Novel agents to treat adrenal insufficiency: findings of preclinical and early clinical trials.

INTRODUCTION: Adrenal insufficiency currently affects over 300/million population, with higher morbidity and mortality compared to the general population. Current glucocorticoid replacement therapy is limited by a lack of reliable biomarkers to guide dosing, inter-patient variation in metabolism and narrow therapeutic window. Increased morbidity and mortality may relate to unappreciated under- or over-exposure to glucocorticoids and impaired cortisol circadian rhythm. New agents are required to emulate physiological cortisol secretion and individualize glucocorticoid dosing. AREAS COVERED: History of glucocorticoid therapy, current limitations, and novel chronotherapeutic glucocorticoid delivery mechanisms. Literature search incorporated searches of PubMed and Embase utilizing terms such as adrenal insufficiency, Chronocort, Plenadren, continuous subcutaneous hydrocortisone infusion (CHSI), and glucocorticoid receptor modulator. EXPERT OPINION: Glucocorticoid chronotherapy is necessary to optimize glucocorticoid exposure and minimize complications. Current oral chronotherapeutics provide improved dosing functionality, but are modifiable only in specific increments and cannot accommodate ultradian cortisol variation. Current data show improvement in quality of life but not morbidity or mortality outcomes. CHSI has significant potential for individualized glucocorticoid dosing, but would require a suitable biomarker of glucocorticoid adequacy to be implementable. Avenues for future research include determining a glucocorticoid sufficiency biomarker, development of interstitial or systemic cortisol monitoring, or development of glucocorticoid receptor modulators.

Salivary Cortisol Response to ACTH Stimulation Is a Reliable Alternative to Serum Cortisol in Evaluating Hypoadrenalism.

CONTEXT: The serum total cortisol response to the ACTH stimulation test is widely used to assess adrenocortical function but is affected by changes in cortisol-binding globulin (CBG) concentration. Salivary cortisol reflects free cortisol concentrations and may offer a reliable alternative. OBJECTIVES: (1) To establish the salivary cortisol response to ACTH stimulation in healthy volunteers and patients with altered CBG concentrations; (2) to evaluate the performance of a lower reference limit (LRL) determined in healthy volunteers in patients with suspected hypoadrenalism (SH-patients). DESIGN: A 250 µg ACTH stimulation test was undertaken in 139 healthy volunteers, 24 women taking an estradiol-containing oral contraceptive pill (OCP-females), 10 patients with low serum protein concentration (LP-patients), and 30 SH-patients. Salivary cortisol was measured by liquid chromatography-tandem mass spectrometry. Mean and LRL of the 30-minute salivary cortisol response (mean-1.96 standard deviation) were derived from log-transformed concentrations. The LRL was applied as a diagnostic cut-off in SH-patients, with comparison to the serum response. RESULTS: Mean CBG concentrations (range) were 58 (42-81) mg/L, 64 (43-95) mg/L, 41 (28-60) mg/L, and 116 (84-159) mg/L in males, females, LP-patients, and OCP-females, respectively. The mean 30-minute salivary cortisol concentration was 19.3 (2.5th-97.5th percentile 10.3-36.2) nmol/L in healthy volunteers. Corresponding values were not different in OCP-females [19.7 (9.5-41.2) nmol/L; P = .59] or LP-patients [19.0 (7.7-46.9) nmol/L; P = .97]. Overall diagnostic agreement between salivary and serum responses in SH-patients was 79%. CONCLUSION: Salivary cortisol response to ACTH stimulation offers a reliable alternative to serum and may be especially useful in conditions of altered CBG concentration.

The Hypothalamus-pituitary-adrenocortical Response to Critical Illness: A Concept in Need of Revision.

