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In this study, we will investigate the possible side effects of psoriasis patients using long-term topical corticosteroids (TCS) such as adrenal insufficiency, Cushing’s Syndrome (CS) and osteoporosis and determine how these side effects develop. Forty-nine patients were included in the study. The patients were divided into two groups based on the potency of the topical steroid they took and the patients’ ACTH, cortisol and bone densitometer values were evaluated. There was no significant difference between the two groups regarding the development of surrenal insufficiency, CS and osteoporosis. One patient in group 1 and 4 patients in group 2 were evaluated as iatrogenic CS. ACTH stimulation tests of these patients in group 2 showed consistent results with adrenal insufficiency, while no adrenal insufficiency was detected in the patient in Group 1. Patients who used more than 50g of superpotent topical steroids per week compared to patients who used 50g of superpotent topical steroids per week. It was identified that patients who used more than 50g of superpotent topical steroids had significantly lower cortisol levels, with a negatively significant correlation between cortisol level and the amount of topical steroid use ( < .01).Osteoporosis was detected in 3 patients in group 1 and 8 patients in Group 2. Because of the low number of patients between two groups, statistical analysis could not be performed to determine the risk factors. Our study is the first study that we know of that investigated these three side effects. We have shown that the development of CS, adrenal insufficiency and osteoporosis in patients who use topical steroids for a long time depends on the weekly TCS dosage and the risk increases when it exceeds the threshold of 50 grams per week. therefore, our recommendation would be to avoid long-term use of superpotent steroids and to choose from the medium-potent group if it is to be used. ABOUT THE CONTRIBUTORS Betul Erdem Department of Dermatology, Van Training and Research Hospital, Van, Turkey. Muzeyyen Gonul Department of Dermatology, Ministry of Health, Ankara Etlik City Hospital, Ankara, Turkey. Ilknur Ozturk Unsal Department of Endocrine and Metabolic Disease, Ministry of Health, Ankara Etlik City Hospital, Ankara, Turkey. Seyda Ozdemir Sahingoz Department of Biochemistry, Ministry of Health, Ankara Etlik City Hospital, Ankara, Turkey. From https://www.physiciansweekly.com/evaluation-of-psoriasis-patients-with-long-term-topical-corticosteroids-for-their-risk-of-developing-adrenal-insufficiency-cushings-syndrome-and-osteoporosis/

The Carling Adrenal Center, a worldwide destination for the surgical treatment of adrenal tumors, becomes the first center to offer the use of amniotic membrane during adrenal surgery which saves functional adrenal tissue in patients undergoing adrenal surgery. This novel technique enables more patients to have a partial adrenalectomy thereby preserving some normal adrenal physiology, potentially eliminating life-long adrenal hormone replacement. Preliminary clinical data from the Carling Adrenal Center suggest that the use of a human amniotic membrane allograph on the adrenal gland remnant following partial adrenal surgery leads to faster recovery of normal adrenal gland function. Rather than removing the entire adrenal gland—which has been standard of care for decades—a portion of the adrenal gland is able to be salvaged with amniotic membrane placed upon the remnant as a biologic covering. The preliminary data from an ongoing clinical trial shows this technique translates into fewer patients needing steroid hormone replacement following adrenal surgery, and if they do, it is for a significantly shorter period of time. "Sometimes it is possible, and preferable, to remove the adrenal tumor without removing the entire adrenal gland. This is called partial adrenal surgery and our study shows this technique is more successful when amniotic membrane is used," said Dr. Carling. He further stresses that "removing only part of the adrenal gland is a more advanced operation and is typically only performed by expert adrenal surgeons. The goal is to leave some normal adrenal tissue so that the patient can avoid adrenal insufficiency which requires a daily dose of several adrenal hormones and steroids. Partial adrenal surgery is especially beneficial for patients with pheochromocytoma, as well as Conn's and Cushing's syndrome. Avoiding daily steroids is life-changing for these patients so this is a major breakthrough." So how does it work? The increased viability of the adrenal gland remnant is presumed to be related to the release of growth factors known to be present in amniotic tissue which is in direct contact with the adrenal gland remnant as a covering. The results are improved rates of viable adrenal cortical tissues with faster regeneration and recovery to normal endocrine physiology by the adrenal cortical cells. These findings come during Adrenal Disease Awareness Month. Adrenal gland diseases cause many debilitating symptoms like chronic headaches, anxiety, depression, fatigue, brain fog, memory loss, dangerously high blood pressure, heart arrythmia, weight gain, tremors, and more, yet they are often misdiagnosed or improperly treated. Since many doctors are inexperienced in the workup of adrenal hormone problems and only see a handful of adrenal tumors during their careers, it is important for patients to know about the symptoms of adrenal tumor disease and request their doctor measure adrenal hormones. Adrenal.com is the leading resource for adrenal gland function, tumors and cancers, and an award-winning resource for adrenal gland surgery. The diagnosis and surgical treatment of all types of adrenal tumor types are discussed. Adrenal.com is edited by Dr. Tobias Carling who has performed more adrenal surgery than any other surgeon and has published some of the most important scientific studies of adrenal disease and adrenal surgery including the understanding of the pathogenesis of pheochromocytoma and adrenal tumors causing Conn's and Cushing's syndrome. Established by Dr. Tobias Carling in 2020, the Carling Adrenal Center located at the Hospital for Endocrine Surgery in Tampa FL, is the highest volume adrenal surgical center in the world. The Center now averages nearly 20 adrenal tumor patients every week. Dr Carling was the Director of Endocrine Surgery at Yale University prior to opening the Center in Tampa. At the new Hospital for Endocrine Surgery, Dr Carling joins the Norman Parathyroid Center, the Clayman Thyroid Center and the Scarless Thyroid Surgery Center as the highest volume endocrine surgery center in the world. About the Carling Adrenal Center: Founded by Dr. Tobias Carling, one of the world's leading experts in adrenal gland surgery, the Carling Adrenal Center is a worldwide destination for the surgical treatment of adrenal tumors. Dr. Carling spent nearly 20 years at Yale University, including 7 as the Chief of Endocrine Surgery before leaving in 2020 to open to Carling Adrenal Center, which performs more adrenal operations than any other hospital in the world. (813) 972-0000. More about partial adrenalectomy for adrenal tumors can be found at the Center's website www.adrenal.com. From https://www.streetinsider.com/PRNewswire/Novel+application+of+amniotic+membrane+saves+adrenal+tissue+in+patients+undergoing+adrenal+surgery/19915274.html

Richard M. Plotzker, MD Although adrenal insufficiency is uncommon, it is not so infrequent that we never encounter patients who have it. The sometimes-tricky presentations, along with the glorious responses to therapy, provide many endocrinologists with a blend of fascination and professional gratification. We think of the condition as a possibility more often than we find the real thing, doing cosyntropin tests that yield normal results for a variety of presentations, from critical illness to hyponatremia. We inherit people with panhypopituitarism and figure it out ourselves when an adult survivor of cancer who received central nervous system radiation years ago begins to gradually underperform. Despite our fascination with the condition and the frequent challenge of figuring out a clinical puzzle, few of us see more than a few dozen of these individuals, each unique in glucocorticoid and mineralocorticoid replacement requirements, and often without reliable laboratory tracking of our therapeutic judgments. These people have a way of generating calls to our offices, either from their own setbacks or emergency department (ED) doctors and surgeons who are skittish about elective outpatient surgery. But despite the central role of the endocrinologist in ongoing care, we have surprisingly little data on how these patients fare over time as they navigate the increasingly baffling maze of medical care of chronic diseases. Until now. A group in Alberta, Canada, performed a review of medical encounters among patients with primary or secondary adrenal insufficiency over a 5-year interval. An accumulation of data from a few central locations combined with computerized sorting capabilities has enabled better exploration of relatively rare conditions like adrenal insufficiency, which, when pooled, exposes common paths this condition takes. We sense from our phone calls that these people need emergency care, but the frequency of setbacks varies from never to a lot. Thus, large clinical databases have made health planning less laborious and more reliable but, as this study reveals, not exactly glitch-free. In Alberta, each person is assigned a personal identification number (PIN) that remains constant for all physician and pharmacy encounters. This allowed the research group to match diagnostic codes for primary and secondary adrenal insufficiency, and to capture individuals receiving multiple refills of glucocorticoids and mineralocorticoids. Because there were three active databases, however, some encounters appeared in multiple places, which the authors corrected to avoid overcounting. They found 2637 unique individuals seeking outpatient or ED care who had a coding diagnosis of primary or secondary adrenal insufficiency. An estimated prevalence of 839 per million Alberta residents exceeded the frequency of other national or regional estimates. The limitations of teasing out the realities of medical care from administrative codes may be best illustrated by the researchers' attempts to sort out how much medical care these people received and for what purpose. On average, the claims and encounter data show 2.2 ED visits and 17.8 outpatient visits per person with adrenal insufficiency. However, the diagnostic codes show that only a small fraction of these have an adrenal or pituitary diagnostic code for most episodes of medical care. The inclusion of physical therapy and radiologic procedures as outpatient visits makes it difficult to assess how the adrenal insufficiency affected other elements of health. The ED visits may be more revealing. Adrenal or pituitary codes rarely appeared as the primary diagnosis; however, among the top 10 were abdominal pain, volume depletion, electrolyte disorders, chest pain, and abscesses, often the sequelae of either adrenal insufficiency or its treatment. The authors determined who the patients were by their PINs and got some sense of what happened to them by tabulating the complications that resulted in emergency care. Unfortunately, the top 10 primary ED codes comprised only a small fraction of the 2699 different diagnostic codes submitted, so it remains unclear how much ED attention was directly or indirectly a consequence of hypoadrenalism, only that these patients seek emergency care considerably more frequently than others in Alberta. This analysis of administrative data confirms what most clinicians providing longitudinal care to these patients already suspected: they need more than average amounts of physician attention and they sometimes need rescue from crises unique to adrenal impairment. However, as we depend more and more on large amounts of aggregated data to isolate specific conditions and assess the treatment history, this study also exposes some of the limitations of how we code, classify, sort, and retrieve these patient encounters. Even data that should be binary, such as you went to the doctor or you didn't, have a way of slipping through the cracks, as not all medical visits in Alberta needed to be centrally reported. As much as physicians, myself among them, dislike our secondary roles as coding clerks, the defaults permitted, including "follow-up visit," often give no medical information yet are sufficient for payment. Having 2699 unique ED visit diagnoses impedes sorting them into the manageable categories we depend on as clinicians to understand diseases and as planners to assess public needs. Even things as basic as why the adrenals or pituitary failed, whether by immune, surgical, trauma, or medication (including opiate use) causes, are not adequately captured for later assessment. Big Data and the ability to access it has expanded our capabilities but, as this study demonstrates, more can be done to make it reveal to clinicians and planners what we most need to know. How many people with other uncommon but threatening diseases still drift in and out of our exam rooms and EDs, controlled by the appropriate specialist but shared with many others? It looks like we can figure out from administrative data more than we knew before but less than we would seek to find out. From https://www.medscape.com/viewarticle/971618

Diurnal’s pioneering phase 2 study evaluates modified-release hydrocortisone for adrenal insufficiency Diurnal has announced that the first patient has been dosed in its phase 2 European clinical trial of modified-release hydrocortisone. It is treating people with adrenal insufficiency (AI), also known as Addison’s disease, while the trial also represents a significant marketing opportunity for the company across Europe and throughout the UK. The CHAMPAIN phase 2 study aims to evaluate the efficacy, safety and tolerability of modified-release hydrocortisone versus Plenadren in AI. It is anticipated that it will take six months to reach completion. Modified-release hydrocortisone is a preparation of hydrocortisone that has been specifically designed for patients with diseases of cortisol deficiency–such as AI–and additionally for congenital adrenal hyperplasia (CAH). It is approved for the latter disease in Europe and the UK under the commercial name Efmody. AI is a long-term endocrine disorder, which affects approximately 298,000 patients in Europe and the UK. It is caused by inadequate production of steroid hormones in the cortex of the adrenal glands. AI can result in severe fatigue and–if left untreated–adrenal crisis may be life-threatening. Martin Whitaker, CEO of Diurnal, commented: “We are pleased to have dosed our first patient in the CHAMPAIN phase 2 study for adults with AI as we seek to explore the efficacy of modified-release hydrocortisone in diseases of cortisol deficiency. “There is a high unmet need for adult patients suffering from AI across Europe with current treatment options leading to poor quality of life. We believe modified-release hydrocortisone has the potential to replicate the physiological overnight rise of cortisol in these patients and we look forward to the data readout from the CHAMPAIN study in H2 2022,” he added. From https://www.pharmatimes.com/news/first_adrenal_insufficiency_patient_dosed_in_phase_ii_study_1387551

Cushing’s disease is a progressive pituitary disorder in which there is an excess of cortisol in the body. While the disease can be treated surgically, this option is not possible for all patients. This is one of the approved medications that assist in controlling cortisol levels in people with Cushing’s disease. sturisa was approved in 2020 to treat adults with Cushing’s disease for whom pituitary surgery is ineffective or not an option. The oral medication works by inhibiting an enzyme called 11-beta-hydroxylase, which is involved in cortisol production. Isturisa, also known as osilodrostat or LCI699, is an approved treatment originally developed by Novartis, but now acquired by Recordati to treat people with Cushing’s disease, a condition in which a pituitary tumor causes the body to produce excessive levels of the stress hormone cortisol. In 2020, the U.S. Food and Drug Administration (FDA) approved Isturisa to treat adults with Cushing’s disease for whom pituitary surgery was not an option, or ineffective. Earlier that same year, the European Commission (EC) approved Isturisa to treat people with endogenous Cushing’s syndrome. The medication also was approved for the same indication in Japan in 2021. How does Isturisa work? Isturisa is an oral medicine that inhibits an enzyme called 11-beta-hydroxylase, which is involved in cortisol production. Blocking the activity of this enzyme prevents excessive cortisol production, normalizing the levels of the hormone in the body and easing the symptoms of Cushing’s disease. Isturisa in clinical trials A Phase 2 clinical trial (NCT01331239) investigated the safety and efficacy of Isturisa as a Cushing’s disease treatment. The trial that concluded in October 2019 initially was named LINC-1, but, through a study protocol amendment, patients who completed the study could continue into a second phase called LINC-2. The company published findings that covered both patient groups in the journal Pituitary. Data showed that Isturisa reduced cortisol levels in the urine of all patients by week 22. Urine cortisol levels reached and remained within a normal range in 79% of the patients by then. Common adverse effects included nausea, diarrhea, lack of energy, and adrenal insufficiency — a condition in which the adrenal glands are unable to produce enough hormones. A Phase 3 clinical trial (NCT02180217) called LINC-3 also assessed the safety and efficacy of Isturisa in 137 patients with Cushing’s disease (77% female, median age 40 years). Participants were given Isturisa for 26 weeks, with efficacy-based dose adjustments during the first 12 weeks. Then, the 71 participants with a complete response (those whose urine cortisol levels were within normal limits) at week 26 and who did not require a dose increase after week 12, were assigned randomly to either continue treatment with Isturisa or switch to a placebo. After this 34-week period, 86% of Isturisa-treated patients had normal urinary cortisol levels, as compared to 29% of participants given placebo. All participants then were given Isturisa for an additional 12 weeks. At the end of the 48-week study, 66% of participants had normal urine cortisol levels. Results from LINC-3 formed the basis for regulatory approvals of Isturisa. Common adverse side effects in the trial included nausea, headache, fatigue, and adrenal insufficiency. A multi-center, randomized, double-blind, placebo-controlled Phase 3 trial (NCT02697734) called LINC-4 further confirmed the safety and efficacy of Isturisa as a Cushing’s disease therapy. During the trial, patients received Isturisa or a placebo through a 12-week period followed by treatment with Isturisa until week 48. Top-line results showed that 77% of patients on Isturisa experienced a complete response after the 12-week randomized period, as compared to 8% of those on placebo. No new safety data were noted. A roll-over, worldwide Phase 2 study (NCT03606408) is recruiting patients who have successfully completed any of the previous clinical trials. Patients can continue to take the dosage they received during the initial trial. The aim of this study is to assess the long-term effects of Isturisa for up to five years.

