0.01). ROC analysis predicted optimal cutoff aldosterone levels of 162 pmol/L for SSST and 106 pmol/L for RSST. At these cutoffs, SSST showed high sensitivity for PA (87%) that markedly exceeded that for RSST (38%; P < 0.001) but similar specificity (94 vs. 94%; not significant). SSST was more sensitive than RSST in detecting both unilateral (n = 28, 93% vs. 68%, P < 0.05) and bilateral (n = 40, 85% vs. 20%, P < 0.001) forms of PA. Only three SSST (vs. 9 RSST and 17 FST) results were inconclusive., Conclusions: SSST is highly sensitive and superior to RSST in identifying both unilateral and bilateral forms of PA and has a low rate of false positives and inconclusive results. It therefore offers a reliable and much less complicated and expensive alternative to FST for confirming PA.

Context: Current threshold values for primary aldosteronism (PA) diagnostic testing are based on measuring aldosterone (PAC) using immunoassays. Quantification of PAC by liquid chromatography-tandem mass spectrometry (LC-MS/MS) yields lower values., Objective: To compare aldosterone measurement by radioimmunoassay (RIA) with LC-MS/MS and evaluate performances of proposed LC-MS/MS-specific cutoffs for PA screening and confirmatory testing., Patients and Intervention: Forty-one patients underwent aldosterone/renin ratio (ARR) testing to screen for, and fludrocortisone suppression testing (FST) to confirm or exclude, PA. Renin (DRC) was measured by chemiluminescent immunoassay., Results: Median serum PACLC-MS/MS was 27.8% lower (P < 0.05) than plasma PACRIA in 164 pairs of FST samples. A positive correlation (Spearman coefficient, 0.894, P < 0.01; Pearson r coefficient, 0.861, P < 0.01) was observed between the two assays. Thirty-seven patients showed consistent FST diagnoses (29 positive, 8 negative), whereas four showed inconsistent FSTs by the two assays. Good agreement (κ coefficient, 0.736; P < 0.01) was observed between the current FST diagnostic PACRIA cutoff of 165 pmol/L and the proposed PACLC-MS/MS cutoff of 133 pmol/L. Among 37 patients with consistent FST results, no differences were observed in sensitivity (89.7% vs 93.1%) or specificity (87.5% vs 87.5%) for PA screening between the current ARR cutoff of 70 pmol/mU (PACRIA/DRC) and the proposed cutoff of 55 pmol/mU (PACLC-MS/MS/DRC)., Conclusions: Adjustment of the current cutoffs for PA diagnostic testing is necessary if PAC is measured by LC-MS/MS. Our preliminary results suggest that the proposed LC-MS/MS cutoffs for ARR and FST perform as well as current RIA cutoffs.

Although the cause of hypertension among individuals with obesity and insulin resistance is unknown, increased plasma insulin, acting in the kidney to increase sodium reabsorption, has been proposed as a potential mechanism. Insulin may also stimulate glucose uptake, but the contributions of tubular insulin signaling to sodium or glucose transport in the setting of insulin resistance is unknown. To directly study the role of insulin signaling in the kidney, we generated inducible renal tubule-specific insulin receptor-KO mice and used high-fat feeding and mineralocorticoids to model obesity and insulin resistance. Insulin receptor deletion did not alter blood pressure or sodium excretion in mice on a high-fat diet alone, but it mildly attenuated the increase in blood pressure with mineralocorticoid supplementation. Under these conditions, KO mice developed profound glucosuria. Insulin receptor deletion significantly reduced SGLT2 expression and increased urinary glucose excretion and urine flow. These data demonstrate a direct role for insulin receptor-stimulated sodium and glucose transport and a functional interaction of insulin signaling with mineralocorticoids in vivo. These studies uncover a potential mechanistic link between preserved insulin sensitivity and renal glucose handling in obesity and insulin resistance.