Based on insights obtained during the past decade, the classical concept of an activated hypothalamus-pituitary-adrenocortical axis in response to critical illness is in need of revision. After a brief central hypothalamus-pituitary-adrenocortical axis activation, the vital maintenance of increased systemic cortisol availability and action in response to critical illness is predominantly driven by peripheral adaptations rather than by an ongoing centrally activated several-fold increased production and secretion of cortisol. Besides the known reduction of cortisol-binding proteins that increases free cortisol, these peripheral responses comprise suppressed cortisol metabolism in liver and kidney, prolonging cortisol half-life, and local alterations in expression of 11ßHSD1, glucocorticoid receptor-α (GRα), and FK506 binding protein 5 (FKBP51) that appear to titrate increased GRα action in vital organs and tissues while reducing GRα action in neutrophils, possibly preventing immune-suppressive off-target effects of increased systemic cortisol availability. Peripherally increased cortisol exerts negative feed-back inhibition at the pituitary level impairing processing of pro-opiomelanocortin into ACTH, thereby reducing ACTH-driven cortisol secretion, whereas ongoing central activation results in increased circulating pro-opiomelanocortin. These alterations seem adaptive and beneficial for the host in the short term. However, as a consequence, patients with prolonged critical illness who require intensive care for weeks or longer may develop a form of central adrenal insufficiency. The new findings supersede earlier concepts such as "relative," as opposed to "absolute," adrenal insufficiency and generalized systemic glucocorticoid resistance in the critically ill. The findings also question the scientific basis for broad implementation of stress dose hydrocortisone treatment of patients suffering from acute septic shock solely based on assumption of cortisol insufficiency.

SCARB1 downregulation in adrenal insufficiency with Allgrove syndrome.

BACKGROUND: Allgrove disease is a rare genetic syndrome characterized by adrenal insufficiency, alacrimia, achalasia and complex neurological involvement. Allgrove disease is due to recessive mutations in the AAAS gene, which encodes for the nucleoporin Aladin, implicated in the nucleocytoplasmic transport. The adrenal insufficiency has been suggested to rely on adrenal gland-ACTH resistance. However, the link between the molecular pathology affecting the nucleoporin Aladin and the glucocorticoid deficiency is still unknown. RESULTS: By analyzing postmortem patient's adrenal gland, we identified a downregulation of Aladin transcript and protein. We found a downregulation of Scavenger receptor class B-1 (SCARB1), a key component of the steroidogenic pathway, and SCARB1 regulatory miRNAs (mir125a, mir455) in patient's tissues. With the hypothesis of an impairment in the nucleocytoplasmic transport of the SCARB1 transcription enhancer cyclic AMP-dependent protein kinase (PKA), we detected a reduction of nuclear Phospho-PKA and a cytoplasmic mislocalization in patient's samples. CONCLUSIONS: These results shed a light on the possible mechanisms linking ACTH resistance, SCARB1 impairment, and defective nucleocytoplasmic transport.

Adrenal histological and functional changes after hepatic encephalopathy: From mice model to an integrative bioinformatics analysis.

Hepatic encephalopathy (HE), which is caused by neurotoxin agents in the liver, is a complicated condition with a variety of neurological manifestations. Recently, endocrine alterations have been more paid attention to for neurological severity in the course of HE, e.g. adrenal gland. To identify the role of adrenal gland in the context of HE, we evaluated the functional changes of adrenal gland (i.e., plasma corticosterone concentrations and histopathological changes) in mice model of HE. To dig deep into the molecular and genetic underpinnings, a comprehensive enrichment analysis for shared genes between HE and adrenal insufficiency (AI) was also performed. Our results showed a significant reduction in the level of plasma corticosterone and severe cellular necrosis in zona fasciculate of adrenal cortex, possibly indicating adrenal insufficiency. Enrichment analysis indicated four common genes, besides predicted five novel genes and some significant MicroRNAs (miRNAs) and transcription factors for both HE and AI. Couples with, several biological processes, such as DNA damage, inflammatory responses, glycolytic processes, and insulin receptor signaling pathway were predicted in both HE and AI. To sum up, data from experimental tests and bioinformatics analyses suggest that AI play an important role in the pathogenesis and progression of HE.

Non-Canonical Effects of ACTH: Insights Into Adrenal Insufficiency.

