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Physiological effects of cortisol.

Physiological effects of cortisol.

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Adrenal insufficiency is defined as impaired adrenocortical hormone synthesis. According to its source, the deficit is classified as primary (adrenal steroidogenesis impairment), secondary (pituitary adrenocorticotropic hormone deficit) or tertiary (hypothalamic corticotropin-releasing hormone deficit). The management of adrenal insufficiency resid...

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... temporarily disconnect the peripheral clocks from the central one which will restore connections a few days after the end of the stress event. 40 An overview of the relevant effects of cortisol is available in Figure 1. ...

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... The recommended daily hydrocortisone dose in pediatric patients with PAI is 7-12 mg/m 2 , with a starting dose of 8 mg/m 2 , which is given in three divided doses [14,25,26]. In children with CAH, daily doses from 10 to 15 mg/m 2 are recommended to adequately suppress adrenal androgen production [25,26]. ...
... The recommended daily hydrocortisone dose in pediatric patients with PAI is 7-12 mg/m 2 , with a starting dose of 8 mg/m 2 , which is given in three divided doses [14,25,26]. In children with CAH, daily doses from 10 to 15 mg/m 2 are recommended to adequately suppress adrenal androgen production [25,26]. In our patients, the average dose of hydrocortisone slightly exceeded the recommended range (16.6 mg/m 2 in patients 1 and 2 and 13 mg/m 2 in patient 3), which suggests that the production of glucocorticoids in patients with pathological NNT variants is greatly reduced. ...
... Corticosteroids, even at physiological doses, can affect BMD [26]. In the adult population, long-term follow-up of patients with Addison disease showed that patients as a group did not exhibit accelerated bone loss, however, among these, around 50% met osteoporotic criteria, which suggests that some patients are more susceptible to bone loss than others [27]. ...
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Nicotinamide nucleotide transhydrogenase (NNT) deficiency causes primary adrenal insufficiency (PAI) and possibly some extra-adrenal manifestations. A limited number of these patients were previously described. We present the clinical and genetic characteristics of three family members with a biallelic novel pathogenic variant in the NNT gene. The patients were followed until the ages of 21.6, 20.2, and 4.2 years. PAI was diagnosed in the eldest two brothers after an Addisonian crisis and the third was diagnosed at the age of 4.5 months in the asymptomatic stage due to the genetic screening of family members. Whole exome sequencing with a targeted interpretation of variants in genes related to PAI was performed in all the patients. The urinary steroid metabolome was determined by gas chromatography–mass spectrometry in the asymptomatic patient. The three patients, who were homozygous for c.1575dup in the NNT gene, developed isolated glucocorticoid deficiency. The urinary steroid metabolome showed normal excretion of cortisol metabolites. The adolescent patients had slow pubertal progression with low–normal testicular volume, while testicular endocrine function was normal. Bone mineral density was in the range for osteopenia in both grown-up siblings. Echocardiography revealed no structural or functional heart abnormalities. This article is among the first with a comprehensive and chronologically-detailed description of patients with NNT deficiency.
... The treatment of CAH requires life-long cortisol replacement therapy. The recommended glucocorticoid for pediatric CAH patients is hydrocortisone (HC, name of synthetic cortisol) due to its short half-life and lower risk for adverse events (Oprea et al., 2019). To mimic the circadian rhythm of cortisol biosynthesis, oral administration of 10-15 mg/m 2 hydrocortisone daily is recommended, divided into two to three doses, and with the highest dose in the morning (Kamoun et al., 2013;Khattab and Marshall, 2019;Dabas et al., 2020). ...
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Congenital adrenal hyperplasia (CAH) is the most common form of adrenal insufficiency in childhood; it requires cortisol replacement therapy with hydrocortisone (HC, synthetic cortisol) from birth and therapy monitoring for successful treatment. In children, the less invasive dried blood spot (DBS) sampling with whole blood including red blood cells (RBCs) provides an advantageous alternative to plasma sampling. Potential differences in binding/association processes between plasma and DBS however need to be considered to correctly interpret DBS measurements for therapy monitoring. While capillary DBS samples would be used in clinical practice, venous cortisol DBS samples from children with adrenal insufficiency were analyzed due to data availability and to directly compare and thus understand potential differences between venous DBS and plasma. A previously published HC plasma pharmacokinetic (PK) model was extended by leveraging these DBS concentrations. In addition to previously characterized binding of cortisol to albumin (linear process) and corticosteroid-binding globulin (CBG; saturable process), DBS data enabled the characterization of a linear cortisol association with RBCs, and thereby providing a quantitative link between DBS and plasma cortisol concentrations. The ratio between the observed cortisol plasma and DBS concentrations varies highly from 2 to 8. Deterministic simulations of the different cortisol binding/association fractions demonstrated that with higher blood cortisol concentrations, saturation of cortisol binding to CBG was observed, leading to an increase in all other cortisol binding fractions. In conclusion, a mathematical PK model was developed which links DBS measurements to plasma exposure and thus allows for quantitative interpretation of measurements of DBS samples.