Aims: AZD9977 is the first mineralocorticoid receptor modulator in clinical development exerting similar organ protection as eplerenone with minimal urinary electrolyte effects in preclinical studies. The aim was to perform the initial clinical assessment of AZD9977., Methods: A first-in-human trial explored doses from 5 to 1200 mg. To study effects on urinary electrolyte excretion an additional randomized placebo controlled cross-over four-period clinical trial was performed. Twenty-three healthy volunteers were administered fludrocortisone alone or in combination with AZD9977, eplerenone or both. AZD9977/eplerenone combination was given to assess if AZD9977 can attenuate eplerenone induced natriuresis., Results: AZD9977 at doses from 5 to 1200 mg was safe and well tolerated and pharmacokinetics were compatible with further development. AZD9977 exhibited similar effects on urinary ln [Na + ]/[K + ] as eplerenone when using fludrocortisone as mineralocorticoid receptor agonist, and the combination had an additive effect on ln [Na + K + ]., Conclusions: The results in man contradict the results in rodent models driven by aldosterone, in which AZD9977 has minimal electrolyte effects. Future clinical studies with AZD9977 should be performed in presence of endogenous or exogenous aldosterone to assess potential benefit of AZD9977 in patients., (© 2018 The British Pharmacological Society.)

Introduction: Sodium chloride supplementation in salt-wasting congenital adrenal hyperplasia (CAH) is generally recommended in infants, but its implementation in routine care is very heterogeneous., Objective: To evaluate oral sodium chloride supplementation, growth, and hydrocortisone and fludrocortisone dose in infants with salt-wasting CAH due to 21-hydroxylase in 311 infants from the AQUAPE CAH database., Results: Of 358 patients with classic CAH born between 1999 and 2015, 311 patients had salt-wasting CAH (133 females, 178 males). Of these, 86 patients (27.7%) received oral sodium chloride supplementation in a mean dose of 0.9 ± 1.4 mmol/kg/day (excluding nutritional sodium content) during the first year of life. 225 patients (72.3%) were not treated with sodium chloride. The percentage of sodium chloride-supplemented patients rose from 15.2% in children born 1999-2004 to 37.5% in children born 2011-2015. Sodium chloride-supplemented and -unsupplemented infants did not significantly differ in hydrocortisone and fludrocortisone dose, target height-corrected height-SDS, and BMI-SDS during the first 2 years of life., Conclusion: In the AQUAPE CAH database, approximately one-third of infants with salt-wasting CAH receive sodium chloride supplementation. Sodium chloride supplementation is performed more frequently in recent years. However, salt supplementation had no influence on growth, daily fludrocortisone and hydrocortisone dose, and frequency of adrenal crisis., (© 2017 S. Karger AG, Basel.)

Background and Objectives: Incomplete distal renal tubular acidosis is a well known cause of calcareous nephrolithiasis but the prevalence is unknown, mostly due to lack of accepted diagnostic tests and criteria. The ammonium chloride test is considered as gold standard for the diagnosis of incomplete distal renal tubular acidosis, but the furosemide/fludrocortisone test was recently proposed as an alternative. Because of the lack of rigorous comparative studies, the validity of the furosemide/fludrocortisone test in stone formers remains unknown. In addition, the performance of conventional, nonprovocative parameters in predicting incomplete distal renal tubular acidosis has not been studied., Design, Setting, Participants, & Measurements: We conducted a prospective study in an unselected cohort of 170 stone formers that underwent sequential ammonium chloride and furosemide/fludrocortisone testing., Results: Using the ammonium chloride test as gold standard, the prevalence of incomplete distal renal tubular acidosis was 8%. Sensitivity and specificity of the furosemide/fludrocortisone test were 77% and 85%, respectively, yielding a positive predictive value of 30% and a negative predictive value of 98%. Testing of several nonprovocative clinical parameters in the prediction of incomplete distal renal tubular acidosis revealed fasting morning urinary pH and plasma potassium as the most discriminative parameters. The combination of a fasting morning urinary threshold pH <5.3 with a plasma potassium threshold >3.8 mEq/L yielded a negative predictive value of 98% with a sensitivity of 85% and a specificity of 77% for the diagnosis of incomplete distal renal tubular acidosis., Conclusions: The furosemide/fludrocortisone test can be used for incomplete distal renal tubular acidosis screening in stone formers, but an abnormal furosemide/fludrocortisone test result needs confirmation by ammonium chloride testing. Our data furthermore indicate that incomplete distal renal tubular acidosis can reliably be excluded in stone formers by use of nonprovocative clinical parameters., (Copyright © 2017 by the American Society of Nephrology.)