Introduction: Adrenocorticotropic hormone (ACTH) is produced from proopiomelanocortin, which is predominantly synthetized in the corticotroph and melanotroph cells of the anterior and intermediate lobes of the pituitary gland and the arcuate nucleus of the hypothalamus. Although ACTH clearly has an effect on adrenal homeostasis and maintenance of steroid hormone production, it also has extra-adrenal effects that require further elucidation. Methods: We comprehensively reviewed English language articles, regardless of whether they reported the presence or absence of adrenal and extra-adrenal ACTH effects. Results: In the present review, we provide an overview on the current knowledge on adrenal and extra-adrenal effects of ACTH. In the section on adrenal ACTH effects, we focused on corticosteroid rhythmicity and effects on steroidogenesis, mineralocorticoids and adrenal growth. In the section on extra-adrenal effects, we have analyzed the effects of ACTH on the osteoarticular and reproductive systems, adipocytes, immune system, brain and skin. Finally, we focused on adrenal insufficiency. Conclusions: The role of ACTH in maintaining the function of the hypothalamic-pituitary-adrenal axis is well known. Conversely, if we broaden our vision and analyze its role as a potential treatment strategy in other conditions, it will be evident in the literature that researchers seem to have abandoned this aspect in studies conducted several years ago. We believe it is worth re-evaluating the role of ACTH considering its noncanonical effects on the adrenal gland itself and on extra-adrenal organs and tissues; however, this would not have been possible without the recent advances in the pertinent technologies.

Adult-born proopiomelanocortin neurons derived from Rax-expressing precursors mitigate the metabolic effects of congenital hypothalamic proopiomelanocortin deficiency.

OBJECTIVE: Proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus are essential regulators of energy balance. Selective loss of POMC production in these cells results in extreme obesity and metabolic comorbidities. Neurogenesis occurs in the adult hypothalamus, but it remains uncertain whether functional POMC neurons emerge in physiologically significant numbers during adulthood. Here, we tested whether Rax-expressing precursors generate POMC neurons in adult mice and rescue the metabolic phenotype caused by congenital hypothalamic POMC deficiency. METHODS: Initially, we identified hypothalamic Rax-expressing cell types using wild-type and Rax-CreERT2:Ai34D mice. Then we generated compound Rax-CreERT2:ArcPomcloxTB/loxTB mice in which endogenous hypothalamic Pomc expression is silenced, but can be restored by tamoxifen administration selectively in neurons derived from Rax+ progenitors. The number of POMC neurons generated by Rax+ progenitors in adult mice and their axonal projections was determined. The metabolic effects of these neurons were assessed by measuring food intake, bodyweight, and body composition, along with glucose and insulin levels. RESULTS: We found that Rax is expressed by tanycytes and a previously unrecognized cell type in the hypothalamic parenchyma of adult mice. Rax+ progenitors generated ~10% of the normal adult hypothalamic POMC neuron population within two weeks of tamoxifen treatment. The same rate and steady state of POMC neurogenesis persisted from young adult to aged mice. These new POMC neurons established terminal projections to brain regions that were involved in energy homeostasis. Mice with Rax+ progenitor-derived POMC neurons had reduced body fat mass, improved glucose tolerance, increased insulin sensitivity, and decreased bodyweight in proportion to the number of new POMC neurons. CONCLUSIONS: These data demonstrate that Rax+ progenitors generate POMC neurons in sufficient numbers during adulthood to mitigate the metabolic abnormalities of hypothalamic POMC-deficient mice. The findings suggest that adult hypothalamic neurogenesis is a robust phenomenon in mice that can significantly impact energy homeostasis.

Synacthen Stimulation Test Following Unilateral Adrenalectomy Needs to Be Interpreted With Caution.

Background: Cortisol levels in response to stress are highly variable. Baseline and stimulated cortisol levels are commonly used to determine adrenal function following unilateral adrenalectomy. We report the results of synacthen stimulation testing following unilateral adrenalectomy in a tertiary referral center. Methods: Data were collected retrospectively for 36 patients who underwent synacthen stimulation testing one day post unilateral adrenalectomy. None of the patients had clinical signs of hypercortisolism preoperatively. No patient received pre- or intraoperative steroids. Patients with overt Cushing's syndrome were excluded. Results: The median age was 58 (31-79) years. Preoperatively, 16 (44%) patients had a diagnosis of pheochromocytoma, 12 (33%) patients had primary aldosteronism and 8 (22%) patients had non-functioning adenomas with indeterminate/atypical imaging characteristics necessitating surgery. Preoperative overnight dexamethasone suppression test results revealed that 6 of 29 patients failed to suppress cortisol to <50 nmol/L. Twenty (56%) patients achieved a stimulated cortisol ≥450 nmol/L at 30 minutes and 28 (78%) at 60 minutes. None of the patients developed clinical adrenal insufficiency necessitating steroid replacement. Conclusions: Synacthen stimulation testing following unilateral adrenalectomy using standard stimulated cortisol cut-off values would wrongly label many patients adrenally insufficient and may lead to inappropriate prescriptions of steroids to patients who do not need them.