Authors Nisticò D , Bossini B, Benvenuto S, Pellegrin MC, Tornese G Received 29 October 2021 Accepted for publication 28 December 2021 Published 11 January 2022 Volume 2022:18 Pages 47—60 DOI https://doi.org/10.2147/TCRM.S294065 Checked for plagiarism Yes Review by Single anonymous peer review Peer reviewer comments 2 Editor who approved publication: Professor Garry Walsh Download Article [PDF] Daniela Nisticò,1 Benedetta Bossini,1 Simone Benvenuto,1 Maria Chiara Pellegrin,1 Gianluca Tornese2 1University of Trieste, Trieste, Italy; 2Department of Pediatrics, Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy Correspondence: Gianluca Tornese Department of Pediatrics, Institute for Maternal and Child Health IRCCS Burlo Garofolo, Via dell’Istria 65/1, Trieste, 34137, Italy Tel +39 040 3785470 Email gianluca.tornese@burlo.trieste.it Abstract: Adrenal insufficiency is an insidious diagnosis that can be initially misdiagnosed as other life-threatening endocrine conditions, as well as sepsis, metabolic disorders, or cardiovascular disease. In newborns, cortisol deficiency causes delayed bile acid synthesis and transport maturation, determining prolonged cholestatic jaundice. Subclinical adrenal insufficiency is a particular challenge for a pediatric endocrinologist, representing the preclinical stage of acute adrenal insufficiency. Although often included in the extensive work-up of an unwell child, a single cortisol value is usually difficult to interpret; therefore, in most cases, a dynamic test is required for diagnosis to assess the hypothalamic-pituitary-adrenal axis. Stimulation tests using corticotropin analogs are recommended as first-line for diagnosis. All patients with adrenal insufficiency need long-term glucocorticoid replacement therapy, and oral hydrocortisone is the first-choice replacement treatment in pediatric. However, children that experience low cortisol concentrations and symptoms of cortisol insufficiency can take advantage using a modified release hydrocortisone formulation. The acute adrenal crisis is a life-threatening condition in all ages, treatment is effective if administered promptly, and it must not be delayed for any reason. Keywords: adrenal gland, primary adrenal insufficiency, central adrenal insufficiency, Addison disease, children, adrenal crisis, hydrocortisone Introduction Primary adrenal insufficiency (PAI) is a condition resulting from impaired steroid synthesis, adrenal destruction, or abnormal gland development affecting the adrenal cortex.1 Acquired primary adrenal insufficiency is termed Addison disease. Central adrenal insufficiency (CAI) is caused by an impaired production or release of adrenocorticotropic hormone (ACTH). It can originate either from a pituitary disease (secondary adrenal insufficiency) or arise from an impaired release of corticotropin-releasing hormone (CRH) from the hypothalamus (tertiary adrenal insufficiency). An underlying genetic cause should be investigated in every case of adrenal insufficiency (AI) presenting in the neonatal period or first few months of life, although AI is relatively rare at this age (1:5.000–10.000).2 Physiology of the Adrenal Gland The adrenal cortex consists of three zones: the zona glomerulosa, the zona fasciculata, and the zona reticularis, responsible for aldosterone, cortisol, and androgens synthesis, respectively.3 Aldosterone production is under the control of the renin-angiotensin system, while cortisol is regulated by the hypothalamic-pituitary-adrenal axis (HPA).4 This explains why patients affected by CAI only manifest glucocorticoid deficiency while mineralocorticoid function is spared. CRH is secreted from the hypothalamic paraventricular nucleus into the hypophyseal-portal venous system in response to light, stress, and other inputs. It binds to a specific cell-surface receptor, the melanocortin 2 receptor, stimulating the release of preformed ACTH and the de novo transcription of the precursor molecule pro-opiomelanocortin (POMC). ACTH is derived from the cleavage of POMC by proprotein convertase-1.5–9 ACTH binds to steroidogenic cells of both the zona fasciculata and reticularis, activating adrenal steroidogenesis. It also has a trophic effect on adrenal tissue; therefore, ACTH deficiency determines adrenocortical atrophy and decreases the capacity to secrete glucocorticoids. Circulating cortisol is 75% bound to corticosteroid-binding protein, 15% to albumin, and 10% free. The endogenous production rate is estimated between 6 and 10 mg/m2/day, even though it depends on age, gender, and pubertal development. Glucocorticoids have multiple effects: they regulate immune, circulatory, and renal function, influence growth, development, energy and bone metabolism, and central nervous system activity. Several studies reported higher cortisol plasma concentrations in girls than in boys and younger children.3,4,8 Cortisol secretion follows a circadian and ultradian rhythm according to varying amplitudes of ACTH pulses. Pulses of ACTH and cortisol occur every 30–120 minutes, are highest at about the time of waking, and decline throughout the day, reaching a nadir overnight.3,8,9 This pattern can change in the presence of serious illness, major surgery, and sleep deprivation. During stressful situations, glucocorticoid secretion can increase up to 10-fold to enhance survival through increased cardiac contractility and cardiac output, sensitivity to catecholamines, work capacity of the skeletal muscles, and availability of energy stores.3 The interaction between the hypothalamus and the two endocrine glands is essential to maintain plasma cortisol homeostasis (Figure 1). Cortisol exerts double-negative feedback on the HPA axis. It acts on the hypothalamus and the corticotrophin cells of the anterior pituitary, reducing CRH and ACTH synthesis and release.6 ACTH inhibits its secretion through a feedback effect mediated at the level of the hypothalamus.3 Increased androgen production occurs in the case of cortisol biosynthesis enzymatic deficits. Figure 1 The hypothalamic–pituitary–adrenal axis. Primary Adrenal Insufficiency PAI affects 10–15 per 100,000 individuals and recognizes different classes of genetic causes (Table 1). Congenital adrenal hyperplasia (CAH) is the main cause of PAI in the neonatal period, being included among the disorders of steroidogenesis secondary to deficits in enzymes. It has an autosomal recessive transmission.1,10,11 The estimated incidence ranges between 1:10,000 and 1:20,000 births. CAH phenotype depends on disease-causing mutations and residual enzyme activity. 21-hydroxylase deficiency (21OHD) accounts for more than 90% of cases, 21-hydroxylase converts cortisol and aldosterone precursors, respectively 17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol and progesterone to deoxycortisone. Less frequent forms of CAH include 11 β -hydroxylase deficiency (11BOHD, 8% of cases), 17α-hydroxylase/17–20 lyase deficiency (17OHD), 3β-hydroxysteroid dehydrogenase deficiency (3BHDS), P450 oxidoreductase deficiency (PORD).12 Steroidogenesis may also be impaired by steroidogenic acute regulatory (StAR) protein deficiency, which is involved in cholesterol transport into mitochondria, or P450 cytochrome side-chain cleavage (P450scc) deficiency, that converts cholesterol into pregnenolone.12,13 Of these conditions, 21OHD and 11BOHD only affect adrenal steroidogenesis, whereas the other deficits also impact gonadal steroid production. In classic CAH, enzyme activity can be absent (salt-wasting form) or low (1–2% enzyme activity, simple virilizing form). The salt-wasting form is the most severe and affects 75% of patients with classic 21OHD.1,10,12,14 Non-classic CAH (NCCAH) is more prevalent than the classic form, in which there is 20–50% of residual enzymatic activity. Two-thirds of NCCAH individuals are compound heterozygotes with different CYP21A2 mutations in two different alleles (classic severe mutation plus mild mutation in two different alleles or homozygous with two mild mutations). Notably, 70% of NCCAH patients carry the point mutation Val281Leu. Table 1 Causes of Primary Adrenal Insufficiency (PAI) Central Adrenal Insufficiency CAI incidence is estimated between 150 and 280 per million, and it should be suspected when mineralocorticoid function is preserved. When, rarely, isolated is due to iatrogenic HPA suppression secondary to prolonged glucocorticoid therapy or the removal of an ACTH- or cortisol-producing tumor (Cushing syndrome).15 Defects in POMC,16 characterized by red or auburn-haired children, pale skin (due to melanocyte stimulating hormone [MSH] - deficiency) and hyperphagia later in life, and in transcription factor TPIT,17 which regulates POMC synthesis in corticotrope cells, are the two leading genetic causes of isolated ACTH deficiency (Table 2). Mainly, it occurs as part of complex syndromes in which a combined multiple pituitary hormone deficiency (CMPD) is associated with craniofacial and midline defects, such as Prader-Willi syndrome, CHARGE syndrome, Pallister-Hall syndrome (anatomical pituitary abnormalities), white vanishing matter disease (progressive leukoencephalopathy).5 Individuals with an isolated pituitary deficiency, usually a growth hormone deficiency (GHD), may develop multiple pituitary hormone deficiencies over the years. Therefore, excluding a latent CAI at GHD onset and periodically monitoring of HPA axis is of utmost importance. Notably, cortisol reduction secondary to an increased basal metabolism when starting GHD or thyroxin substitutive therapy may unleash a misdiagnosed CAI. CMPD can be caused by several defective genes, such as GLI1, LHX3, LHX4, SOX2, SOX3, HESX1: in such cases, hypoglycemia or small penis with undescended testes may respectively suggest concomitant GH and gonadotropins deficits.18 Table 2 Causes of Central Adrenal Insufficiency (CAI) Clinical Manifestations of Adrenal Insufficiency AI is an insidious diagnosis presenting non-specific symptoms and may be mistaken with other life-threatening endocrine conditions (septic shock unresponsive to inotropes or recurrent sepsis, acute surgical abdomen).1,19 Children can be initially misdiagnosed as having sepsis, metabolic disorders, or cardiovascular disease, highlighting the need to consider adrenal dysfunction as a differential diagnosis for an unwell or deteriorating infant. With age-related items, clinical features depend on the type of AI (primary or central) and could manifest in an acute or chronic setting (Table 3). Table 3 Features of Isolated Adrenal Insufficiency in Pediatric Age Clinical signs of PAI are based on the deficiency of both gluco- and mineralocorticoids. Signs due to glucocorticoid deficiency are weakness, anorexia, and weight loss. Hypoglycemia with normal or low insulin levels is frequent and often severe in the pediatric population. Mineralocorticoid deficiency contributes to hyponatremia, hyperkalemia, acidosis, tachycardia, hypotension, and salt craving. The lack of glucocorticoid-negative feedback is responsible for the elevated ACTH levels. The high levels of ACTH and other POMC peptides, including the various forms of MSH, cause melanin hypersecretion, stimulating mucosal and cutaneous hyperpigmentation. Searching for an increased pigmentation may represent an essential diagnostic tool since all the other symptoms of PAI are non-specific. However, hyperpigmentation is variable, dependent on ethnic origin, and more prominent in skin exposed to sun and in extension surface of knees, elbows, and knuckles.15 In autoimmune PAI, vitiligo may be associated with hyperpigmentation. In the classic CAH simple virilizing form, salt wasting is absent due to the presence of aldosterone production. In males, diagnosis typically occurs between 3 and 4 years of age with pubarche, accelerated growth velocity, and advanced bone age at presentation.1,10,12,14 NCCAH may occur in late childhood with signs of hyperandrogenism (premature pubarche, acne, adult apocrine odor, advanced bone age) or be asymptomatic. In adolescents and adult women, conditions of androgen excess (acne, oligomenorrhea, hirsutism) may underlie an NCCAH.20,21 The clinical presentation of CAI may be more complex when caused by an underlying central nervous system disease or by CMPD. In the case of a pituitary or hypothalamic tumor, patients may present headache, vomiting, visual disturbances, short stature, delayed or precocious puberty. In the case of CMPD, manifestations vary considerably and depend on the number and severity of the associated hormonal deficiencies. In CAI, aldosterone production is spared, which means that serum electrolytes are usually normal. However, cortisol contributes to regulating free water excretion, so patients with CAI are at risk for dilutional hyponatremia, with normal serum potassium levels. Since adrenal androgen secretion is under the control of ACTH, girls with ACTH deficiency may present light pubic hair. Patients with partial and isolated ACTH defects can be “asymptomatic”, and adrenal crisis appears during stress or in case of major illness (high fever, surgery). The acute adrenal crisis is a life-threatening condition in all ages. Patients present with profound malaise, fatigue, nausea, vomiting, abdominal or flank pain, muscle pain or cramps, and dehydration, which lead to hypotension, shock, and metabolic acidosis. Hyponatremia and hyperkalemia are less common in CAI than in PAI, but possible in acute AI. Severe hypoglycemia causes weakness, pallor, sweatiness, and impaired cognitive function, including confusion, loss of consciousness, and coma. Immediate treatment is required (see below). Children and adolescents affected by autoimmune primary adrenal insufficiency develop a chronic AI, with an insidious onset and slow progress to an acute adrenal crisis over months or even years. Initial symptoms are decreased appetite, anorexia, nausea, abdominal pain, unintentional weight loss, lethargy, headache, weakness, and fatigue, with prominent pain in the joints and muscles. Due to salt loss through the urine and the subsequent reduction in blood volume, blood pressure decreases, and orthostatic hypotension develops together with salt craving. An increased risk of infection in AI patients is reported only in those exposed to glucocorticoids. However, in APECED (Autoimmune Polyendocrinopathy-Candidiasis- Ectodermal-Dystrophy) patients, there is an increased risk of candidiasis and splenic atrophy increases the likelihood for severe infections. In neonates, AI classically presents with failure to thrive and hypoglycemia, commonly severe and associated with seizures. The condition can be life-threatening and, if misdiagnosed, may result in coma and unexplained neonatal death. In newborns, cortisol deficiency causes delayed bile acid synthesis and transport maturation, determining prolonged cholestatic jaundice with persistently raised serum liver enzymes. The cholestasis can be resolved within ten weeks of correct treatment. StAR deficiency and P450scc cause salt-losing AI with female external genitalia in genetically male neonates.22 In the classic CAH salt-wasting form, the mineralocorticoid deficiency presents with the adrenal crisis at 10–20 days of life. Females show atypical genitalia with signs of virilization (clitoral enlargement, labial fusion, urogenital sinus), whereas males have normal-appearing genitalia, except for subtle signs as scrotal hyperpigmentation and enlarged phallus.1,10,12,14 Neonates with CMPD may display non-specific symptoms including hypoglycemia, lethargy, apnea, poor feeding, jaundice, seizures, hyponatremia without hyperkalemia, temperature and hemodynamic instability, recurrent sepsis, and poor weight gain. A male with hypogonadism may have undescended testes and micropenis. Infants with optic nerve hypoplasia or agenesis of the corpus callosum may present with nystagmus. Furthermore, infants with midline defects may have