This case report details a 51-year-old man with Alport's syndrome resulting in chronic nephritis with stable renal function and sensorineural deafness. The patient was being investigated for persistently raised potassium refractory to dietary and pharmacological modification. Subsequently, the patient was found to have type 4 renal tubular acidosis, and potassium normalised with the addition of fludrocortisone., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

This study aimed at describing the pharmacokinetics and the concentration-effect relationships of fludrocortisone and hydrocortisone on urinary sodium/potassium excretion in healthy volunteers. This was a placebo-controlled, randomized, double blind, crossover study, of oral fludrocortisone and intravenous hydrocortisone, given alone or in combination, in 12 healthy male volunteers. Nonlinear mixed-effects modeling was used to describe the pharmacokinetics and pharmacokinetic-pharmacodynamic relationships on urinary sodium/potassium ratio for each drug. A one-compartment model was used to describe fludrocortisone and hydrocortisone pharmacokinetics. Mean plasma half-life was 1.40 h (95%CI [0.80;2.10]) for fludrocortisone and 2.10 h (95%CI [1.78;2.40]) for hydrocortisone. Clearance was 40.8 L/h (95%CI [33.6;48]) for fludrocortisone and 30 L/h (95%CI [25.3;34.7]) for hydrocortisone. An indirect response model was used to describe effects on urinary sodium/potassium ratio. Fludrocortisone plasma concentrations showed a wider inter-individual dispersion than hydrocortisone plasma concentrations. Urinary sodium/potassium ratio variability was also higher with fludrocortisone as compared to hydrocortisone. The plasma concentration of drug producing 50% of maximal inhibition of urinary sodium/potassium (IC 50 ) was about 200 times lower for fludrocortisone (0.08 μg/L, 95%CI [0.035;0.125]) than for hydrocortisone (16.7 μg/L, 95%CI [10.5;22.9]). Simulations showed that a 4-time per day administration regimen allow to achieve steady fludrocortisone plasma concentrations with stable decrease in urinary sodium/potassium ratio after the second administration of fludrocortisone. Fludrocortisone and hydrocortisone have short and similar plasma elimination half-lives in healthy subjects. Fludrocortisone plasma concentrations and effect on urinary sodium/potassium ratio had a higher inter-individual variability as compared to hydrocortisone. The administration regimen of fludrocortisone should be reconsidered.