Characterization of patients with adrenal insufficiency and frequent adrenal crises.

OBJECTIVE: This study aimed to characterize the clinical and biochemical features of patients with primary (PAI) and secondary (SAI) adrenal insufficiency who developed adrenal crises (ACs) and estimate the incidence of ACs in these patients. DESIGN: Retrospective case-control analysis of the European Adrenal Insufficiency Registry (EU-AIR; NCT01661387). METHODS: Two thousand six hundred and ninety-four patients with AI (1054 PAI; 1640 SAI) enrolled in EU-AIR. Patients who developed ≥ 1 AC were matchd 1:3 with patients without ACs for age, sex and AI type. Data were collected at baseline and follow-up (mean ± s.d.: PAI 3.2 ± 1.7 years; SAI 2.9 ± 1.7 years). RESULTS: One hundred and forty-eight out of 2694 patients (5.5%; n = 84 PAI; n = 64 SAI) had an AC during the study: 6.53 (PAI) and 3.17 (SAI) ACs/100 patient-years. Of patients who experienced an AC, 16% (PAI) and 9.4% (SAI) experienced ≥ 1 AC/year. The incidence of adverse events, infectious intercurrent illnesses and infectious serious adverse events were higher in patients with ACs than without ACs. No differences were observed in BMI, HbA1c, blood pressure and frequencies of diabetes mellitus or hypertension between subgroups (PAI and SAI, with and without ACs). At baseline, PAI patients with AC had higher serum potassium (4.3 ± 0.5 vs 4.2 ± 0.4 mmol/L; P = 0.03) and lower sodium (138.5 ± 3.4 vs 139.7 ± 2.9 mmol/L; P = 0.004) than patients without AC. At last observation, SAI patients with AC had higher hydrocortisone doses than patients without AC (11.9 ± 5.1 vs 10.1 ± 2.9 mg/m2; P < 0.001). CONCLUSIONS: These results demonstrate that concomitant diseases and cardiovascular risk factors do not feature in the risk profile of AC; however, patients with AC had a higher incidence of infectious events.

Adrenal cortex development and related disorders leading to adrenal insufficiency.

The adult human adrenal cortex produces steroid hormones that are crucial for life, supporting immune response, glucose homeostasis, salt balance and sexual maturation. It consists of three histologically distinct and functionally specialized zones. The fetal adrenal forms from mesodermal material and produces predominantly adrenal C19 steroids from its fetal zone, which involutes after birth. Transition to the adult cortex occurs immediately after birth for the formation of the zona glomerulosa and fasciculata for aldosterone and cortisol production and continues through infancy until the zona reticularis for adrenal androgen production is formed with adrenarche. The development of this indispensable organ is complex and not fully understood. This article gives an overview of recent knowledge gained of adrenal biology from two perspectives: one, from basic science studying adrenal development, zonation and homeostasis; and two, from adrenal disorders identified in persons manifesting with various isolated or syndromic forms of primary adrenal insufficiency.

COVID-19, adrenal gland, glucocorticoids, and adrenal insufficiency.

The current Coronavirus disease outbreak requires that physicians work in collaboration with other physicians especially in intensive care and emergency units. To fight against this new disease, whose pathogenesis, effects, and results have not been clearly demonstrated, especially in patients with the pre-existing chronic disease, requires special expertise and perspectives. Due to the need for dynamic glucocorticoid treatment at different stages of the disease in patients with adrenal insufficiency, the existence of reports indicating that "coronavirus disease 2019" also affects the adrenal reserve, and the use of glucocorticoids also in advanced stages in patients with Coronavirus disease require this issue to be emphasized with precision. Herein, treatment of the pre-existing adrenal insufficiency in patients with actual Coronavirus disease and the effects of the this critical disease on the adrenal gland have been reviewed.

A Prospective Study of Children Aged 0-8 Years with CAH and Adrenal Insufficiency Treated with Hydrocortisone Granules.