various neuro-psychological problems or sensorineural deafness. Genetic Disorders and Other Conditions at Increased Risk for Adrenal Insufficiency Among the cholesterol biosynthesis disorder, there is the Smith-Lemli-Opitz syndrome,23 where microcephaly, micrognathia, low-set posteriorly rotated ears, syndactyly of the second and third toes, and atypical genital may, although rarely, combine with AI; this autosomal recessive disorder is due to defective 7-dehydrocholesterol reductase so that elevated 7-dehydrocholesterol is diagnostic. In lysosomal acid lipase A deficiency,24 AI is due to calcification of the adrenal gland as a result of the accumulation of esterified lipids; in infantile form, that is Wolman disease, hepatosplenomegaly with hepatic fibrosis and malabsorption lead to death in the first year of life, if not treated with enzyme replacement therapy such as sebelipase alfa.25 Adrenal development may be impaired in X-linked congenital adrenal hypoplasia (AHC),13,26 a disorder caused by defective nuclear receptor DAX-1, presenting with salt-losing AI in infancy in approximately half of the cases, but also later in childhood or adolescence with two other key features such as hypogonadotropic hypogonadism and impaired spermatogenesis. Two syndromes combine adrenal hypoplasia with intrauterine growth restriction (IUGR): in IMAGe syndrome,27 caused by CDKN1C gain-of-function mutations, IUGR and AI present with metaphyseal dysplasia and genitourinary anomalies; MIRAGE syndrome28 is instead characterized by myelodysplasia, infections, genital abnormalities, and enteropathy, as a result of gain-of-function mutations in SAMD9, with elevated mortality rates. In some other conditions, AI is due to ACTH resistance. Familial Glucocorticoid Deficiency type 1 (FGD1)13,29 and type 2 (FGD2)30 derive from defective ACTH receptor (MC2R) or its accessory protein MRAP, and both present with early glucocorticoid insufficiency (hypoglycemia, prolonged jaundice) and pronounced hyperpigmentation; there is usually an excellent response to cortisol replacement therapy, even though ACTH levels remain elevated. In Allgrove or Triple-A Syndrome,13,31 defective Aladin protein (an acronym for alacrimia-achalasia-adrenal insufficiency) leads to primary ACTH-resistant adrenal insufficiency with achalasia and absent lacrimation, often combined with neurological dysfunction, either peripheral, central, or autonomic. It is an autosome recessive condition, phenotypically characterized by microcephaly, short stature, and skin hyperpigmentation.32,33 Among metabolic disorders associated with AI, Sphingosine-1-Phosphate Lyase (SGPL1) Deficiency34 is a sphingolipidosis with various features such as steroid-resistant nephrotic syndrome, primary hypothyroidism, undescended testes, neurological impairment, lymphopenia, ichthyosis; interestingly, in cases where nephrotic syndrome develops before AI, the latter may be masked by glucocorticoid treatment. Adrenoleukodystrophy (ALD)35–37 is an X-linked recessive proximal disorder of beta-oxidation due to defective ABCD1, where the accumulation of very-long-chain fatty acids (VLCFA) affects in almost all cases adrenal gland among other tissues. Most patients present with progressive neurological impairment, but in some, AI is the only (approximately 10%) or first manifestation, so that every unexplained AI in boys should receive plasma VLCFA evaluation to diagnose ALD and reduce cerebral involvement through a low VLCFAs diet (Lorenzo’s oil) and allogeneic bone marrow transplantation. Early disease-modifying therapies have been developed. Gene therapy adds new functional copies of the ABCD1 gene in hematopoietic stem cells through a lentiviral vector reinfusing the modified cells in the patient’s bloodstream. Recent trials show encouraging results.38 In Zellweger syndrome, caused by mutations in peroxin genes (PEX), peroxisomes are absent, and disease presentation occurs in the neonatal period, with low survival rates after the first year of life. Finally, mitochondrial disorders have been described to occasionally develop AI: Pearson syndrome (sideroblastic anemia, pancreatic dysfunction), MELAS syndrome (encephalopathy with stroke-like episodes), and Kearns-Sayre syndrome (external ophthalmoplegia, heart block, retinal pigmentary changes) belong to this class.39 Autoimmune pathogenesis (Addison disease) accounts for approximately 15% of cases of primary AI in children, in contrast with adolescents and adults where it is the most common mechanism; half of these children present other glands involvement as well. Two syndromes recognize specific combinations: in Autoimmune Polyglandular Syndrome Type 1 (APS1, or APECED)40 defective autoimmune regulator AIRE causes AI, hypoparathyroidism, hypogonadism, malabsorption, chronic mucocutaneous candidiasis; APS2 usually present later in life (third-fourth decades) with AI, thyroiditis, and type 1 diabetes mellitus (T1DM). Antibodies against 21-hydroxylase enzyme are the hallmark of APS. Apart from a genetic disorder, a strong link between autoimmune conditions and autoimmune primary AI has been established, with more than 50% of patients with the latter also having one or more other autoimmune endocrine disorders; on the other hand, only a few patients with T1DM or autoimmune thyroiditis or Graves’ disease develop AI. As an example, in a study of 629 patients with T1DM, only 11 (1.7%) presented 21-hydroxylase autoantibodies, with three of them having AI.41 Nevertheless, these patients are to be considered at increased risk for a condition that is potentially fatal yet easy to diagnose and treat; that is why it is reasonable to screen for autoimmune AI at least patients with T1DM, significantly if associated with DQ8 HLA combined with DRB*0404 HLA alleles, who have been observed to develop AI in 80% of cases if also 21-hydroxylase autoantibodies positive.42 Regarding immunological disruption, the link with celiac disease is instead well established: celiac patients have an 11-fold increased risk for AI, while in a study, 6 of 76 patients with AI had celiac disease, so that mutual evaluation should be granted in these patients.43,44 Subclinical Adrenal Insufficiency Subclinical AI is a particularly insidious challenge for a pediatric endocrinologist. It represents the preclinical stage of Addison disease when 21-hydroxylase autoantibodies are already detectable but still absent from evident symptoms. 21-hydroxylase autoantibodies positivity carries a greater risk to develop overt AI in children than in adults: in a study, estimated risk was 100% in children versus 32% in adults on a medium six-year period of follow-up.45 As the adrenal crisis is a potentially lethal condition, it is essential to recognize and adequately manage subclinical AI. Although asymptomatic by definition, subclinical AI may present with non-specific symptoms such as fatigue, lethargy, gastrointestinal symptoms (nausea, vomiting, diarrhea, constipation), hypotension; physical or psychosocial stresses may sometimes exacerbate these symptoms. When symptoms lack, subclinical AI may be identified thanks to the co-occurrence with other autoimmune endocrinopathies.46 21-hydroxylase autoantibodies titer is considered a marker of autoimmune activity and correlates with disease progression.47 Other reported risk factors for the disease evolution include young age, male sex, hypoparathyroidism or candidiasis coexistence, increased renin activity, or an altered synacthen test with normal baseline cortisol and ACTH.45 ACTH elevation has been reported as the best predictor of progression to the clinical stage in 2 years (94% sensitivity and 78% specificity).48 Management of patients with subclinical AI should include serum cortisol, ACTH, renin measurement, and a synacthen test. If normal, cortisol and ACTH should be repeated in 12–18 months, while synacthen test every two years. After synacthen test results are subnormal, cortisol and ACTH should be assessed every 6–9 months if ACTH remains in range or every six months if ACTH becomes elevated.49 In the latter case, therapy with hydrocortisone should be started.19 This strategy will prevent acute crises and possibly improve the quality of life in patients reporting non-specific symptoms. Diagnosis Laboratory evaluation of a stable patient with suspected AI should start with combined early morning (between 6 and 8 AM) serum cortisol and ACTH measurements (Figure 2). Figure 2 Diagnostic algorithm for adrenal insufficiency. Although often included in the extensive work-up of an unwell child, a single cortisol value is usually challenging to interpret: circadian cortisol rhythm is highly variable and morning peak is unpredictable; morning cortisol levels in children with diagnosed AI may range up to 706 nmol/L (97th percentile); several factors, such as exogenous estrogens, may alter total serum cortisol values by influencing the free cortisol to cortisol binding globulin or albumin-bound cortisol ratio.7 Significant variability is also observed depending on the specific type of cortisol assay; therefore, it is recommended to check the reference ranges with the laboratory. Mass spectrometry analysis and the new platform methods (Roche Diagnostics Elecsys Cortisol II)50 have more specificity because it detects lower cortisol concentrations than standard immunoassays.15 Low serum cortisol with normal or low ACTH levels is compatible with CAI. In such cases, morning serum cortisol levels below 3 µg/dL (83 nmol/L) best predict AI, while greater than 13 µg/dL (365 nmol/L) values tend to exclude it.51 This is why in most cases, a dynamic test is required for diagnosis and has been introduced to assess the hypothalamic-pituitary-adrenal (HPA) axis in case of intermediate values.5 The insulin tolerance test (ITT) is considered the gold standard for CAI diagnosis as hypoglycemia results in an excellent HPA axis activation; moreover, it allows simultaneous growth hormone evaluation in patients with suspected CPHD. Serum cortisol is measured at baseline and 15, 30, 45, 60, 90, and 120 minutes after intravenous administration of 0.1 UI/Kg regular insulin; the test is valid if serum glucose is reduced by 50% or below 2.2 mmol/L (40 mg/dL).52 CAI is diagnosed for a <20 µg/dL (550 nmol/L) cortisol value at its peak.15 Hypoglycemic seizures and hypokalemia (due to glucose infusion) are the main risks of this test so that it is contraindicated in case of a history of seizures or cardiovascular disease. Glucagon stimulation test (GST, 30 µg/Kg up to 1 mg i.m. glucagon with cortisol measurements every 30 min for 180 min) allows both CAI and growth hormone deficiency evaluation as well but is characterized by frequent gastrointestinal side effects and poor specificity.8 Metyrapone is an 11-hydroxylase inhibitor, thereby decreasing cortisol synthesis and removing its negative feedback on ACTH release. Overnight metyrapone test is based on oral administration of 30 mg/Kg metyrapone at midnight, and 11-deoxycortisol measurement on the following morning: in case of CAI, its level will not reach 7 µg/dL (200 nmol/L). This test may, however, induce an adrenal crisis so that it is rarely performed. Given their safety profile and accuracy, corticotropin analogs such as tetracosactrin (Synacthen®) or cosyntropin (Cortrosyn®) are recommended as first-line stimulation tests. Nevertheless, false-negative results are probable in the case of recent or moderate ACTH deficiency, which would not have induced adrenal atrophy. The standard dose short synacthen test (SDSST) is based on a 250 µg Synacthen vial administration with serum cortisol measurement at baseline and 30 and 60 minutes after. CAI is diagnosed if peak cortisol level is <16 µg/dL (440 nmol/L), or excluded if >39 µg/dL (1076 nmol/L). However, the cut-offs for both the new platform immunoassay and mass spectrometry serum cortisol assays are 13.5 to 14.9 mcg/dL (373 to 412 nmol/L).53 The 250 µg Synacthen dose is considered a supraphysiological stimulus since it is 500 times greater than the minimum ACTH dose reported to induce a maximal cortisol response (500 ng/1.73 m2). The low dose short synacthen test (LDSST) has been introduced as a more sensitive first-line test in children greater than two years.54 The recommended dose is 1 µg55, which is contained in 1 mL of the solution obtained by diluting a 250 µg vial into 250 mL saline. Serum cortisol level is then measured at baseline and after 30 minutes, resulting in diagnose of CAI if <16 µg/dL (440 nmol/L), otherwise ruling it out if >22 µg/dL (660 nmol/L). Using these thresholds, LDSST is more precise than SDSST in children, with an area under the ROC curve of 0.99 (95% CI 0.98–1.00).56 LDSST has not been validated in acutely ill patients, pituitary acute disorders or surgery or radiation therapy, and impaired sleep-wake cycle. Patients with an indeterminate LDSST result should be furtherly studied with ITT or metyrapone test. Finally, the CRH test is based on 1 µg/Kg human CRH (Ferring®) administration and may differentiate secondary from tertiary AI, but its thresholds are still not precisely defined.57 Once CAI is diagnosed, other pituitary hormones should be assessed (prolactin, IGF1, LH, FSH, fT4, TSH), and an MRI of the pituitary region should be performed to exclude neoplastic or infiltrative processes. Primary adrenal insufficiency (PAI) should be suspected in case of low serum cortisol with elevated ACTH levels. When hypocortisolemia has been confirmed, ACTH levels >66 pmol/L or greater than twice the upper limit best predict PAI. Nevertheless, a confirmatory dynamic test is always recommended for diagnosis.19 Given the comparable accuracy between standard and low dose SST reported in these patients, SDSST is recommended as the most feasible test.58 Moreover, suspected PAI cases should receive plasma renin activity or direct renin and aldosterone assessment to evaluate mineralocorticoid deficiency. Etiologic work-up of confirmed PAI should start from 21-hydroxylase antibodies assessment: if positive, differential diagnosis will include Addison disease and APS1 or APS2. Adrenal autoantibody negative patients should instead be screened for CAH by measuring 17-hydroxyprogesterone, ALD (if young male) by assessing VLCFA, and tuberculosis if endemic; adrenal glands imaging will complete the work-up in order to exclude infection, hemorrhage, or tumor.6 While universal newborn screening is already implemented for CAH in many countries, allowing a timely replacement therapy, basal salivary cortisol, and salivary cortisone measurements could improve CAI screening in the future: this technique is simple, cost-effective, and independent of binding proteins.15 Treatment All patients with adrenal insufficiency need long-term glucocorticoid replacement therapy. Individuals with PAI also require mineralocorticoids replacement, together with salt intake as required (Table 4). Otherwise, guidelines do not recommend androgen replacement.5,9,19 Table 4 Management of Adrenal Insufficiency (AI) Oral hydrocortisone is the first-choice replacement treatment in children due to its short half-life, rapid peak in plasma concentration, lower potency, and fewer adverse effects than prednisolone and dexamethasone.5,8 Based on endogenous production, dosing replacement regimens vary from 7.5 to 15 mg/m2/day, divided into two, three, or four doses.19 The first and largest dose should be taken at awakening, the next in the early afternoon to avoid sleep disturbances. Small and frequent dosing mimic the physiological rhythm of cortisol secretion, but high peak cortisol levels after drug assumption and prolonged periods of hypocortisolemia between doses are described.8,9 Some children experience low cortisol concentrations and symptoms of cortisol insufficiency (eg, fatigue, nausea, headache) despite modifications in dosing. This cohort of patients can take advantage of using a modified-release