Risk taking is influenced by stress, with riskier decisions after exposure to an acute stressor and consecutively elevated cortisol levels. In the brain, cortisol acts on two receptors with different functional profiles: the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). In the current study we investigated the effect of MR stimulation on risk taking behavior in 80 young healthy participants (40 women, mean age=23.9). We administered 0.4mg fludrocortisone, a MR agonist, in a between-subjects, placebo controlled design. Subsequently, participants conducted an established risk taking paradigm, the Balloon-Analogue-Risk-Task (BART). We also used two questionnaires to assess risk taking and decision behavior as trait measures. We found a treatment effect with riskier decisions in the fludrocortisone group. Furthermore, we found a sex effect with more risk taking in men. There was no statistically significant interaction between both factors. Our results indicate that acute MR stimulation leads to riskier decisions in women and men. Our findings argue for an important role of the MR in decision making processes., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objectives: Stress hormones such as cortisol are known to influence a wide range of cognitive functions, including hippocampal based spatial memory. In the brain, cortisol acts via two different receptors: the glucocorticoid (GR) and the mineralocorticoid receptor (MR). As the MR has a high density in the hippocampus, we examined the effects of pharmacological MR stimulation on spatial memory., Methods: Eighty healthy participants (40 women, 40 men, mean age=23.9years±SD=3.3) completed the virtual Morris Water Maze (vMWM) task to test spatial encoding and spatial memory retrieval after receiving 0.4mg fludrocortisone, a MR agonist, or placebo., Results: There was no effect of MR stimulation on spatial encoding during the vMWM task. However, participants who received fludrocortisone exhibited improved spatial memory retrieval performance. There was neither a main effect of sex nor a sex-by-treatment interaction., Conclusion: In young healthy participants, MR stimulation improved hippocampal based spatial memory retrieval in a virtual Morris Water Maze task. Our study not only confirms the importance of MR function in spatial memory, but suggests beneficial effects of acute MR stimulation on spatial memory retrieval in humans., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Reversible left ventricular dysfunction, also termed Takotsubo cardiomyopathy, is rarely reported in Addison's disease after initiation of hormone replacement therapy. The pathogenesis of this cardiomyopathy is unknown., Case Presentation: A 41-year-old white woman with a history of autoimmune Hashimoto thyroiditis diagnosed 3 years earlier and acute adrenal insufficiency diagnosed 3 weeks earlier presented with new onset of heart failure New York Heart Association class IV, which had started shortly after initiation of hormone replacement therapy with hydrocortisone 20 mg/day and fludrocortisone 0.3 mg/day. Nine days before admission she had collapsed because of dizziness and had a cerebral concussion and open fracture of her nasal bone, however, no further investigations were carried out at that time. A physical examination revealed leg edema, tachycardia, tachypnea, bilateral basal crepitations, and blood pressure 110/70 mmHg. An electrocardiogram showed sinus tachycardia, low voltage, negative T-waves in V 5 and V 6 and a corrected QT interval of 590 ms. Echocardiography revealed a reduced left ventricular systolic function with an ejection fraction of 30 %, and septal, apical, and anterior wall akinesia. Cardiac magnetic resonance imaging showed relative enhancement of gadolinium, indicating hyperemia and capillary leakage, and no myocardial scars. Because of the improvement in her cardiac function, lack of cardiovascular risk factors, and lack of signs for ischemia on magnetic resonance imaging, no coronary angiography was carried out. The results of sellar and renal magnetic resonance imaging were normal. Her troponin T was slightly elevated. Bisoprolol and ramipril were started. Her fludrocortisone dose was reduced to 0.05 mg/day. Her electrocardiogram and systolic function, documented by echocardiography and magnetic resonance imaging, normalized within 6 months., Conclusions: Although we could not exclude coronary artery disease by coronary angiography, her clinical course and instrumental findings suggest Takotsubo cardiomyopathy of the apical type. Fludrocortisone overdosage and increased myocardial vulnerability due to cortisol deficiency might be pathogenetic factors, whereas myocarditis is unlikely. When hormone replacement in patients with Addison's disease is initiated, cardiac function should be monitored by electrocardiogram and echocardiography.