... A clinical trial of immediate-release granulated hydrocortisone formulation called Infacort (Diurnal, Cardiff, UK) for pediatric use is also underway. 41) Florinef (fludrocortisone) is given in 1 or 2 doses per day at a total of 50-200 μg/day for MC replacement. It normalizes blood pressure, electrolyte balance, and PRA. ...
Article
Primary adrenal insufficiency (PAI) in pediatric age is a rare, but potentially fatal condition caused by diverse etiologies including biochemical defects of steroid biosynthesis, developmental abnormalities of the adrenal gland, or reduced responsiveness to adrenocorticotropic hormone. Compared to adult PAI, pediatric PAI is more often the result of genetic (monogenic, syndromic disorders) than acquired conditions. During the past decade, rare monogenic disorders associated with PAI have helped unravel the underlying novel molecular genetic mechanism. The diagnosis of adrenal insufficiency in children and young infancy is often challenging, usually based on clinical suspicion and endocrine laboratory findings. Pediatric endocrinologists sometimes encounter therapeutic difficulty in finding the balance between undertreatment and overtreatment, determining how to optimize the dose over the patient’s lifetime, and maximizing mimicry of normal cortisol secretion with glucocorticoid replacement therapy.
... It is the most common etiology of Cushing's syndrome (CS), and the optimal treatment is transsphenoidal surgery (TSS) performed by an experienced pituitary surgeon [1][2][3]. Typically, a transient central adrenal insufficiency (CAI) occurs after successful TSS. e patients will receive physiological hydrocortisone replacement until the suppressed hypothalamic-pituitary-adrenal (HPA) axis returns to normal function [4][5][6]. ...
... p � 0.002, Figure 2(a)). Based on the Youden index, the optimal cutoff of MSC was 6 ...
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Background: The suppressed hypothalamic-pituitary-adrenal (HPA) axis after successful surgery for Cushing's disease (CD) will recover in almost all patients. We aimed to identify the predictive factors for HPA axis recovery in CD patients with postoperative remission. Design and Methods. This observational retrospective cross-sectional study enrolled 69 CD patients with postoperative remission in Huashan Hospital from 2015 to 2019. All subjects had a detailed clinical evaluation. The low-dose ACTH stimulation test (LDT) was conducted as the gold standard for assessing the HPA axis function. Results: Peak cortisol in LDT was found only to be positively correlative with morning serum cortisol (MSC) (ρ=0.451, p < 0.001). The MSC was higher (p < 0.001), and the median postoperative course was significantly longer (p=0.025) in the patients with the recovered HPA axis function compared with unrecovered patients. The AUC value of MSC for predicting the recovery of the HPA axis was 0.701, and the optimal cutoff was 6.25 μg/dl (sensitivity 85.19% and specificity 47.62%). Other useful cutoff values were 10.74 μg/dl (specificity 100%) and 4.18 μg/dl (sensitivity 100%). Besides, combined with the postoperative course, the AUC values were higher than MSC alone (0.935 vs. 0.701, p < 0.001). Conclusions: MSC is a viable first-step diagnostic predictor for HPA axis recovery in CD patients with postoperative remission. For the patients with cortisol levels between 4.18 and 10.74 μg/dl, a confirmatory test should be conducted. When the MSC level was 10.74 μg/dl or greater, the replacement therapy could be discontinued.
... Hydrocortisone is a corticosteroid indicated for replacement therapy in pediatric patients with adrenocortical insufficiency [1,2]. Guidance for this therapeutic strategy in this specific population is to administer the lowest possible dose and to use the native hormone, that is, hydrocortisone (cortisol), rather than synthetic steroids such as prednisolone and dexamethasone, which have a greater suppressive effect on growth [3]. ...
Article
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Hydrocortisone has been utilized in the management of adrenal insufficiency. For pediatric patients, the commercially available enteral form of hydrocortisone tablets (Cortoril®) is administered in powder form after being compounded by a pharmacist. However, the stability and quality of compounded hydrocortisone powder have not been verified. In this study, we formulated a 20 mg/g oral hydrocortisone powder by adding lactose monohydrate to crushed and filtered hydrocortisone tablets and assessed the stability and physical properties of this compounded product in polycarbonate amber bottles or coated paper packages laminated with cellophane and polyethylene. Stability was examined over 120 days in three storage conditions: closed bottle, in-use bottle, and laminated paper. Drug dissolution and powder X-ray diffraction analysis were conducted to assess its physicochemical stabilities. Validated liquid chromatography-diode array detection was used to detect and quantify hydrocortisone and its degradation products. Although impurity B (cortisone) and G (hydrocortisone-21-aldehyde) were found after 120 days of storage, no crystallographic and dissolution changes were noted. Hydrocortisone content was maintained between 90% and 110% of initial contents for 120 days at 25 ± 2 °C and 60 ± 5% relative humidity in all packaging conditions.