hydrocortisone formulation, such as Chronocort® and Plenadren®. Plenadren®, approved for adults, consists of a coating of hydrocortisone released rapidly, followed by a slow release of hydrocortisone from the tablet center. It is available as 5 and 20 mg tablets. Park et al demonstrate smoother cortisol profiles and normal growth and weight gain patterns using Plenadren® in children.59 In a few cases, the continuous subcutaneous infusion of hydrocortisone using insulin pump technology proved to be a feasible, well-tolerated and safe option for selected patients with poor response to conventional therapy.19 Monitoring glucocorticoid therapy is based on growth, weight gain, and well-being. Cortisol measurements are usually not useful, apart from cases when a discrepancy between daily doses and patient symptoms exists.15 The concomitant use of hydrocortisone and CYP3A4 inducers, such as Rifampicin, Phenytoin, Carbamazepine, requires an increased dose of glucocorticoids. Conversely, the inhibition of CYP3A4 impairs hydrocortisone metabolism.5 Mineralocorticoid replacement is unnecessary if the patient has a normal renin-angiotensin-aldosterone axis and, hence, normal aldosterone secretion, as well as in CAI. By contrast, patients with PAI and confirmed aldosterone deficiency need fludrocortisone at the dosage of 0.1–0.2 mg/day when given together with hydrocortisone, which has some mineralocorticoid activity. When using other synthetic glucocorticoids for replacement, higher fludrocortisone doses may be needed. Infants younger than one year should also be supplemented with sodium chloride due to their relatively low dietary sodium intake and relative renal resistance to mineralocorticoids. The dose is approximately 1 gram (17 mEq) daily.19 Surgery and anesthesia increase the glucocorticoid requirement during the pre-, intra-, and post-operative periods (Table 4). All children with AI should receive an intravenous dose of hydrocortisone at induction (2 mg/kg for minor or major surgery under general anesthesia). For minor procedures or sedation, the child should receive a double morning dose of hydrocortisone orally.60 Adrenal crisis is a life-threatening condition, treatment is effective if administered promptly, and it must not be delayed for any reason. Hydrocortisone should be administered as soon as possible with an intravenous bolus of 4 mg/kg followed by a continuous infusion of 2 mg/kg/day until stabilization. In the alternative, it can be administered as a bolus every four hours intravenous or intramuscular. In difficult peripheral venous access, the intramuscular route must be used as the first choice. In order to counteract hypotension, a bolus of normal saline 0.9% should be given at a dose of 20 mL/kg; it can repeat up to a total of 60 mL/kg within one hour for shock. If there is hypoglycemia, 10% dextrose at a 5 mL/kg dose should be administered.5,19,61,62 Patients with AI require additional doses of glucocorticoids in case of physiologic stress such as illness or surgical procedures to avoid an adrenal crisis. Home management of illness with a fever (> 38°C), vomiting or diarrhea, is based on the increase from two to three times the usual dose orally. If the child is unable to tolerate oral therapy, intramuscular injection of hydrocortisone should be administered (Table 4). Education for caregivers and patients (if adolescent) is crucial to prevent adrenal crisis. They should recognize signs and symptoms of adrenal crisis and should receive a steroid emergency card with the sick day rules. Prescribing doctors should provide for additional oral glucocorticoids and adequate training in hydrocortisone emergency self-injection. Abbreviations AI, adrenal insufficiency; PAI, primary adrenal insufficiency; CAI, central adrenal insufficiency; HPA, hypothalamic-pituitary-adrenal axis; CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone; POMC, pro-opiomelanocortin; CAH, congenital adrenal hyperplasia; STAR, steroidogenic acute regulatory; 21OHD, 21-hydroxylase deficiency; 11BOHD, 11-B-hydroxylase deficiency; P450scc, P450 cytochrome side-chain cleavage deficiency; 17-OHP, 17-hydroxyprogesterone; NCCAH, non-classic congenital adrenal hyperplasia; ALD, adrenoleukodystrophy; VLCFA, very long-chain fatty acids; CMPD, combined multiple pituitary hormone deficiency; GHD, growth hormone deficiency; MSH, melanocyte stimulating hormone; IUGR, intrauterine growth restriction; APS1, autoimmune polyglandular syndrome type 1; SDSST, standard dose short synacthen test; LDSST, low dose short synacthen test. Take Home Messages In neonates and infants CAH is the commonest cause of PAI, causing almost 71.8% of cases. Adrenoleukodystrophy should be considered in any male with hypoadrenalism. Unexplained hyponatremia, hyperpigmentation and the loss of pubic and axillary hair should raise the suspicion of AI. Adrenal insufficiency can present with non-specific clinical features; therefore a single cortisol measurement should be included in the biochemical work-up of an unwell child. Patients and parents should be well-trained in adrenal crisis recognition and management. Disclosure The authors report no conflicts of interest in this work. References 1. Charmandari E, Nicolaides N, Chrousos G. Adrenal insufficiency. Lancet. 2021;383(9935):2152–2167. doi:10.1016/S0140-6736(13)61684-0 2. White PC. Adrenocortical insufficiency. In: Nelson Textbook of Pediatrics. Elsevier. 2019:11575–11617. 3. White PC. Physiology of the adrenal gland. Nelson Textbook of Pediatrics. Elsevier. 2019. 4. 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Predicting the onset of Addison’s disease: ACTH, renin, cortisol and 21-hydroxylase autoantibodies. Clin Endocrinol. 2012;76:617–624. doi:10.1111/j.1365-2265.2011.04276.x 49. Thuillier P, Kerlan V. Subclinical adrenal diseases: silent pheochromocytoma and subclinical Addison’s disease. Ann Endocrinol. 2012;73(Suppl 1):S45–S54. doi:10.1016/S0003-4266(12)70014-8 50. Raverot V, Richet C, Morel Y, Raverot G, Borson-Chazot F. Establishment of revised diagnostic cut-offs for adrenal laboratory investigation using the new Roche Diagnostics Elecsys® Cortisol II assay. Ann Endocrinol. 2016;77(5):620–622. doi:10.1016/j.ando.2016.05.002 51. Grossman A. The diagnosis and management of central hypoadrenalism. J Clin Endocrinol Metab. 2010;95:4855e63. doi:10.1210/jc.2010-0982 52. Petersenn S, Quabbe HJ, Schöfl C, et al. The rational use of pituitary stimulation tests. Dtsch Arztebl Int. 2010;107(25):437–443. doi:10.3238/arztebl.2010.0437 53. Kline GA, Buse J, Krause RD. 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Ospina N, Al Nofal A, Bancos I, et al. ACTH stimulation tests for the diagnosis of adrenal insufficiency: systematic review and meta-analysis. J Clin Endocrinol Metab. 2016;101(2):427–434. doi:10.1210/jc.2015-1700 59. Park J, Das U, Didi M, et al. The challenges of cortisol replacement therapy in childhood: observations from a case series of children treated with modified-release hydrocortisone. Pediatr Drugs. 2018;20(6):567–573. doi:10.1007/s40272-018-0306-0 60. Woodcock T, Barker P, Daniel S, et al. Guidelines for the management of glucocorticoids during the peri-operative period for patients with adrenal insuf fi ciency Guidelines from the Association of Anaesthetists, the Royal College of Physicians and the Society for Endocrinology UK. Anaesthesia. 2020;75:654–663. doi:10.1111/anae.14963 61. Rushworth R, Torpy DJ, Falhammar H. Adrenal crisis. N Engl J Med. 2019;381(9):852–861. doi:10.1056/NEJMra1807486 62. Miller BS, Spencer SP, Geffner ME, et al. Emergency management of adrenal insufficiency in children: advocating for treatment options in outpatient and field settings. J Investig Med. 2020;68:16–25. doi:10.1136/jim-2019-000999 This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms. Download Article [PDF] From https://www.dovepress.com/pediatric-adrenal-insufficiency-challenges-and-solutions-peer-reviewed-fulltext-article-TCRM

Front Endocrinol (Lausanne). 2021 Dec 24;12:805647. doi: 10.3389/fendo.2021.805647. eCollection 2021. ABSTRACT Adrenal insufficiency (AI) is a life-threatening disorder, with increased morbidity and mortality, especially in case of an acute illness that can increase the requirement of cortisol. A novel infectious disease, termed Coronavirus Disease 2019 (COVID-19), appeared in 2020. Therefore, AI patients are experiencing a novel challenge: the risk of infection. In our experience, a prompt contact to the Endocrine center (with a telemedicine consultation) and a full awareness of diseases (cortisol deficiency, COVID-19 and the self-management of an adrenal crisis) are important to motivate patients. Vaccine is an effective treatment to prevent hospitalization and aggressive course of COVID-19. Some patients manifest challenges due to inequitable access and vaccine hesitancy, resulting in a delay in the acceptance of vaccines despite the availability of vaccination services. Therefore, an effort of all physicians must be conducted in order to advise patients with AI. In this short review, we try to answer some frequently asked questions regarding the management of patients with AI. PMID:35002978 | PMC:PMC8739913 | DOI:10.3389/fendo.2021.805647 From https://www.docwirenews.com/abstracts/frequently-asked-questions-in-patients-with-adrenal-insufficiency-in-the-time-of-covid-19-2/

This article is based on reporting that features expert sources. Adrenal Fatigue: Is It Real? More You may have heard of so-called 'adrenal fatigue,' supposedly caused by ongoing emotional stress. Or you might have come across adrenal support supplements sold online to treat it. But if someone suggests you have the controversial, unproven condition, seek a second opinion, experts say. And if someone tries to sell you dietary supplements or other treatments for adrenal fatigue, be safe and save your money. (GETTY IMAGES) Physicians tend to talk about 'reaching' or 'making' a medical diagnosis. However, when it comes to adrenal fatigue, endocrinologists – doctors who specialize in diseases involving hormone-secreting glands like the adrenals – sometimes use language such as 'perpetrating a diagnosis,' 'misdiagnosis,' 'made-up diagnosis,' 'a fallacy' and 'nonsense.' About 20 years ago, the term "adrenal fatigue" was coined by Dr. James Wilson, a chiropractor. Since then, certain practitioners and marketers have promoted the notion that chronic stress somehow slows or shuts down the adrenal glands, causing excessive fatigue. "The phenomenon emerged from the world of integrative medicine and naturopathic medicine," says Dr. James Findling, a professor of medicine and director of the Community Endocrinology Center and Clinics at the Medical College of Wisconsin. "It has no scientific basis, and there's no merit to it as a clinical diagnosis." An online search of medical billing code sets in the latest version of the International Classification of Diseases, or the ICD-10, does not yield a diagnostic code for 'adrenal fatigue' among the 331 diagnoses related either to fatigue or adrenal conditions or procedures. In a March 2020 position statement, the American Association of Clinical Endocrinologists and American College of Endocrinology addressed the use of adrenal supplements "to treat common nonspecific symptoms due to 'adrenal fatigue,' an entity that has not been recognized as a legitimate diagnosis." The position statement warned of known and unknown health risks of off-label use and misuse of hormones and supplements in patients without an established endocrine diagnosis, as well as unnecessary costs to patients and the overall health care system. Study after study has refuted the legitimacy of adrenal fatigue as a medical diagnosis. An August 2016 systematic review combined and analyzed data from 58 studies on adrenal fatigue including more than 10,000 participants. The conclusion in a nutshell: "Adrenal fatigue does not exist," according to review authors in the journal BMC Endocrine Disorders. Adrenal Action You have two adrenal glands in your body. These small triangular glands, one on top of each kidney, produce essential hormones such as aldosterone, cortisol and male sex hormones such as DHEA and testosterone. Cortisol helps regulate metabolism: How your body uses fat, protein and carbohydrates from food, and cortisol increases blood sugar as needed. It also plays a role in controlling blood pressure, preventing inflammation and regulating your sleep/wake cycle. As your body responds to stress, cortisol increases. This response starts with signals between two sections in the brain: The hypothalamus and the pituitary gland, which act together to release a hormone that stimulates the adrenal glands to make cortisol. This interactive unit is called the hypothalamic pituitary adrenal axis. While some health conditions really do affect the body's cortisol-making ability, adrenal fatigue isn't among them. "There's no evidence to support that adrenal fatigue is an actual medical condition," says Dr. Mary Vouyiouklis Kellis, a staff endocrinologist at Cleveland Clinic. "There's no stress connection in the sense that someone's adrenal glands will all of a sudden just stop producing cortisol because they're so inundated with emotional stress." If anything, adrenal glands are workhorses that rise to the occasion when chronic stress occurs. "The last thing in the body that's going to fatigue are your adrenal glands," says Dr. William F. Young Jr., an endocrinology clinical professor and professor of medicine in the Mayo Clinic College of Medicine at Mayo Clinic in Rochester, Minnesota. "Adrenal glands are built for stress – that's what they do. Adrenal glands don't fatigue. This is made up – it's a fallacy." The idea of adrenal glands crumbling under stress is "ridiculous," Findling agrees. "In reality, if you take a person and subject them to chronic stress, the adrenal glands don't shut down at all," Findling says. "They keep making cortisol – it's a stress hormone. In fact, the adrenal glands are just like the Energizer Bunny – they just keep going. They don't stop." Home cortisol tests that allow consumers to check their own levels can be misleading, Findling says. "Some providers who make this (adrenal fatigue) diagnosis, provide patients with testing equipment for doing saliva cortisol levels throughout the day," he says. "And then, regardless of what the results are, they perpetrate this diagnosis of adrenal fatigue." Saliva cortisol is a legitimate test that's frequently used in diagnosing Cushing's syndrome, or overactive adrenal glands, Findling notes. However, he says, a practitioner pursuing an adrenal fatigue diagnosis could game the system. "What they do is: They shape a very narrow normal range, so narrow, in fact, that no normal human subject could have all their saliva cortisol (levels) within that range throughout the course of the day," he says. "Then they convince the poor patients that they have adrenal fatigue phenomena and put them on some kind of adrenal support." Loaded Supplements How do you know what you're actually getting if you buy a dietary supplement marketed for adrenal fatigue or 'adrenal support' use? To find out, researchers purchased 12 such supplements over the counter in the U.S. Laboratory tests revealed that all supplements contained a small amount of thyroid hormone and most contained at least one steroid hormone, according to the study published in the March 2018 issue of Mayo Clinic Proceedings. "These results may highlight potential risks for hidden ingredients in unregulated supplements," the authors concluded. Supplements containing thyroid hormones or steroids can interact with a patient's prescribed medications or have other side effects. "Some people just assume they have adrenal fatigue because they looked it up online when they felt tired and they ultimately buy these over-the-counter supplements that can be very dangerous at times," Vouyiouklis