CONTEXT: Children with congenital adrenal hyperplasia (CAH) and adrenal insufficiency (AI) require daily hydrocortisone replacement with accurate dosing. OBJECTIVE: Prospective study of efficacy and safety of hydrocortisone granules in children with AI and CAH monitored by 17-OHP (17-hydroxyprogesterone) saliva profiles. METHODS: Seventeen children with CAH (9 male) and 1 with hypopituitarism (male), aged from birth to 6 years, had their hydrocortisone medication changed from pharmacy compounded capsules to hydrocortisone granules. Patients were followed prospectively for 2 years. In children with CAH, the therapy was adjusted by 17-OHP salivary profiles every 3 months. The following parameters were recorded: hydrocortisone dose, height, weight, pubertal status, adverse events, and incidence of adrenal crisis. RESULTS: The study medication was given thrice daily, and the median duration of treatment (range) was 795 (1-872) days, with 150 follow-up visits. Hydrocortisone doses were changed on 40/150 visits, with 32 based on salivary measurements and 8 on serum 17-OHP levels. The median daily mg/m2 hydrocortisone dose (range) at study entry for the different age groups 2-8 years, 1 month to 2 years, <28 days was 11.9 (7.2-15.5), 9.9 (8.6-12.2), and 12.0 (11.1-29.5), respectively, and at end of the study was 10.2 (7.0-14.4), 9.8 (8.9-13.1), and 8.6 (8.2-13.7), respectively. There were no trends for accelerated or reduced growth. No adrenal crises were observed despite 193 treatment-emergent adverse events, which were mainly common childhood illnesses. INTERPRETATION: This first prospective study of glucocorticoid treatment in children with AI and CAH demonstrates that accurate dosing and monitoring from birth results in hydrocortisone doses at the lower end of the recommended dose range and normal growth, without occurrence of adrenal crises.

Stimulated Salivary Cortisol as a Noninvasive Diagnostic Tool for Adrenal Insufficiency.

BACKGROUND: Salivary cortisol is routinely used as a diagnostic test for Cushing syndrome. The diagnostic use of salivary cortisol for adrenal insufficiency (AI), however, is less established. We aimed to investigate the utility of morning basal and adrenocorticotropic hormone-stimulated salivary cortisol in diagnosing AI in Korean adults. METHODS: We prospectively included 120 subjects (female, n=70) from Seoul National University Hospital. AI was defined as a stimulated serum cortisol level of <496.8 nmol/L during the short Synacthen test (SST). Serum and saliva samples were drawn between 8:00 AM and 10:00 AM. Salivary cortisol levels were measured using an enzyme immunoassay kit. RESULTS: Thirty-four patients were diagnosed with AI according to the SST results. Age, sex, body mass index, serum albumin levels, and serum creatinine levels did not significantly differ between the normal and AI groups. Basal and stimulated salivary cortisol levels were positively correlated with basal (r=0.538) and stimulated serum cortisol levels (r=0.750), respectively (all P<0.001). Receiver operating characteristic curve analysis yielded a cutoff level of morning basal salivary cortisol of 3.2 nmol/L (sensitivity, 84.9%; specificity, 73.5%; area under the curve [AUC]=0.822). The optimal cutoff value of stimulated salivary cortisol was 13.2 nmol/L (sensitivity, 90.7%; specificity, 94.1%; AUC=0.959). Subjects with a stimulated salivary cortisol level above 13.2 nmol/L but a stimulated serum cortisol level below 496.8 nmol/L (n=2) had lower serum albumin levels than those showing a concordant response. CONCLUSION: The diagnostic performance of stimulated salivary cortisol measurements after the SST was comparable to serum cortisol measurements for diagnosing AI.

Endocrine and metabolic aspects of the COVID-19 pandemic.

COVID-19 infection has tremendously impacted our daily clinical practice as well as our social living organization. Virtually all organs and biological systems suffer from this new coronavirus infection, either because the virus targets directly specific tissues or because of indirect effects. Endocrine diseases are not an exception and some of endocrine organs are at risk of direct or indirect lesion by COVID-19. Although there is still no evidence of higher predisposition to contract the infection in patients with diabetes and/or obesity, the coexistence of these conditions contributes to a worse prognosis because both conditions confer an impaired immunologic system. Cytokines storm can be amplified by these two latter conditions thereby leading to multisystemic failure and death. Glycaemic control has been demonstrated to be crucial to avoiding long hospital stays, ICU requirement and also prevention of excessive mortality. Endocrine treatment modifications as a consequence of COVID-19 infection are required in a proactive manner, in order to avoid decompensation and eventual hospital admission. This is the case of diabetes and adrenal insufficiency in which prompt increase of insulin dosage and substitutive adrenal steroids through adoption of the sick day's rules should be warranted, as well as easy contact with the health care provider through telematic different modalities. New possible endocrinological targets of COVID-19 have been recently described and warrant a full study in the next future.