Memory and executive function are often impaired in older adults with major depression. Mineralocorticoid receptors (MR) are abundantly expressed in the hippocampus and in the prefrontal cortex, brain areas critical for memory and executive function. In both aging and depression, MR expression in the brain is reduced. Therefore, diminished MR function could contribute to impaired cognition in older adults with depression and might be a promising target for pharmacological intervention. Twenty-three older adults with major depression (mean age 61.6 yrs ± 8.1, n = 13 women) without medication and 24 age-, sex- and education-matched healthy participants received the MR-agonist fludrocortisone (0.4 mg) or placebo in a randomized, double-blind, within-subject cross-over design. We measured psychomotor speed, executive function, verbal learning and memory, and visuospatial memory. Compared to controls, depressed patients performed worse in psychomotor speed (group effect p = 0.01), executive function (group effect p < 0.01), verbal learning (group effect p = 0.02), and verbal memory (group effect p < 0.01) but not in visuospatial memory. There were no significant treatment effects. However, we found a group × treatment interaction in verbal learning (p = 0.04) and visuospatial memory (p = 0.02) indicating that depressed patients performed worse after fludrocortisone whereas controls performed better after fludrocortisone. Our data suggest that -in contrast to younger depressed patients-older adults with depression do not benefit from MR stimulation but deteriorate in cognitive function., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: As renin and aldosterone levels vary during the menstrual cycle, and are critical criteria for interpretation of aldosterone suppression tests to confirm or exclude primary aldosteronism, outcome of testing may vary depending on the menstrual cycle phase. We assessed the effect of timing within the menstrual cycle on levels of renin, aldosterone and female sex steroids during fludrocortisone suppression testing (FST)., Methods: In 22 women undergoing FST who experienced regular menstrual cycles, renin (measured as both plasma renin activity and direct renin concentration), aldosterone (mass spectrometry) and cortisol, progesterone, oestradiol, LH and FSH (immunoassay) levels were compared, relative to phase of cycle. Aldosterone levels were compared to those in age-matched males undergoing FST., Results: Progesterone (P < 0·0001) and aldosterone (P = 0·006) levels were higher in nine women (after one of 10 was excluded with anovulatory cycle) studied during the luteal phase than in the 12 studied during the follicular phase. All studied during the luteal phase had positive FST, and all three with negative FST were studied during the follicular phase. There were no significant differences in other parameters measured except FSH, which was higher (P = 0·02) during the follicular phase. Aldosterone was higher (P = 0·01) in women studied in the luteal (but not follicular) phase compared to men., Conclusion: The menstrual cycle may affect the outcome of FST and other suppression testing used to diagnose primary aldosteronism. Larger patient numbers and preferably restudy of the same patient in both phases should clarify this and determine the optimum time in the cycle for testing., (© 2014 John Wiley & Sons Ltd.)

A 60-year-old man with Addison's disease, primary hypothyroidism and type 2 diabetes mellitus who was treated with stable doses of hydrocortisone and fludrocortisone developed increasing skin pigmentation and a bitemporal hemianopia. The plasma ACTH level was 14,464 pg/mL, and an invasive pituitary macroadenoma with suprasellar extension was found on magnetic resonance imaging leading to transnasal-transsphenoidal adenomectomy. The tumor demonstrated features of an eosinophilic adenoma and stained uniformly for ACTH. Residual tumor was treated with stereotactic radiotherapy. This case and the 13 cases published previously indicate that primary adrenal failure may predispose to corticotroph hyperplasia, and in some patients to the development of an invasive corticotroph adenoma. The ACTH level should be measured, and a pituitary magnetic resonance imaging is indicated when skin pigmentation increases in a patient with primary adrenal failure who is receiving customary treatment with glucocorticoids and mineralocorticoids.

Primary hyperaldosteronism is an increasingly recognized syndrome in cats, and diagnosis can be difficult. A potential diagnostic method has been reported, utilizing oral fludrocortisone administered twice daily for 4 days followed by collection of urine. In the current study, we sought to determine if blood sampling and a shorter dosing period would provide a possible means to test for primary hyperaldosteronism. Also, cortisol concentrations were measured to assess the potential of fludrocortisone to act as a glucocorticoid in cats. In phase I, 8 healthy laboratory cats were studied in a placebo-controlled, crossover design. Serum aldosterone and cortisol concentrations were measured before and on the second, third, and fourth day of treatment and compared within groups. In phase II, based on the results obtained in phase I, 8 healthy client-owned cats were administered 3 doses of fludrocortisone or placebo. Serum aldosterone and cortisol concentrations were compared before and after treatment within groups. In both phases, serum aldosterone and cortisol concentrations were significantly suppressed in fludrocortisone-treated cats. Thus, it was determined that oral administration of fludrocortisone causes suppression of serum aldosterone in healthy adult cats after only 3 doses. Further research is needed to determine the effects of oral fludrocortisone in cats with primary hyperaldosteronism and cats with other disorders causing hypertension and/or hypokalemia to determine if this protocol can be used as a tool for the definitive diagnosis of primary hyperaldosteronism., (© 2015 The Author(s).)