Kellis says. "Some of them contain animal (ingredients), like bovine adrenal extract. That can suppress the pituitary axis. So, as a result, your body stops making its own cortisol or starts making less of it, and as a result, you can actually worsen the condition rather than make it better." Any form of steroid from outside the body, whether a prescription drug like prednisone or extract from cows' adrenal glands, "can shut off the pituitary," Vouyiouklis Kellis explains. "Because it's signaling to the pituitary like: Hey, you don't need to stimulate the adrenals to make cortisol, because this patient is taking it already. So, as a result, the body ultimately doesn't produce as much. And, so, if you rapidly withdraw that steroid or just all of a sudden decide not to take it anymore, then you can have this acute response of low cortisol." Some adrenal support products, such as herbal-only supplements, may be harmless. However, they're unlikely to relieve chronic fatigue. Fatigue: No Easy Answers If you're suffering from ongoing fatigue, it's frustrating. And you're not alone. "I have fatigue," Young Jr. says. "Go to the lobby any given day and say, 'Raise your hand if you have fatigue.' Most of the people are going to raise their hands. It's a common human symptom and people would like an easy answer for it. Usually there's not an easy answer. I think 'adrenal fatigue' is attractive because it's like: Aha, here's the answer." There aren't that many causes of endocrine-related fatigue, Young Jr. notes. "Hypothyroidism – when the thyroid gland is not working – is one." Addison's disease, or adrenal insufficiency, can also lead to fatigue among a variety of other symptoms. Established adrenal conditions – like adrenal insufficiency – need to be treated. "In adrenal insufficiency, there is an intrinsic problem in the adrenal gland's inability to produce cortisol," Vouyiouklis Kellis explains. "That can either be a primary problem in the adrenal gland or an issue with the pituitary gland not being able to stimulate the adrenal to make cortisol." Issues can arise even with necessary medications. "For example, very commonly, people are put on steroids for various reasons: allergies, ear, nose and throat problems," Vouyiouklis Kellis says. "And with the withdrawal of the steroids, they can ultimately have adrenal insufficiency, or decrease in cortisol." Opioid medications for pain also result in adrenal sufficiency, Vouyiouklis Kellis says, adding that this particular side effect is rarely discussed. People with a history of autoimmune disease can also be at higher risk for adrenal insufficiency. Common symptoms of adrenal insufficiency include: Fatigue. Weight loss. Decreased appetite. Salt cravings. Low blood pressure. Abdominal pain. Nausea, vomiting or diarrhea. Muscle weakness. Hyperpigmentation (darkening of the skin). Irritability. Medical tests for adrenal insufficiency start with blood cortisol levels, and tests for the ACTH hormone that stimulates the pituitary gland. "If the person does not have adrenal insufficiency and they're still fatigued, it's important to get to the bottom of it," Vouyiouklis Kellis says. Untreated sleep apnea often turns out to be the actual cause, she notes. "It's very important to tease out what's going on," Vouyiouklis Kellis emphasizes. "It can be multifactorial – multiple things contributing to the patient's feeling of fatigue." The blood condition anemia – a lack of healthy red blood cells – is another potential cause. "If you are fatigued, do not treat yourself," Vouyiouklis Kellis says. "Please seek a physician or a primary care provider for evaluation, because you don't want to go misdiagnosed or undiagnosed. It's very important to rule out actual causes that would be contributing to symptoms rather than ordering supplements online or seeking an alternative route like self-treating rather than being evaluated first." SOURCES The U.S. News Health team delivers accurate information about health, nutrition and fitness, as well as in-depth medical condition guides. All of our stories rely on multiple, independent sources and experts in the field, such as medical doctors and licensed nutritionists. To learn more about how we keep our content accurate and trustworthy, read our editorial guidelines. James Findling, MD Findling is a professor of medicine and director of the Community Endocrinology Center and Clinics at the Medical College of Wisconsin. Mary Vouyiouklis Kellis, MD Vouyiouklis Kellis is a staff endocrinologist at Cleveland Clinic. William F. Young Jr., MD Young Jr. is an endocrinology clinical professor and professor of medicine in the Mayo Clinic College of Medicine at Mayo Clinic in Rochester, Minnesota From https://health.usnews.com/health-care/patient-advice/articles/adrenal-fatigue-is-it-real?

– AI false positives pose serious danger to patients; cutoff changes recommended by Scott Harris , Contributing Writer, MedPage Today November 15, 2021 share to facebook share to twitter share to linkedin email article This Reading Room is a collaboration between MedPage Today® and: For adrenal insufficiency (AI), reducing false positives means more than reducing resource utilization. Treatments like glucocorticoid replacement therapy can cause serious harm in people who do not actually have AI. Research published in the Journal of the Endocrine Society makes multiple findings that report authors say could help bring down false positive rates for AI. This retrospective study ultimately analyzed 6,531 medical records from the Imperial College Healthcare NHS Trust in the United Kingdom. Sirazum Choudhury, MBBS, an endocrinologist-researcher with the trust, served as a co-author of the report. He discussed the study with MedPage Today. The exchange has been edited for length and clarity. This study ultimately addressed two related but distinct questions. What was the first? Choudhury: Initially the path we were following had to do with when cortisol levels are tested. Cortisol levels follow a diurnal pattern; levels are highest in the morning and then decline to almost nothing overnight. This means we ought to be measuring the level in the morning. But there are logistical issues to doing so. In many hospitals, we end up taking measurements of cortisol in the afternoon. That creates a dilemma, because if it comes back low, there's an issue as to what we ought to do with the result. Here at Imperial, we call out results of <100 nmol/L among those taken in the afternoon. Patients and doctors then have to deal with these abnormal results, when in fact they may not actually be abnormal. We may be investigating individuals who should really not be investigated. So the first aim of our study was to try and ascertain whether we could bring that down to a lower level and in doing so stop erroneously capturing people who are actually fine. What was the second aim of the study? Choudhury: As we went through tens of thousands of data sets, we realized we could answer more than that one simple question. So the next part of the study became: if an individual is identified as suspicious for AI, what's the best way to prove this diagnosis? We do this with different tests like short Synacthen Tests (SST), all with different cutoff points. Obviously, we want to get the testing right, because if you falsely label a person as having AI, the upshot is that treatments will interfere with their cortisol access and they will not do well. Simply put, we would be shortening their life. So, our second goal was to look at all the SSTs we've done at the center and track them to see whether we could do better with the benchmarks. What did you find? Choudhury: When you look at the data, you see that you can bring those benchmarks down and potentially create a more accurate test. First, we can be quite sure that a patient who is tested in the afternoon and whose cortisol level is >234 does not have AI. If their level is <53.5 then further investigation is needed There were similar findings for SSTs, which in our case were processed using a platform made by Abbott. For this platform, we concluded that the existing cut-offs should be dropped down to 367 at 30 minutes or 419 at about 60 minutes. Did anything surprise you about the study or its findings? Choudhury: If you look at the literature, the number of individuals who fail at 30 minutes but pass at 60 minutes is around 5%. But I was very surprised to see that our number at Imperial was about 20%. This is a key issue because, as I mentioned, if individuals are wrongly labelled adrenally insufficient, you're shortening their life. It's scary to think about the number of people who might have been given steroids and treated for AI when they didn't have the condition. What do you see as the next steps? Choudhury: I see centers unifying their cutoffs for SST results and making sure we're all consistent in the way we treat these results. From a research perspective, on the testing we're obviously talking about one specific platform with Abbott, so research needs to be done on SST analyzers from other manufacturers to work out what their specific cutoffs should be. Read the study here and expert commentary on the clinical implications here. The study authors did not disclose any relevant relationship with industry. Primary Source Journal of the Endocrine Society Source Reference: Ramadoss V, et al "Improving the interpretation of afternoon cortisol levels and SSTs to prevent misdiagnosis of adrenal insufficiency" J Endocrine Soc 2021; 5(11): bvab147. From https://www.medpagetoday.com/reading-room/endocrine-society/adrenal-disorders/95661

Purpose: This study aimed to identify predictive factors and to develop a predictive model for adrenal insufficiency (AI) related to topical corticosteroids use. Methods: The research was conducted using a cross-sectional design. Adult patients with dermatological conditions who had been prescribed topical steroids for at least 12 months by the dermatology outpatient departments of the Faculty of Medicine, Chiang Mai University from June through October 2020 were included. Data on potential predictors, including baseline characteristics and laboratory investigations, were collected. The diagnoses of AI were based on serum 8AM cortisol and low-dose ACTH stimulation tests. Multivariable logistic regression was used for the derivation of the diagnostic score. Results: Of the 42 patients, 17 (40.5%) had AI. The statistically significant predictive factors for AI were greater body surface area of corticosteroids use, age < 60 years, and basal serum cortisol < 7 μg/dL. In the final predictive model, duration of treatment was added as a factor based on its clinical significance for AI. The four predictive factors with their assigned scores were: body surface area involvement 10– 30% (20), > 30% (25); age < 60 years old (15); basal serum cortisol of < 7 μg/dL (30); and duration of treatment in years. Risk of AI was categorized into three groups, low, intermediate and high risk, with total scores of < 25, 25– 49 and ≥ 50, respectively. The predictive performance for the model was 0.92 based on area under the curve. Conclusion: The predictive model for AI in patients using topical corticosteroids provides guidance on the risk of AI to determine which patients should have dynamic ACTH stimulation tests (high risk) and which need only close follow-up (intermediate and low risk). Future validation of the model is warranted. Keywords: adrenal insufficiency, topical corticosteroids, predictive model, skin diseases Introduction Topical corticosteroids are frequently used for inflammatory skin diseases owing to their anti-inflammatory and immunosuppressive effects. Common indications for use include diseases such as psoriasis, eczema, atopic dermatitis, and vitiligo.1 In clinical practice, a variety of delivery vehicles and potencies of topical corticosteroids are used.1 Prolonged and/or inappropriate use of topical corticosteroids can lead to adverse side effects.2 These adverse side effects can be categorized as cutaneous and systemic side effects. The most common cutaneous side effect is skin atrophy. Systemic side effects include hypothalamic-pituitary-adrenal (HPA) axis suppression, glaucoma, hyperglycemia and hypertension.3 One of the most worrisome adverse side effects from the use of topical corticosteroids is adrenal insufficiency (AI) resulting from HPA axis suppression. Topically applied corticosteroids can be absorbed systemically through the skin and can suppress the HPA axis.4–8 This adverse outcome, the inability to increase cortisol production after stress, can lead to adrenal crisis, which is potentially life-threatening. Tests that are normally used to diagnose or exclude AI include serum morning cortisol and the dynamic ACTH stimulation test.9 Secondary AI from percutaneous absorption of topical corticosteroids is less common than with parenteral or oral administration. The cumulative doses and the durations of oral corticosteroid therapy associated with HPA axis suppression have been well documented.10 Data regarding the dose and duration of oral corticosteroids and HPA axis suppression have similarly been well established. A study by Curtis et al reported that the use of oral prednisolone >7.5 mg/day for an extended period (>3 weeks) was linked to this adverse event, and that the incidence increased with duration.10 However, corresponding data for topical corticosteroids has been limited. The degree of risk of HPA axis suppression from topical corticosteroids use is associated with the level of percutaneous absorption which, in turn, depends on numerous factors including the age of the patient (younger patients are more susceptible), body surface area treated, quantity of topical corticosteroids used, potency of the drug, duration of therapy, body region of application, the associated compounds used, eg, urea or salicylic acid, the characteristics of the diseased skin, the degree of impairment of skin integrity, and the coexistence of hepatic and/or renal disease.11–13 One study reported that HPA axis suppression occurs when high potency steroids are administered at a cumulative dose per week of >50 g.2 Presently, there is a lack of data on predictive factors for AI and no predicative model of the relationship between secondary AI resulting from HPA axis suppression and topical corticosteroids use. A simple predictive model which could help preclude and predict the risk of AI which incorporates both demographic and biochemical data could potentially reduce the number of dynamic ACTH stimulation tests performed. This study aimed to identify potential predictive factors and to design an easy-to-use model for predicting the risk of AI following topical corticosteroids use in dermatological patients. Materials and Methods This cross-sectional study was conducted with 42 patients who were seen at the dermatology outpatient departments at the Faculty of Medicine, Chiang Mai University Hospital over a 5-month period (June – October 2020). The study protocol was approved by the Faculty of Medicine, Chiang Mai University, Ethical Committee (Ethical number: MED-2563-07037). Recruited participants were adult dermatological patients (≥18 years) who had used topical corticosteroids for at least 12 months. Patients with pituitary or adrenal diseases, pregnant women and patients who had been treated with either systemic corticosteroids or other local corticosteroids were excluded. Those who meet all the inclusion criteria gave their informed consent prior to the study. This study was conducted in accordance with the Declaration of Helsinki. Adrenal Function Evaluation Adrenal function was evaluated by serum morning (8 AM) cortisol and the low-dose ACTH stimulation test. Patients were instructed to suspend use of topical corticosteroids for at least 24 hours before serum morning cortisol measurement and ACTH stimulation