Emerging roles of melanocortin receptor accessory proteins (MRAP and MRAP2) in physiology and pathophysiology.

Melanocortin-2 receptor accessory protein (MRAP) has an unusual dual topology and influences the expression, localisation, signalling and internalisation of the melanocortin receptor 2 (MC2); the adrenocorticotropic hormone (ACTH) receptor. Mutations in MRAP are associated with familial glucocorticoid deficiency type-2 and evidence is emerging of the importance of MRAP in adrenal development and ACTH signalling. Human MRAP has two functional splice variants: MRAP-α and MRAP-ß, unlike MRAP-ß, MRAP-α has little expression in brain but is highly expressed in ovary. MRAP2, identified through whole human genome sequence analysis, has approximately 40% sequence homology to MRAP. MRAP2 facilitates MC2 localisation to the cell surface but not ACTH signalling. MRAP and MRAP2 have been found to regulate the surface expression and signalling of all melanocortin receptors (MC1-5). Additionally, MRAP2 moderates the signalling of the G-protein coupled receptors (GCPRs): orexin, prokineticin and GHSR1a; the ghrelin receptor. Whilst MRAP appears to be mainly involved in glucocorticoid synthesis, an important role is emerging for MRAP2 in regulating appetite and energy homeostasis. Transgenic models indicate the importance of MRAP in adrenal gland formation. Like MC3R and MC4R knockout mice, MRAP2 knockout mice have an obese phenotype. In vitro studies indicate that MRAP2 enhances the MC3 and MC4 response to the agonist αMSH, which, like ACTH, is produced through precursor polypeptide proopiomelanocortin (POMC) cleavage. Analysis of cohorts of individuals with obesity have revealed several MRAP2 genetic variants with loss of function mutations which are causative of monogenic hyperphagic obesity with hyperglycaemia and hypertension. MRAP2 may also be associated with female infertility. This review summarises current knowledge of MRAP and MRAP2, their influence on GPCR signalling, and focusses on pathophysiology, particularly familial glucocorticoid deficiency type-2 and obesity.

Sphingosine-1-phosphate lyase (SGPL1) deficiency is associated with mitochondrial dysfunction.

Deficiency in Sphingosine-1-phosphate lyase (S1P lyase) is associated with a multi-systemic disorder incorporating primary adrenal insufficiency (PAI), steroid resistant nephrotic syndrome and neurological dysfunction. Accumulation of sphingolipid intermediates, as seen with loss of function mutations in SGPL1, has been implicated in mitochondrial dysregulation, including alterations in mitochondrial membrane potentials and initiation of mitochondrial apoptosis. For the first time, we investigate the impact of S1P lyase deficiency on mitochondrial morphology and function using patient-derived human dermal fibroblasts and CRISPR engineered SGPL1-knockout HeLa cells. Reduced cortisol output in response to progesterone stimulation was observed in two patient dermal fibroblast cell lines. Mass spectrometric analysis of patient dermal fibroblasts revealed significantly elevated levels of sphingosine-1-phosphate, sphingosine, ceramide species and sphingomyelin when compared to control. Total mitochondrial volume was reduced in both S1P lyase deficient patient and HeLa cell lines. Mitochondrial dynamics and parameters of oxidative phosphorylation were altered when compared to matched controls, though differentially across the cell lines. Mitochondrial dysfunction may represent a major event in the pathogenesis of this disease, associated with severity of phenotype.

Paediatric population pharmacokinetic modelling to assess hydrocortisone replacement dosing regimens in young children.