Introduction: Infants with congenital adrenal hyperplasia (CAH) require higher doses of fludrocortisone (FC) due to physiological mineralocorticoid resistance. The adequacy of mineralocorticoid replacement should be closely monitored to avoid hypertension., Objective: To evaluate blood pressure (BP) in infants with CAH due to 21-hydroxylase deficiency., Patients and Methods: Thirty-three patients (18f/15 m) diagnosed by newborn screening were followed until the age of 4 years. Mean start of HC and FC treatment was day 9·8 ± 9·2 postnatally. Mean daily HC dose ranged from 8·6 to 12·3 mg/m(2) /day., Results: During the first year of life prevalence of systolic hypertension was up to 45·5%. At 12 and at 18 months, BP was highest. Prevalence of systolic hypertension was up to 57·6% at 18 months of age. After 24 months BP levels were lower and at 48 months prevalence of hypertension decreased to 15·2%. Systolic and diastolic BP correlated significantly with the administered fludrocortisone dose (r = 0·3, P = 0·005), but not with body mass index. Hypertensive children received significantly higher FC doses and had significantly lower plasma renin activity during the study period., Conclusion: High prevalence of transient, most likely FC induced hypertension was found in young children with classic CAH diagnosed by newborn screening. The changing mineralocorticoid sensitivity in infants is a risk factor for the development of hypertension in patients with CAH, who are treated with FC. Therefore suppressed plasma renin activity should be avoided to prevent arterial hypertension., (© 2014 John Wiley & Sons Ltd.)

Context: Failure of aldosterone suppression by sodium loading during fludrocortisone suppression testing (FST) or saline suppression testing (SST) confirms primary aldosteronism (PA). We previously found recumbent SST (RSST) to lack sensitivity. Aldosterone levels can be higher upright (e.g. seated) than recumbent in patients with PA and upright levels are used during FST. We therefore hypothesized that seated SST (SSST) is more sensitive than RSST, especially for posture-responsive PA., Setting and Design: Of 66 patients who underwent FST (upright plasma aldosterone levels measured at 10am basally and after 4 days fludrocortisone 0.1 mg 6-hourly and oral salt loading), 31 underwent SST (aldosterone levels measured basally at 8am and after infusion of 2 L normal saline over 4h) both recumbent and seated in randomized order and at least 2 weeks apart., Results: FST confirmed PA in 23 of 31 patients (day 4 upright aldosterone level >165 pmol/L), excluded PA in three and was originally "inconclusive" in five. However, one with "inconclusive" FST had PA confirmed by lateralizing AVS and was reclassified "unilateral PA". Of 24 with confirmed PA (eight unilateral, 11 bilateral, and five undetermined subtype), 23 (96%) tested positive by SSST (4-h aldosterone level >165 pmol/L) compared with 8 (33%) by RSST (4-h plasma aldosterone level >140 pmol/L) (P < .001). RSST missed one unilateral, all bilateral, and four with as-yet undetermined subtype. RSST was positive in 7 of 10 (70%) posture-unresponsive vs one of 14 (7.1%) posture-responsive patients (P < .005)., Conclusion: These preliminary results suggest that seated SST may be superior to recumbent SST in terms of sensitivity for detecting PA, especially posture-responsive forms, and may represent a reliable alternative to FST.

Hydrocortisone enhances the pressor response to catecholamines in healthy volunteers and septic shock patients. Similar data do not exist for fludrocortisone. We assessed the effects of single administrations of fludrocortisone and hydrocortisone on systolic blood pressure until 2 hours after treatments injection and on in vitro vascular contraction of mesenteric artery rings to phenylephrine at 3 hours, in normal and endotoxemic rats. Intravenous fludrocortisone (5 and 20 μg/kg) and hydrocortisone (4 and 20 mg/kg) were administered in 16 groups (8 without and 8 with lipopolysaccharide-induced endotoxemic shock) of 10 Wistar rats according to four 2 × 2-factorial designs. Fludrocortisone and hydrocortisone similarly increased systolic blood pressure (P < 0.001 for both) but more in endotoxemic than in normal animals. Fludrocortisone and hydrocortisone significantly modified contractile response to phenylephrine (P = 0.039 and P = 0.007, respectively). At dose 1, fludrocortisone had no effect and hydrocortisone decreased contraction, whereas, at dose 2, both fludrocortisone and hydrocortisone increased contraction, especially in endotoxemic rats and with additive effect. Our results show that single intravenous administrations of fludrocortisone and hydrocortisone increase blood pressure and contractile response of mesenteric arteries to phenylephrine. The magnitude of these effects depends on dose and pathophysiological conditions and is higher in endotoxemic than in normal rats.