tests. In those with serum morning cortisol between 3 and 17.9 µg/dL, ACTH stimulation tests were performed on the same day between 9–11AM to either exclude or diagnose AI. Serum cortisol concentrations were measured at 8 AM 0 (basal cortisol) as well as 20 and 40 minutes after 5 µg ACTH was administered intravenously. Data Collection Epidemiological data collected included gender, age, blood pressure, underlying dermatologic diseases, other underlying diseases, body surface area involvement, sensitive area involvement, topical corticosteroid potency, amount and duration of topical corticosteroids use, symptoms of AI and the presence of Cushingoid features. Biochemical data included serum cortisol at 8 AM, 0 (basal cortisol) and at 20 and 40 minutes after ACTH intravenous injection, serum creatinine, electrolytes and albumin. Serum cortisol levels were measured by electrochemiluminescence assay (ECLIA) (Elecsys® Cortisol II assay, Roche Diagnostics GmbH, Mannheim, Germany). Definitions An 8AM cortisol level of ❤️ µg/dL or a peak serum cortisol level of <18 µg/dL at 20 or 40 minutes after an ACTH stimulation test was defined as having AI.14 Sensitive area involvement included the axilla, groin, face and genitalia. Topical corticosteroids are classified by potency based on a skin vasoconstriction assay, and range from ultra-high potency (class I) to low potency (class VII).15 Since some patients had concurrently used more than one class of corticosteroids in one treatment period, the new variable potency·dose·time (summary of corticosteroids potency (I–VII)16 multiplied by total doses (mg) of corticosteroids use and multiplied by duration (months) of corticosteroids use) was created. Symptoms of AI included lethargy, nausea and vomiting, orthostatic hypotension and significant weight loss. Significant weight loss was defined as a loss of 5% of body weight in one month or a loss of 10% over a period of six months.17 Having Cushingoid features was defined as at least one of the excess glucocorticoid features, eg, easy bruising, facial plethora, proximal myopathy, striae, dorsocervical fat pad, facial fullness, obesity, supraclavicular fullness, hirsutism, decreased libido and menstrual abnormalities. Statistical Analysis All statistical analyses were performed using Stata 16 (StataCorp, College Station, Texas, USA). Categorical variables are reported as frequency and percentage, while continuous variables are reported as mean ± standard deviation or median and interquartile range (IQR), according to their distribution. For univariable comparison, Fisher’s exact probability test was used for categorical variables, and the independent t-test or the Mann–Whitney U-test was used for continuous variables. p-values less than 0.05 were considered statistically significant. Multivariable logistic regression was used in the derivation of the prediction model for AI. Predictors with significant p-values in the univariable analysis were included in the multivariable model. We also included age and treatment duration in the model due to the clinical significance of those factors.4,18 The clinical collinearity among the predictors was also evaluated before the selection of the predictors. We generated a weighted score for each predictor by dividing the logit coefficient of the predictor by the lowest coefficient in the model. The discriminative ability of the final multivariable model was assessed using the area under the receiver operating characteristics (ROC) curve. The calibration of the scores was evaluated using the Hosmer-Lemeshow goodness-of-fit test, where a p-value >0.01 was considered a good fit. For clinical applicability, the appropriate cut-off points for the scores were identified based on sensitivity and specificity. We identified one cut-off point with high sensitivity for ruling out AI and another cut-off point with high specificity for ruling in AI. The positive predictive value for each score category with its corresponding confidence interval were presented. A sample size of at least 25 patients with at least 5 patients with AI was estimated to give 80% power at the 5% significance level.4 There was no missing data in this study. Results Baseline characteristics and biochemical investigations are shown in Table 1. Forty-two patients with dermatological diseases were included in this study. Of these, 17 patients (40.5%) had AI of whom 5 (29.4%) were female. The mean age of the group was 56.5 ±15.4 years, the mean duration of treatment was 10.1 ± 6 years, and the majority of patients had psoriasis (n = 14, 82.4%). There was no significant difference in sex, age, duration of treatment, potency dose-time, comorbidities, or underlying skin disease between the AI and non-AI groups. The average body surface area of corticosteroids use was significantly higher in patients with AI than in the non-AI group (27.5 ±18.7 m2 and 10.7 ±11.7 m2, p < 0.001, respectively). Basal serum cortisol levels were significantly lower in the AI group (6.52 ± 4.04 µg/dL) than in the non-AI group (10.48 ± 3.45 µg/dL, p 0.003). Although lower serum morning cortisol levels were observed in the AI group, the difference was not statistically significant (5.24 ± 4.65 µg/dL vs 13.39 ± 15.68 µg/dL, p = 0.069). Three patients were identified as having Cushingoid features. All patients with Cushingoid features had AI. Table 1 Comparison of Clinical Characteristics Between Patients with a History of Topical Corticosteroids Use for at Least 12 Months Who Were Diagnosed with Adrenal Insufficiency and Those without Adrenal Insufficiency (n = 42) Based on the multivariate logistic regression analysis (shown in Table 2), the significant predictive factors for AI in patients who used topical corticosteroids for more than 12 months were body surface area of corticosteroids use of 10–30% and >30% (POR 18.9, p =0.042, and POR 59.2, p = 0.035, respectively), age less than 60 years (POR 13.8, p = 0.04), and basal serum cortisol of <7 µg/dL (POR 131.5, p = 0.003). Only serum basal cortisol was included in the final multivariable model as there was clinical collinearity among serum morning cortisol and basal cortisol as well as 20- and 40-minute cortisol measurements. Table 2 Multivariable Model for Prediction of Adrenal Insufficiency in Patients with a History of Topical Corticosteroids Use for at Least 12 Months (n = 38) Predictive risk score was created to determine the probability of patients having AI using the aforementioned three significant predictive factors from the multivariable analysis (Table 2). As previous studies have demonstrated that duration of treatment is a strong predictive factor for AI in corticosteroid users,4,18 this factor was also incorporated in the model. The transformed score for body surface area, age and basal serum cortisol had a range of 0 to 30. For treatment duration, the transformed score was based on cumulative years of treatment. The total score was categorized into three groups: low, intermediate, and high risk (Table 3). Table 3 Accuracy of the Score to Rule in and Rule Out Adrenal Insufficiency in Patients with a History of Topical Corticosteroids Use for at Least 12 Months (n = 38) The cut-off point of ≥50 suggests high risk for developing AI with a sensitivity of 46.2% and a specificity of 100%, a score of <25 suggests a low risk with a sensitivity of 100% and a specificity of 52%, and a score between 25 and 49 indicates an intermediate risk of having AI. The ROC curve for the model assessing predictive performance which included all significant factors had an AuROC of 0.92 (Figure 1). The Hosmer-Lemeshow goodness-of-fit test revealed non-statistically significant results (p = 0.599), indicating that our newly derived scoring system fits the data well. Figure 1 Model discrimination via receiver operating characteristic curve in patients with a history of topical corticosteroids use for at least 12 months (n = 42). Discussion The present study proposes an easy-to-use predictive model for AI following topical corticosteroids use in dermatological patients based on demographic and biochemical factors. The accuracy of the model shows an excellent diagnostic accuracy of 92% based on AuROC. Currently, the diagnosis of AI in dermatological patients with topical corticosteroids use involves multiple steps including screening for serum morning cortisol followed by dynamic ACTH stimulation testing. The proposed simple predictive model, which requires only three demographic data items (age, body surface area of corticosteroids use, duration of use) and one biochemical test (serum basal cortisol), could potentially reduce the number of dynamic ACTH stimulation tests performed, resulting in cost- and time-saving for both patients and health-care facilities. Based on the proposed cut-off points, we suggest screening of individuals at high risk for having AI, including serum morning cortisol and the ACTH stimulation tests to confirm a diagnosis of AI. If there is evidence of AI, the patient should begin to receive treatment for AI to reduce future complications. For those in the low-risk group, only clinical follow-up should be carried out. In the intermediate-risk group, we recommend regular and close biochemical follow-up including serum morning cortisol and clinical follow-up for signs and symptoms of AI. Signs and symptoms that should raise a high index of suspicion for AI include significant weight loss, nausea and/or vomiting, orthostatic hypotension and lethargy. However, this proposed predictive model was studied in adults and cannot simply be generalized and extrapolated to children or infants. In our study, 40.5% of the patients were determined to have AI. A previous meta-analysis by Broersen et al reported the percentage of patients with AI secondary to all potencies of topical corticosteroids based on a review of 15 studies was 4.7%, 95% CI (1.1–18.5%).19 The higher prevalence of AI in our study could be a result of differences in patients’ baseline characteristics, eg, duration of treatment, corticosteroids potency and body surface area involvement. In the predictive model, we incorporated both clinical and biochemical factors which are easy to obtain in actual clinical practice. Some of those predictive factors have been previously reported to be linked to AI. Body surface area of corticosteroids use larger than 10% found to be significantly related to AI, especially in patients with a lesion area of over 30%. This finding is consistent with a study by Kerner et al which suggests the extent of surface area to which the corticosteroids are applied may influence absorption of the drug.20 Regarding the age of the patients, our study found that individuals over 60 years old tended to be at high risk of AI following topical corticosteroids therapy. The underlying explanation is that the stratum corneum acts as a rate-limiting barrier to percutaneous absorption as the stratum corneum in younger individuals is thinner than in older people. Diminished effectiveness of topical corticosteroid treatment in older people was demonstrated in a study by Malzfeldt et al.21 Even though serum basal cortisol is not recommended as a standard test to diagnose AI, a prior study reported that it can be considered as an alternative choice to diagnose AI when serum morning cortisol results are not available. In fact, it has been reported that there is no difference in diagnostic accuracy between serum morning cortisol and basal cortisol22 which supports our finding that serum basal cortisol <7 µg/dL is one of the significant factors related to AI. The final model found no statistically significant relationship between the incidence of AI and the duration of corticosteroids treatment. However, we decided to include this factor in the final model since previous publications have reported that the duration of treatment is a relevant risk factor for developing AI following continuous topical corticosteroids use. The duration of AI events has been reported to vary between 2 weeks to 18 months.4,18 Additionally, a case report of AI demonstrated that 5 years of topical corticosteroids use can cause AI.6 Together, this suggests that patients with a longer duration of topical corticosteroids use are at increased risk of AI, especially those who also have other risk factors. Although both potency and dosage of topical corticosteroids have been reported to be significantly linked to HPA axis suppression, the present study found only a non-significance link. This could be the result of the small sample size as well as of other factors, eg, body surface area involvement and serum cortisol levels, which could have masked the association between potency and dosage of topical corticosteroids with HPA suppression. To the best of our knowledge, this study is the first to use these novel predictive factors to develop a predictive model for AI in patients using topical corticosteroids. This model has multiple potential implications. First, the model uses clinical and biochemical factors which are obtainable in many institutes. Second, the model’s risk score provides good diagnostic accuracy in terms of both sensitivity and specificity. Finally, each of the predictive factors in the model has an underlying pathophysiological explanation and is not due simply to chance. There are some limitations in this study. First, the sample size is relatively small, although it does offer sufficient statistical power for each of the predictive factors. Second, further external validation is needed to validate the predictive performance of the model. Third, the cut-off level of serum cortisol after ACTH stimulation test was based on the older generation of ECLIA assay. There was a study proposed that the cut-off for serum cortisol in the newer generation of cortisol assay should be lower (~14–15 µg/dL) than the previous one (18 µg/dL).23 However, this proposed cut-off has not yet been established in the current guideline for AI. In the future, if the newer cut-off for serum cortisol will have been employed in the standard guideline, our predictive model may lead to overdiagnosis of AI. Conclusions The proposed predictive model uses both demographic and biochemical factors to determine the risk of AI in dermatological patients following topical corticosteroids use with a high level of diagnostic accuracy. This model has advantages in terms of a reduction in the number of dynamic ACTH stimulation tests needed, thus saving time and resources. Additionally, it can provide guidance to clinical practitioners regarding which patients should be closely followed up for development of AI. Future external validation of this predictive model is warranted. Acknowledgments The authors are grateful to Lamar G. Robert, PhD and Chongchit S. Robert, PhD for editing the manuscript. Disclosure The authors report no conflict of interest in this work. References 1. Ference JD, Last AR. Choosing topical corticosteroids. Am Fam Physician. 2009;79(2):135–140. 2. Hengge UR, Ruzicka T, Schwartz RA, Cork MJ. Adverse effects of topical glucocorticosteroids. J Am Acad Dermatol. 2006;54(1):1–15;quiz 16–8. doi:10.1016/j.jaad.2005.01.010 3. Rathi SK, D’Souza P. Rational and ethical use of topical corticosteroids based on safety and efficacy. Indian J Dermatol. 2012;57(4):251–259. doi:10.4103/0019-5154.97655 4. Carruthers JA, August PJ, Staughton RC. Observations on the systemic effect of topical clobetasol propionate (Dermovate). Br Med J. 1975;4(5990):203–204. doi:10.1136/bmj.4.5990.203 5. Staughton RC, August PJ. Cushing’s syndrome and pituitary-adrenal suppression due to clobetasol propionate. Br Med J. 1975;2(5968):419–421. doi:10.1136/bmj.2.5968.419 6. Young CA, Williams IR, MacFarlane IA. Unrecognised Cushing’s syndrome and adrenal suppression due to topical clobetasol propionate. Br J Clin Pract. 1991;45(1):61–62. 7. Abma EM, Blanken R, De Heide LJ. Cushing’s syndrome caused by topical steroid therapy for psoriasis. Neth J Med. 2002;60(3):148–150. 