CONTEXT: Accurate hydrocortisone dosing in children with adrenal insufficiency is important to avoid the risks of over and under treatment including iatrogenic Cushing's syndrome and adrenal crisis. OBJECTIVE: To establish a population pharmacokinetic model of hydrocortisone in children and use this to refine hydrocortisone replacement regimens. DESIGN AND METHODS: Pharmacokinetic study of hydrocortisone granules, available in 0.5, 1, 2 and 5 mg dose strengths, in 24 children with adrenal insufficiency aged 2 weeks to 6 years. Cortisol concentrations quantified by LC-MS/MS were used to refine an adult pharmacokinetic model to a paediatric population model which was then used to simulate seven different hydrocortisone treatment regimens. RESULTS: Pre-dose cortisol levels were undetectable in 54% of the 24 children. The developed pharmacokinetic model had good predictive performance. Simulations for the seven treatment regimens using either three- or four-times daily dosing showed treatment regimens delivered an AUC0-24h within the 90% reference range for healthy children except in neonates where two regimens had an AUC below the 5th percentile. Cortisol concentrations at individual time points in the 24 h were outside the 90% reference range for healthy individuals in 50%, 55-65% and 70-75% for children, infants and neonates, respectively, with low cortisol levels being most prevalent. CONCLUSIONS: Current paediatric hydrocortisone treatment regimens based on either three- or four-times daily administration replicate cortisol exposure based on AUC0-24h, but the majority of cortisol levels are above or below physiological cortisol levels with low levels very common before the next dose.

Triple-A Syndrome (TAS): An In-Depth Overview on Genetic and Phenotype Heterogeneity.

Triple-A Syndrome (TAS) is a rare autosomal recessive disorder characterized by three cardinal symptoms: alacrimia, achalasia and adrenal insufficiency due to ACTH insensitivity. Various progressive neurological abnormalities and skin changes have been described in association with the syndrome. The disease is caused by mutation in the AAAS gene on chromosome 12q13. Mutations in AAAS were identified in more than 90% of individuals and families with TAS. The protein encoded by AAAS was termed ALADIN and is part of the WD repeat family of proteins, that have been found to be involved in many different functions such as protein-protein interaction, RNA processing, cytoskeleton assembly, control of cell division, signal transduction and apoptosis. Immunohistochemical analysis showed that mutated or truncated ALADIN localizes to the cytoplasm rather than to the nuclear pore complex. The exact function of ALADIN and the mechanisms that lead to the ACTH-resistant adrenal phenotype remains largely unknown. Nonetheless, recent studies provided some insights on the role of ALADIN as a member of the Nuclear Pore Complex not only implicated in the import of proteins involved in DNA repair and oxidative stress homeostasis but also in the strengthening of the mitotic spindle assembly. Early identification of the syndrome is challenging, given the rarity of the condition and high phenotypic heterogeneity even among members of the same family. In this review, we aim to summarize the current knowledge of clinical and molecular profile of patients with TAS and recommendations for the diagnosis, management, and follow-up of patients.

Axis-specific analysis and predictors of endocrine recovery and deficits for non-functioning pituitary adenomas undergoing endoscopic transsphenoidal surgery.

PURPOSE: Endoscopic transsphenoidal surgery (ETSS) is a well-established treatment for patients with nonfunctioning pituitary adenomas (NFPAs). Data on the rates of pituitary dysfunction and recovery in a large cohort of NFPA patients undergoing ETSS and the predictors of endocrine function before and after ETSS are scarce. This study is purposed to analyze the comprehensive changes in hormonal function and identify factors that predict recovery or worsening of hormonal axes following ETSS for NFPA. METHODS: A retrospective review of 601 consecutive patients who underwent ETSS between 2010 and 2018 at one institution was performed. Recovery or development of new hypopituitarism was analyzed in 209 NFPA patients who underwent ETSS. RESULTS: Patients with preoperative endocrine deficits (59.8%) in one or more pituitary axes had larger tumor volumes (P = 0.001) than those without preoperative deficits. Recovery of preoperative pituitary deficit occurred in all four axes, with overall mean recovery of 29.7%. The cortisol axis showed the highest recovery whereas the thyroid axis showed the lowest, with 1-year cumulative recovery rates of 44.3% and 6.1%, respectively. Postoperative hypopituitarism occurred overall in 17.2%, most frequently in the thyroid axis (24.3%, 27/111) and least frequently in the cortisol axis (9.7%, 16/165). Axis-specific predictors of post-operative recovery and deficiency were identified. CONCLUSIONS: Dynamic alterations in pituitary hormones were observed in a proportion of patients following ETSS in NFPA patients. Postoperative endocrine vulnerability, recovery, and factors that predicted recovery or loss of endocrine function depended on the hormonal system, necessitating an axis-specific surveillance strategy postoperatively.