... It is advised against routine hormonal monitoring, instead for titration of treatment based on clinical response. In cases where malabsorption is suspected further analysis with serum or salivary cortisol day curves are recommended as a guide for dosing [4] but there is a lack of reliable biomarkers for treatment monitoring and notably measured concentrations of ACTH are not a useful parameter [11,17]. ...
Chapter
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The advent of synthetic corticosteroids in the 20th century provided a vital breakthrough in the management of adrenal insufficiency. In this chapter we review the main indications and guidance for appropriate hormone replacement and also look into the management of therapy during special circumstances. For decades hydrocortisone has remained the cornerstone for glucocorticoid replacement but we explore the alternatives including recently introduced modified-release drug preparations and the future treatment considerations currently undergoing research and pre-clinical trials.
... To investigate the molecular drivers behind the steady weight gain in ZBTB32 À/À mice, the functionality of the HPA axis during food deprivation was determined after 24h fasting in ZBTB32 +/+ and ZBTB32 À/À mice. The major motivation to study the GC levels in this study is that besides glucagon and epinephrine, they are the major activators of lipolysis in WAT (Oprea et al., 2019) and, moreover, we have collected convincing evidence that ZBTB32 performs protein-protein interaction with GR (see further). Since the adrenal glands are the main producers of GCs, we studied the GC levels after starvation in the plasma of ZBTB32 +/+ and ZBTB32 À/À mice. ...
Article
The hypothalamic-pituitary-adrenal (HPA) axis forms a complex neuroendocrine system that regulates the body’s response to stress such as starvation. In contrast with the glucocorticoid receptor (GR), ZBTB32 (zinc finger and BTB domain containing 32) is a transcription factor with poorly described functional relevance in physiology. This study shows that ZBTB32 is essential for the production of glucocorticoids (GCs) in response to starvation, since ZBTB32-/- mice fail to increase their GC production in the absence of nutrients. In terms of mechanism, GR-mediated upregulation of adrenal Scarb1 gene expression was absent in ZBTB32-/- mice, implicating defective cholesterol import as the cause of the poor GC synthesis. These lower GC levels are further associated with aberrations in the metabolic adaptation to starvation, which could explain the progressive weight gain of ZBTB32-/- mice. In conclusion, ZBTB32 performs a crosstalk with the GR in the metabolic adaptation to starvation via regulation of adrenal GC production.
... The dose of tetracosactide hexaacetate used to diagnose central adrenal insufficiency, the timing for collection of blood samples for cortisol measurement, and the cut-off peak cortisol concentration for both the low-dose and standard ACTH test are the subject of much controversy. Stimulated cortisol concentrations ≥18 mg/dL (497 nmol/L) are indicative of a normal hypothalamo-pituitary-adrenal axis (145). ...
... It is also important to highlight that cortisol deficiency can mask DI as cortisol is needed for water excretion. DI may develop after starting treatment with hydrocortisone and therefore close monitoring of fluid balance and electrolytes is important after starting glucocorticoid therapy (145). ...
Article
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Introduction: Congenital hypopituitarism (CH) is characterized by a deficiency of one or more pituitary hormones. The pituitary gland is a central regulator of growth, metabolism, and reproduction. The anterior pituitary produces and secretes growth hormone (GH), adrenocorticotropic hormone, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, and prolactin. The posterior pituitary hormone secretes antidiuretic hormone and oxytocin. Epidemiology: The incidence is 1 in 4,000–1 in 10,000. The majority of CH cases are sporadic; however, a small number of familial cases have been identified. In the latter, a molecular basis has frequently been identified. Between 80–90% of CH cases remain unsolved in terms of molecular genetics. Pathogenesis: Several transcription factors and signaling molecules are involved in the development of the pituitary gland. Mutations in any of these genes may result in CH including HESX1, PROP1, POU1F1, LHX3, LHX4, SOX2, SOX3, OTX2, PAX6, FGFR1, GLI2 , and FGF8 . Over the last 5 years, several novel genes have been identified in association with CH, but it is likely that many genes remain to be identified, as the majority of patients with CH do not have an identified mutation. Clinical manifestations: Genotype-phenotype correlations are difficult to establish. There is a high phenotypic variability associated with different genetic mutations. The clinical spectrum includes severe midline developmental disorders, hypopituitarism (in isolation or combined with other congenital abnormalities), and isolated hormone deficiencies. Diagnosis and treatment: Key investigations include MRI and baseline and dynamic pituitary function tests. However, dynamic tests of GH secretion cannot be performed in the neonatal period, and a diagnosis of GH deficiency may be based on auxology, MRI findings, and low growth factor concentrations. Once a hormone deficit is confirmed, hormone replacement should be started. If onset is acute with hypoglycaemia, cortisol deficiency should be excluded, and if identified this should be rapidly treated, as should TSH deficiency. This review aims to give an overview of CH including management of this complex condition.