8. Böckle BC, Jara D, Nindl W, Aberer W, Sepp NT. Adrenal insufficiency as a result of long-term misuse of topical corticosteroids. Dermatology. 2014;228(4):289–293. doi:10.1159/000358427 9. Ospina NS, Al Nofal A, Bancos I, et al. ACTH stimulation tests for the diagnosis of adrenal insufficiency: systematic review and meta-analysis. J Clin Endocrinol Metab. 2016;101(2):427–434. doi:10.1210/jc.2015-1700 10. Curtis JR, Westfall AO, Allison J, et al. Population-based assessment of adverse events associated with long-term glucocorticoid use. Arthritis Rheum. 2006;55(3):420–426. doi:10.1002/art.21984 11. Brazzini B, Pimpinelli N. New and established topical corticosteroids in dermatology: clinical pharmacology and therapeutic use. Am J Clin Dermatol. 2002;3(1):47–58. doi:10.2165/00128071-200203010-00005 12. Dhar S, Seth J, Parikh D. Systemic side-effects of topical corticosteroids. Indian J Dermatol. 2014;59(5):460–464. doi:10.4103/0019-5154.139874 13. Levin C, Maibach HI. Topical corticosteroid-induced adrenocortical insufficiency: clinical implications. Am J Clin Dermatol. 2002;3(3):141–147. doi:10.2165/00128071-200203030-00001 14. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(2):364–389. doi:10.1210/jc.2015-1710 15. Goa KL. Clinical pharmacology and pharmacokinetic properties of topically applied corticosteroids. A review. Drugs. 1988;36(Suppl 5):51–61. doi:10.2165/00003495-198800365-00011 16. Davallow Ghajar L, Wood Heickman LK, Conaway M, Rogol AD. Low risk of adrenal insufficiency after use of low- to moderate-potency topical corticosteroids for children with atopic dermatitis. Clin Pediatr. 2019;58(4):406–412. doi:10.1177/0009922818825154 17. Gaddey HL, Holder K. Unintentional weight loss in older adults. Am Fam Physician. 2014;89(9):718–722. 18. Melian EB, Spencer CM, Jarvis B. Clobetasol propionate foam, 0.05%. Am J Clin Dermatol. 2001;2(2):89–92;discussion 93. doi:10.2165/00128071-200102020-00005 19. Broersen LH, Pereira AM, Jørgensen JO, Dekkers OM. Adrenal insufficiency in corticosteroids use: systematic review and meta-analysis. J Clin Endocrinol Metab. 2015;100(6):2171–2180. doi:10.1210/jc.2015-1218 20. Kerner M, Ishay A, Ziv M, Rozenman D, Luboshitzky R. Evaluation of the pituitary-adrenal axis function in patients on topical steroid therapy. J Am Acad Dermatol. 2011;65(1):215–216. doi:10.1016/j.jaad.2010.12.033 21. Malzfeldt E, Lehmann P, Goerz G, Lippold BC. Influence of drug solubility in the vehicle on clinical efficacy of ointments. Arch Dermatol Res. 1989;281(3):193–197. doi:10.1007/bf00456392 22. Manosroi W, Phimphilai M, Khorana J, Atthakomol P. Diagnostic performance of basal cortisol level at 0900-1300h in adrenal insufficiency. PLoS One. 2019;14(11):e0225255. doi:10.1371/journal.pone.0225255 23. Vogeser M, Kratzsch J, Ju Bae Y, et al. Multicenter performance evaluation of a second generation cortisol assay. Clin Chem Lab Med. 2017;55(6):826–835. doi:10.1515/cclm-2016-0400 This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms. Download Article [PDF] From https://www.dovepress.com/novel-predictive-model-for-adrenal-insufficiency-in-dermatological-pat-peer-reviewed-fulltext-article-IJGM

Cushing's Help Podcast: Adrenal Crisis Be sure to print this page to carry with you. Definition: Acute adrenal crisis is a life-threatening state caused by insufficient levels of cortisol, which is a hormone produced and released by the adrenal gland. Alternative Names: Adrenal crisis; Addisonian crisis; Acute adrenal insufficiency Causes, incidence, and risk factors: The two adrenal glands are located on top of the kidneys. They consist of the outer portion, called the cortex, and the inner portion, called the medulla. The cortex produces three types of hormones, all of which are called corticosteroids. Cortisol is a glucocortoid, a corticosteroid that maintains glucose (blood sugar) regulation, suppresses the immune response, and is released as part of the body's response to stress. Cortisol production is regulated by a small gland just below the brain called the pituitary gland. Cortisol is essential for life. Acute adrenal crisis is a medical emergency caused by a lack of cortisol. Patients may experience lightheadedness or dizziness, weakness, sweating, abdominal pain, nausea and vomiting, or even loss of consciousness. Adrenal crisis occurs if the adrenal gland is deteriorating (Addison's disease, primary adrenal insufficiency), if there is pituitary gland injury (secondary adrenal insufficiency), or if adrenal insufficiency is not adequately treated. Risk factors for adrenal crisis include physical stress such as infection, dehydration, trauma, or surgery, adrenal gland or pituitary gland injury, and ending treatment with steroids such as prednisone or hydrocortisone too early. Symptoms: Headache Profound weakness Fatigue Slow, sluggish movement Nausea Vomiting Low blood pressure Dehydration High fever Shaking chills Confusion or coma Darkening of the skin Rapid heart rate Joint pain Abdominal pain Unintentional weight loss Rapid respiratory rate (see tachypnea) Unusual and excessive sweating on face and/or palms Skin rash or lesions may be present Flank pain Loss of appetite Signs and tests: An ACTH (cortrosyn) stimulation test shows low cortisol. The baseline cortisol level is low. Fasting blood sugar may be low. Serum potassium is elevated ( usually primary adrenal insufficiency). Serum sodium is decreased (usually primary adrenal insufficiency). Treatment: In adrenal crisis, an intravenous or intramuscular injection of hydrocortisone (an injectable corticosteroid) must be given immediately. Supportive treatment of low blood pressure with intravenous fluids is usually necessary. Hospitalization is required for adequate treatment and monitoring. If infection is the cause of the crisis, antibiotic therapy may be needed. Expectations (prognosis): Death may occur due to overwhelming shock if early treatment is not provided. Complications: shock coma seizures Calling your health care provider: Call your health care provider if you have Addison's disease and are unable to retain usual medications because of vomiting.Go to the emergency room or call the local emergency number (such as 911) if symptoms of acute adrenal crisis develop. Prevention: People who have Addison's disease should be taught to recognize signs of potential stress that may cause an acute adrenal crisis. Most people with Addison's disease are taught to give themselves an emergency injection of hydrocortisone or increase their dose of oral prednisone in times of stress. It is important for the individual with Addison's disease to always carry a medical identification card that states the type of medication and the proper dose needed in case of an emergency. Never omit medication. If unable to retain medication due to vomiting, notify the health care provider. Health Alert: Adrenal Crisis Causes Death in Some People Who Were Treated With hGH Recently, doctors conducting the follow-up study of individuals treated with hGH looked at causes of death among recipients and found some disturbing news. Many more people have died from a treatable condition called adrenal crisis than from CJD. THIS RISK DOES NOT AFFECT EVERY RECIPIENT. IT CAN AFFECT THOSE WHO LACK OTHER HORMONES IN ADDITION TO GROWTH HORMONE. Please read on to find out if this risk applies to you. Death from adrenal crisis can be prevented. Adrenal crisis is a serious condition that can cause death in people who lack the pituitary hormone ACTH. ACTH is responsible for regulating the adrenal gland. Often, people are unaware that they lack this hormone and therefore do not know about their risk of adrenal crisis. Most people who were treated with hGH did not make enough of their own growth hormone. Some of them lacked growth hormone because they had birth defects, tumors or other diseases that cause the pituitary gland to malfunction or shut down. People with those problems frequently lack other key hormones made by the pituitary gland, such as ACTH, which directs the adrenal gland to make cortisol, a hormone necessary for life. Having too little cortisol can be fatal if not properly treated. TREATMENT WITH HGH DOES NOT CAUSE ADRENAL CRISIS, but because a number of people lacking growth hormone also lack ACTH, adrenal crisis has occurred in some people who were treated with hGH. In earlier updates we have talked about how adrenal crisis can be prevented, but people continue to die from adrenal crisis, which is brought on by lack of cortisol. These deaths can be prevented. Please talk to your doctor about whether you are at risk for adrenal crisis. Why should people treated with hGH know about adrenal crisis? Among the people who received hGH, those who had birth defects, tumors, and other diseases affecting the brain lacked hGH and often, other hormones made by the pituitary gland. A shortage of the hormones that regulate the adrenal glands can cause many health problems. It can also lead to death from adrenal crisis. This tragedy can be prevented. What are adrenal hormones? The pituitary gland makes many hormones, including growth hormone and ACTH, a hormone which signals the adrenal glands to make cortisol, a hormone needed for life. If the adrenal gland doesn't make enough cortisol, replacement medications must be taken. The most common medicines used for cortisol replacement are: Hydrocortisone Prednisone Dexamethasone What is adrenal crisis? Adrenal hormones are needed for life. The system that pumps blood through the body cannot work during times of physical stress, such as illness or injury, if there is a severe lack of cortisol (or its replacement). People who lack cortisol must take their cortisol replacement medication on a regular basis, and when they are sick or injured, they must take extra cortisol replacement to prevent adrenal crisis. When there is not enough cortisol, adrenal crisis can occur and may rapidly lead to death. What are the symptoms of lack of adrenal hormones? If you don't have enough cortisol or its replacement, you may have some of these problems: feeling weak feeling tired all the time feeling sick to your stomach vomiting no appetite weight loss When someone with adrenal gland problems has weakness, nausea, or vomiting, that person needs immediate emergency treatment to prevent adrenal crisis and possible death. • Why are adrenal hormones so important? Cortisol (or its replacement) helps the body respond to stress from infection, injury, or surgery. The normal adrenal gland responds to serious illness by making up to 10 times more cortisol than it usually makes. It automatically makes as much as the body needs. If you are taking a cortisol replacement drug because your body cannot make these hormones, you must increase the cortisol replacement drugs during times of illness, injury, or surgery. Some people make enough cortisol for times when they feel well, but not enough to meet greater needs when they are ill or injured. Those people might not need cortisol replacement every day but may need to take cortisol replacement medication when their body is under stress. Adrenal crisis is extremely serious and can cause death if not treated promptly. Discuss this problem with your doctor to help decide whether you need more medication or other treatment to protect your health. • How is adrenal crisis treated? People with adrenal crisis need immediate treatment. ANY DELAY CAN CAUSE DEATH. When people with adrenal crisis are vomiting or unconscious and cannot take medicine, the hormones can be given as an injection. Getting an injection of adrenal hormones can save your life if you are in adrenal crisis. If you lack the ability to make cortisol naturally, you should carry a medical ID card and wear a Medic-Alert bracelet to tell emergency workers that you lack adrenal hormones and need treatment. This precaution can save your life if you are sick or injured. • How can I prevent adrenal crisis? • If you are always tired, feel weak, and have lost weight, ask your doctor if you might have a shortage of adrenal hormones. • If you take hydrocortisone, prednisone, or dexamethasone, learn how to increase the dose when you become ill. • If you are very ill, especially if you are vomiting and cannot take pills, seek emergency medical care immediately. Make sure you have a hydrocortisone injection with you at all times, and make sure that you and those around you (in case you're not conscious) know how and when to administer the injection. • Carry a medical ID card and wear a bracelet telling emergency workers that you have adrenal insufficiency and need cortisol. This way, they can treat you right away if you are injured. Remember: SOME PEOPLE WHO LACKED GROWTH HORMONE MAY ALSO LACK CORTISOL, A HORMONE NECESSARY FOR LIFE. LACK OF CORTISOL CAN CAUSE ADRENAL CRISIS, A PREVENTABLE CONDITION THAT CAN CAUSE DEATH IF TREATED IMPROPERLY . Deaths from adrenal crisis can be prevented if patients and their families recognize the condition and are careful to treat it right away. Adrenal crisis is a medical emergency. Know the symptoms and how to adjust your medication when you are ill. TAKING THESE PRECAUTIONS CAN SAVE YOUR LIFE. DebMV suggested that you should have a Medic Alert bracelet from medicalert.org Toll free number in the USA is: by phone 7 days a week, 24 hours a day: 888-633-4298 209-668-3333 from outside the U.S. Lorrie got this important info for us. Alternative names: adrenal crisis; Addisonian crisis; acute adrenal insufficiency Definition: An abrupt, life-threatening state caused by insufficient cortisol, a hormone produced and released by the adrenal gland. Causes, incidence, and risk factors: The two adrenal glands are located on top of the kidneys. They consist of the outer portion, called the cortex, and the inner portion, called the medulla. The cortex produces three types of hormones, which are called corticosteroids. The androgens and estrogens affect sexual development and reproduction. The glucocorticoids maintain glucose regulation, suppress the immune response, and provide for the response to stress (cortisol). The mineralocorticoids regulate sodium and potassium balance. These hormones are essential for life. Acute adrenal crisis is an emergency caused by decreased cortisol. The crisis may occur in a person with Addison's disease, or as the first sign of adrenal insufficiency. More uncommonly, it may be caused by a pituitary gland disorder. It may also be caused by sudden withdrawal of corticosteroids, removal or injury of the adrenal glands, or destruction of the pituitary gland. Risk factors are stress, trauma, surgery, or infection in a person with Addison's disease, or injury or trauma to the adrenal glands or the pituitary gland. The incidence is 4 out of 100,000 people. Prevention: People who have Addison's disease should be taught to recognize signs of potential stress that may precipitate an acute adrenal crisis (cause it to occur suddenly and unexpectedly). Most people with Addison's disease are taught to give themselves an emergency injection of hydrocortisone in times of stress. It is important for the individual with Addison's disease to always carry a medical identification card that states the type of medication and the proper dose needed in case of an emergency. Never omit medication. If unable to retain medication due to vomiting, notify the health care provider. Symptoms: headache profound weakness fatigue slow, sluggish, lethargic movement nausea vomiting low blood pressure dehydration high fever chills shaking confusion or coma darkening of the skin rapid heart rate joint pain abdominal pain unintentional weight loss rapid respiratory rate unusual and excessive sweating on face and/or palms skin rash or lesion may be present flank pain appetite, loss Signs and tests: An ACTH (cortrosyn) stimulation test shows low cortisol. The cortisol level is low. The fasting blood