Purpose of Review: The purpose of this article is to review the current therapy of Addison's disease and to highlight recent developments in this field., Recent Findings: Conventional steroid replacement for Addison's disease consists of twice or three-times daily oral hydrocortisone and once-daily fludrocortisone; however, new treatment modalities such as modified-released hydrocortisone and continuous subcutaneous hydrocortisone infusion have recently been developed. These offer the potential for closer simulation of the physiological serum cortisol rhythm. Two studies have also looked at modifying the natural history of adrenal failure using adrenocorticotropic hormone (ACTH) stimulation and immunomodulatory therapies, leading to the concept of residual adrenal function in some Addison's disease patients., Summary: Following more than 60 years with no significant innovation in the management of Addison's disease, these new approaches hold promise for improved patient health and better quality of life in the future.

Unlabelled: Patients with primary adrenal insufficiency (Addison's disease) lack the endogenous steroid hormones cortisol and aldosterone and require daily steroid therapy (usually hydrocortisone and fludrocortisone) to replace them. These patients are unable to adapt physiologically to stress and may need supplemental steroid therapy when having dental procedures, to prevent adrenal crisis. This paper provides guidance on dental procedures for which steroid supplementation may be required in patients with primary adrenal insufficiency and gives advice on doses and timing of supplementation. It does not address the management of patients with secondary adrenal insufficiency caused by long-term use of high doses of steroids. This document is for guidance only. Patients with primary adrenal insufficiency should be assessed individually as steroid requirements will vary., Clinical Relevance: Although patients with primary adrenal insufficiency (Addison's disease) are invariably very well informed about their steroid requirements prior to a dental procedure, dental staff should have an understanding of the steroid supplementation that may be required.

Quality of life remains altered in the adrenal insufficient patient treated by hydrocortisone and fludrocortisone. Due to its pharmacokinetics properties, hydrocortisone requires 2 to 3 daily doses - including a morning intake of 2/3 or half of the daily dose respectively - while fludrocortisone requires a once morning daily dose. Titration of hydrocortisone and fludrocortisone relies on the clinical symptoms of over- or under-replacement together with biochemical indexes such as plasma sodium, potassium and renin. DHEA replacement may improve quality of life and mood and may increase lean body mass and bone mineral density, especially in women with adrenal insufficiency. The new slow release hydrocortisone formulations may help reproduce a more physiological cortisol plasma profile and thus reduce the impact of over-replacement on cardiovascular risk factors and glucose metabolism. Acute adrenal insufficiency is a life-threatening complication of glucocorticoid and mineralocorticoid under-replacement, which may be prevented by educational programs towards the adrenal insufficient patient., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Congenital adrenal hyperplasia (CAH) is a common disorder of impaired adrenal cortisol biosynthesis with associated androgen excess. The clinical presentation of 21-hydroxylase deficiency, the commonest cause of CAH, forms a spectrum and can be divided into classic and non-classic types. The former consists of life threatening salt wasting and non-life threatening simple virilizing phenotypes. Patients with the non-classic form are asymptomatic or have mild features of androgen excess. Most developed countries have newborn screening facilities for CAH. In the absence of newborn screening, the diagnosis of CAH may be missed or delayed. This can result in neonatal mortality in salt wasting forms and incorrect sex of rearing in females with simple virilizing form. The diagnosis is reached by demonstrating high serum 17-hydroxyprogesterone (17OHP) levels. Preterm birth and neonatal illness can cause physiological elevation of 17OHP, thus complicating the diagnosis of CAH in the newborn period. Prenatal diagnosis and treatment with dexamethasone to prevent virilization of affected female fetuses is another area of controversy. The management of CAH is complicated by the need to use supraphysiologic doses of glucocorticoids to suppress adrenal androgen synthesis. In this review, the authors address pertinent issues related to the diagnosis and management of CAH in children.