... However, studies have shown that it is far from perfectly replicate the physiological circadian cortisol rhythm [1]. So, patients may suffer from symptoms of under treatment with a decrease in the quality of life or from the consequences of chronic overtreatment such as metabolic disturbances and a loss of bone mineral density [2]. Reproducing the physiological secretion of cortisol during Ramadan intermittent fasting is a challenge [3]. ...
... To date, there is a lack of a reliable biomarker for glucocorticoid activity. Several tools such as plasma cortisol, ACTH, and 24 h-urinary cortisol have been proposed to evaluate the adequacy of glucocorticoid replacement therapy, but they all showed a lack of reliability and some weakness [2]. SC closely reflects plasma free cortisol concentrations [9][10][11]. ...
Article
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Objective Patients with adrenal insufficiency have difficulties in fasting during the month of Ramadan with an increased risk of complications. Cortisol levels are unknown in these patients. The objective of this study was to assess the daily cortisol profile in hydrocortisone-treated patients with secondary adrenal insufficiency (SAI) and healthy controls during a fasting day.MethodsA cross-sectional matched case-control study on 50 hydrocortisone-treated SAI patients and 69 controls who are used to fast. Clinical and therapeutic data were collected. Five salivary samples for cortisol measurement were collected throughout a fasting day of the third week of Ramadan 2019.ResultsSalivary cortisol levels were significantly higher on awakening, at midnight and before the predawn meal in patients compared with controls. The circadian cortisol rhythm was disrupted in patients. The area under the salivary cortisol level versus time curve (AUC) was lower than the 2.5th percentile of the controls in one patient (2.5%) and higher than the 97.5th percentile in 23 patients (59%) who were considered overtreated. Age ≥ 35 years was independently associated with overtreatment (adjusted odds ratio = 12.0; 95% CI (2.0–70.4); p = 0.006). Seven patients broke their fasting for a complication compared with no one of the controls (p = 0.001). No factor was associated with this risk.Conclusions Salivary cortisol levels were high in fasting hydrocortisone-treated SAI patients with a disruption of the circadian rhythm.
... 11 Each case was initially treated with acetazolamide or topiramate; physiologic hydrocortisone therapy (6-9 mg/m 2 /d) was initiated with AI diagnosis. 12 Cases are presented individually. Mean values were calculated without software. ...
Article
Importance: Pediatric pseudotumor cerebri syndrome pathophysiology is complex and not well delineated. Therefore, it is important to identify potential contributors or targets underlying the primary pathogenesis for its development. Objective: To report cases highlighting the association of pediatric pseudotumor cerebri syndrome with adrenal insufficiency. Design, setting, and participants: This noncontrolled, observational case series included pediatric patients diagnosed with pseudotumor cerebri syndrome and adrenal insufficiency at an urban academic children's hospital in Houston, Texas, from June 2015 to October 2019. Main outcomes and measures: Monitoring optic nerve edema by clinical examination, fundus photography, and optical coherence topography images of the optic nerve. Results: Data were collected from 5 pediatric patients (age range, 5-10 years) diagnosed with pseudotumor cerebri syndrome and adrenal insufficiency. One was a girl; all were White and prepubertal. Three patients had unrecognized glucocorticoid exposure. All patients had bilateral optic nerve edema that was initially treated with acetazolamide or topiramate, but cortisol functional testing by either 8 am cortisol or cosyntropin stimulation tests revealed a diagnosis of central adrenal insufficiency. Treatment with physiological doses of hydrocortisone resulted in resolution of optic nerve edema and clinical symptoms of pseudotumor cerebri syndrome, as well as a shorter time receiving medical therapy. Conclusions and relevance: In this case series, adrenal insufficiency was associated with both primary and secondary prepubertal pediatric pseudotumor cerebri syndrome. As a potential target specific to causative mechanism, physiologic hydrocortisone therapy resolved the condition. To date, there remains a global unawareness among clinicians about the suppressive outcome that glucocorticoids may have on the developing hypothalamic-pituitary-adrenal axis, resulting in adrenal insufficiency and so-called episodic pseudotumor cerebri syndrome in young children. Ophthalmologists and pediatric subspecialists should implement cortisol testing via either 8 am cortisol or cosyntropin stimulation tests at initial evaluation of all children with pseudotumor cerebri syndrome and risk factors for adrenal insufficiency, no predisposing causes, or nonresponse to conventional treatment. Further management and treatment should be in combination with ophthalmology and endocrine services.