Orthostatic hypotension (OH) is a relatively common heterogeneous and multifactorial disorder often caused by autonomic dysfunction. This condition has a deleterious impact on quality of life and contributes to higher mortality rates. Supine hypertension is very common in patients with autonomic failure, limits the use of pressor agents, and can result in end-organ damage. Current recommendations on the optimal management of these patients are based on expert opinion and poor-quality small cross-sectional studies including patients with primary autonomic failure and severe orthostatic hypotension. The authors present their treatment approach in 12 patients with disabling orthostatic hypotension and supine hypertension not related to primary autonomic failure, presenting to a referral center over a 4-year period. The first step is to educate the patient about the pathophysiology and course of their disorder. Nonpharmacologic therapies and maneuvers are usually effective in relieving symptoms and preventing syncope. If needed, pharmacologic options such as fludrocortisones and midodrine are also available in patients with severe symptoms. Supine hypertension represents a challenge in the treatment of this condition. Therefore, elevation of the bed of the head and dosing of short-acting antihypertensive agents at bedtime is often indicated., (©2014 Wiley Periodicals, Inc.)

Background: Testicular adrenal rest tumors (TART) are the nodular testicular lesions deriving from the adrenal remnant tissue reported in boys and men with congenital adrenal hyperplasia. Until now, the diagnostics of TART have been based on a combination of clinical features, imaging methods (primarily two dimensional ultrasound--2D US), response of the foci to glycocorticosteroid (GCS) therapy and exclusion of the neoplastic process. Application of 2D US supplies however a limited range of information about the volume, demarcation, structure and vascularization of the lesions., Objective: To define whether the use of 3D US, power Doppler and elastography changes the algorithm of the diagnostics and monitoring or treatment of TART., Material and Methods: In this study, modern ultrasound techniques such as 3D US and elastography were introduced in two boys with TART., Results: The 3D power Doppler option gives the opportunity for accurate assessment of the volume of testes and adrenal tissue foci and their vascularization. Sonographic elastography allows the assessment of stiffness of adrenal tissue areas compared to normal testis parenchyma., Conclusion: The use of these modern techniques enables more adequate and advanced diagnostics, and more precise monitoring of the effects of treatment in patients with TART., (Copyright © 2013 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Background: Midodrine and fludrocortisone are considered the first-line pharmacologic treatments for orthostatic hypotension (OH). Although OH is thought to require long-term therapy, it is unknown how long patients remain on treatment ("persistence")., Methods: We assembled a retrospective cohort of patients with OH aged ≥ 50 years enrolled in Tennessee Medicaid (1996-2008), and identified new episodes of midodrine and fludrocortisone use. Follow-up continued from the first medication fill through treatment discontinuation (90 days without medication), change in treatment, death, hospitalization, and loss of enrollment or study end. We compared persistence on treatment using Cox regression models and fludrocortisone as reference. Covariates included demographics, healthcare utilization measurements and co-morbidities., Results: We identified 1704 OH patients, who initiated 1767 episodes of fludrocortisone (1103) or midodrine (664) use. The median age was 69 years, 53% were female and 80% were white. During 738 person years of follow-up, episodes of use ended because of treatment discontinuation in 467 (27% fludrocortisone, 25% midodrine); treatment change in 72 (3% fludrocortisone, 6% midodrine) and death in 53 (3% fludrocortisone, 2% midodrine). Overall median persistence on fludrocortisone and midodrine was 254 (IQR: 119-783) and 259 (IQR: 119-807) days, respectively. The adjusted hazard ratio (aHR) for overall non-persistence on midodrine compared to fludrocortisone was 1.07 (95% CI: 0.90-1.28)., Conclusions: Overall duration of OH treatment with first-line medications was short, and similar for fludrocortisone and midodrine. Further research is warranted to determine the causes of this low persistence. (Words#234)., (© 2013.)