sugar may be low. The serum potassium is elevated. The serum sodium is decreased. This disease may also alter the results of the following tests: sodium, urine 17-hydroxycorticosteroids Treatment: In adrenal crisis, an intravenous or intramuscular injection of hydrocortisone (an injectable corticosteroid) must be given immediately. Supportive treatment of low blood pressure is usually necessary. Hospitalization is required for adequate treatment and monitoring. Low blood pressure may be treated with intravenous fluids. If infection is the cause of the crisis, antibiotic therapy is indicated. Expectations (prognosis): Death may occur due to overwhelming shock if early treatment is not provided. Complications: shock coma seizures For more personal experiences, see the message boards A Personal Experience Shauna Wrote...What adrenal crisis feels like As with most mornings, this one began with nausea. I'm used to it, so didn't think much about it. I made it to the bathroom and was feeling really awful. Decided to just go to the toilet because I had that impending feeling. Next thing I knew I was waking up, but it wasn't like a normal awakening. I remember being in a tunnel and then thinking, "Well, this isn't where I normally sleep." Then I realized of course it wasn't where I normally slept! Normally I sleep in a bed, not wedged between a wall and the toilet. (Not that I was that coherent). I was completely disoriented as to time, place, etc. I had one big yell in me and yelled "HELP". My four year old brought me the phone and my son got me a towel. I called 911 (thank God I had a 911 sticker on the phone because I really couldn't remember the number). I kept telling the dispatcher I was in adrenal crisis. Of course, that meant nothing to him. I had my son get my shot but somewhere I knew that I wasn't together enough to give myself the shot. So I puked a few more times and told my son to take my daughter upstairs so she wasn't scared when the ambulance came. I decided to rest on the floor of the bathroom. I had, at first, tried to go to the couch but I was much, much too weak. So my son directed the medics into the bathroom. They eventually carried me to the couch. I kept telling them about my shot, but couldn't remember where I had my letter from Dr. Cook. They thought I was an overdose or a psych case (they told me later). They had all my pills lined up and were asking when I took this or that one last. I finally told them to look at the friggin date on the bottle and see that they were all 3/4 full. (I was agitated, too) They put the heart monitor on me and inserted an IV and took me to the hospital. I puked one more time in the ambulance and when we arrived (though my tummy was empty). My brother and sister-in-law where there (hospital) when I arrived and my mom had arrived at my house to take care of the kids as we were leaving. Then she met us up there. Before we arrived at the hospital, my husband had faxed a copy of Dr. Cook's letter on how to treat me over (Brian was at work when this happened). So they came in and inserted another fluid bag. Then about ten minutes later (after my brother told the doctor, "I fully expect that my sister will have her shot withing the next ten minutes" - patient advocates are a good thing because I could've cared less at that point) I had my 100 mg shot of solu-medrol. I was lucky because my doctor in the ER knew about adrenal crisis. Then I had another bag and repeated tests of my bp and heartrate. It wasn't pretty - every time my bp was low, generally around 80/50, sometimes lower and my heart rate was 120+. They decided to admit me, but I fought and fought. Once I got a shot of Zofran (anti-nausea, best in the world) and my cortisone and some fluid, I was feeling decent. I look and feel like I've been through a war, but I'm alive. As to why this happened, we're not entirely sure at this point. I have one urine test that they're culturing or something. I might also have shingles, but again - that'll show up in due time (a day or two, if I have it). Or, as Dr. Cook said when I talked to him, sometimes we just don't know. I was doing so well on my meds, back up to 27.5 and feeling good. Now I'm on 40 for the next day, and 30 for a week. Frustrating. Adrenal crisis is awful. It's terrifying. And what makes me want to cry as I write this (who am I kidding, I am crying) is that I couldn't have cared less if I lived or died. I was not in my right mind, I felt so horrid. All the surgeries combined, today was the worst day I've ever had. And it was a huge wake-up call. I need to have a better medic-alert bracelet because they had no idea what "Stress dose steroids" were. I need to have a list of what to do in crisis on my fridge, in my purse and with every family member. Same with the letter from my endo on how to treat me. Because when I'm in crisis, I don't know any better. I need to have things that speak for me. Thank God for family that knows, and for good doctors. Anyway, I didn't post this to scare anyone but Adrenal Crisis is not something to take lightly. When I felt myself hurting the night before (back pain, possibly shingles though I doubt it) I should've just taken an extra 5 mgs. Would've been a heck of a lot easier than what happened today. A few funny parts of the day: My daughter had to dress herself and my mom was in a hurry to get her to daycare and come see me. So my daughter spent the day at daycare in tights, too small shorts and a turtleneck (none of which came close to matching). Oh, and black patent leather shoes. Also, the medics asked what I weighed. Out of habit, I said 222 (my highest Cushing's weight). They ALL did a double take and said no way. One guessed 140 - bless his heart. I never did get myself weighed so I don't even know. Oh, and if any of you called at about 8 am and spoke with a medic, call me back. lol I had a blocked call at 8am, and I vaguely remember the medic talking to someone but I wasn't with it enough to ask who called. lol Something I don't say enough: I love and value you all. More personal experiences. Sue sent this along: Early Crisis Intervention The following is from the June 2002 issue of Addison News. Joan Hoffman, editor/publisher, kindly sent this issue to me and I wanted to share this with you. This is a flow chart to show the pathway of events in a crisis. It is very important to intervene as early as possible. Use your injectable and head for the hospital! The rate at which these events take varies with individuals and circumstances. The chart is a variation of one found in a nursing encyclopedia.

The occurrence of different subtypes of endogenous Cushing’s syndrome (CS) in single individuals is extremely rare. We here present the case of a female patient who was successfully cured from adrenal CS 4 years before being diagnosed with Cushing’s disease (CD). The patient was diagnosed at the age of 50 with ACTH-independent CS and a left-sided adrenal adenoma, in January 2015. After adrenalectomy and histopathological confirmation of a cortisol-producing adrenocortical adenoma, biochemical hypercortisolism and clinical symptoms significantly improved. However, starting from 2018, the patient again developed signs and symptoms of recurrent CS. Subsequent biochemical and radiological workup suggested the presence of ACTH-dependent CS along with a pituitary microadenoma. The patient underwent successful transsphenoidal adenomectomy, and both postoperative adrenal insufficiency and histopathological workup confirmed the diagnosis of CD. Exome sequencing excluded a causative germline mutation but showed somatic mutations of the β-catenin protein gene (CTNNB1) in the adrenal adenoma, and of both the ubiquitin specific peptidase 8 (USP8) and the glucocorticoid receptor (NR3C1) genes in the pituitary adenoma. In conclusion, our case illustrates that both ACTH-independent and ACTH-dependent CS may develop in a single individual even without evidence for a common genetic background. Introduction Endogenous Cushing´s syndrome (CS) is a rare disorder with an incidence of 0.2–5.0 per million people per year (1, 2). The predominant subtype (accounting for about 80%) is adrenocorticotropic hormone (ACTH)-dependent CS. The vast majority of this subtype is due to an ACTH-secreting pituitary adenoma [so called Cushing´s disease (CD)], whereas ectopic ACTH-secretion (e.g. through pulmonary carcinoids) is much less common. In contrast, ACTH-independent CS can mainly be attributed to cortisol-producing adrenal adenomas. Adrenocortical carcinomas, uni-/bilateral adrenal hyperplasia, and primary pigmented nodular adrenocortical disease (PPNAD) may account for some of these cases as well (3, 4). Coexistence of different subtypes of endogenous CS in single individuals is even rarer but has been described in few reports. These cases were usually observed in the context of prolonged ACTH stimulation on the adrenal glands, resulting in micronodular or macronodular hyperplasia (5–9). A sequence of CD and PPNAD was also described in presence of Carney complex, a genetic syndrome characterized by the loss of function of the gene encoding for the regulatory subunit type 1α of protein kinase A (PRKAR1A) (10). Moreover, another group reported the case of a patient with Cushing's disease followed by ectopic Cushing's syndrome more than 30 years later (8). To our knowledge, however, we here describe the first case report on a single patient with a cortisol-producing adrenocortical adenoma and subsequent CD. Read the rest of the article at https://www.frontiersin.org/articles/10.3389/fendo.2021.731579/full

This article was originally published here J Clin Endocrinol Metab. 2021 Jul 29:dgab557. doi: 10.1210/clinem/dgab557. Online ahead of print. ABSTRACT CONTEXT: Coronavirus disease 2019 (COVID-19) is a proinflammatory and prothrombotic condition, but its impact on adrenal function has not been adequately evaluated. CASE REPORT: A 46-year-old woman presented with abdominal pain, hypotension, and skin hyperpigmentation after COVID-19 infection. The patient had hyponatremia, serum cortisol <1.0 µg/dL, adrenocorticotropin (ACTH) of 807 pg/mL, and aldosterone ❤️ ng/dL. Computed tomography (CT) findings of adrenal enlargement with no parenchymal and minimal peripheral capsular enhancement after contrast were consistent with bilateral adrenal infarction. The patient had autoimmune hepatitis and positive antiphospholipid antibodies, but no previous thrombotic events. The patient was treated with intravenous hydrocortisone, followed by oral hydrocortisone and fludrocortisone. DISCUSSION: We identified 9 articles, including case reports, of new-onset adrenal insufficiency and/or adrenal hemorrhage/infarction on CT in COVID-19. Adrenal insufficiency was hormonally diagnosed in 5 cases, but ACTH levels were measured in only 3 cases (high in 1 case and normal/low in other 2 cases). Bilateral adrenal nonhemorrhagic or hemorrhagic infarction was identified in 5 reports (2 had adrenal insufficiency, 2 had normal cortisol levels, and 1 case had no data). Interestingly, the only case with well-characterized new-onset acute primary adrenal insufficiency after COVID-19 had a previous diagnosis of antiphospholipid syndrome. In our case, antiphospholipid syndrome diagnosis was established only after the adrenal infarction triggered by COVID-19. CONCLUSION: Our findings support the association between bilateral adrenal infarction and antiphospholipid syndrome triggered by COVID-19. Therefore, patients with positive antiphospholipid antibodies should be closely monitored for symptoms or signs of acute adrenal insufficiency during COVID-19. PMID:34463766 | DOI:10.1210/clinem/dgab557

With the goal of reducing false positives for adrenal insufficiency (AI), scientists are recommending a new, more precise diagnostic cutoff of 14-15 μg/dL of serum cortisol, rather than the current 18 μg/dL. The new data were published in the Journal of the Endocrine Society. Among the 110 patients evaluated in the retrospective analysis, new cortisol cutoffs after adrenocorticotropic hormone (ACTH) stimulation were identified when using several of the newer, more widely used diagnostic assays currently available, including Elecsys II (14.6 μg/dL), Access (14.8 μg/dL), and liquid chromatography-tandem mass spectrometry (LC-MS/MS) (14.5 μg/dL). Bradley Javorsky, MD, an endocrinologist and researcher at the Medical College of Wisconsin, served as the study's first author. He recently discussed the findings with MedPage Today. The exchange has been edited for length and clarity. What was the key knowledge gap your study was designed to address? Javorsky: It is safe to say that most clinicians, including many endocrinologists -- not to mention practice guidelines and clinical information resources -- still regard 18 μg/dL as the cutoff for making the biochemical diagnosis of AI after ACTH stimulation testing. However, this cutoff was derived from older polyclonal immunoassays that are no longer being used in many institutions. Newer, more specific monoclonal immunoassays and LC-MS/MS are being used instead. With these more specific assays, one might expect the cutoffs to be lower. What was your finding? Javorsky: After ACTH stimulation, the cutoff values for the newer, more specific cortisol assays were indeed lower at 14-15 μg/dL. Although there was excellent correlation between the new and older assays, the results from the new assays were 22-39% lower than those found by the older and less-specific Elecsys I assay, hence the lowered threshold. Did anything surprise you about the study results? Javorsky: Baseline cortisol had to be very low (approximately <2 μg/dL) in order to be predictive of subnormal cortisol values. This underscores the observation that ACTH stimulation testing is not perfectly sensitive. What are the clinical takeaways from these results? Javorsky: To avoid false-positive ACTH stimulation testing results -- and by extension avoid over-treating patients with glucocorticoids -- clinicians should be aware of the cortisol assay used in their institution and the new cortisol cutoff when evaluating patients for adrenal insufficiency. It should also be reinforced that careful interpretation in the context of clinical history is still essential to making the correct diagnosis. Discordant results among different assays underscore the importance of clinical judgment from an experienced physician when diagnosing AI. What are the takeaways? Javorsky: I think it is important that laboratories make the type of cortisol assay used in their institution easily accessible to clinicians and strongly consider posting the new cortisol cutoff after ACTH stimulation testing when reporting results. Read the study here and expert commentary on the clinical implications here. Disclosures Javorsky reported being a consultant for Clarus Therapeutics and a research investigator for Novartis Pharmaceuticals. Primary Source Journal of the Endocrine Society Source Reference: Javorsky BR, et al "New cutoffs for the biochemical diagnosis of adrenal insufficiency after ACTH stimulation using specific cortisol assays" J Endocrine Soc 2021; 5(4): bvab022. From https://www.medpagetoday.com/endocrine-society/adrenal-disorders/93188

DEER PARK, Ill., June 15, 2021 (GLOBE NEWSWIRE) -- Eton Pharmaceuticals, Inc (Nasdaq: ETON), the U.S. marketer of ALKINDI SPRINKLE®, a treatment for adrenocortical insufficiency in pediatric patients, today announced that it has acquired U.S. and Canadian rights to Crossject’s ZENEO® hydrocortisone needleless autoinjector, which is under development as a rescue treatment for adrenal crisis. “The ZENEO autoinjector is a revolutionary delivery system, and this product is a terrific strategic fit with our current adrenal insufficiency business. Patients, advocacy groups, and physicians in the adrenal insufficiency community have repeatedly expressed to us the need for a hydrocortisone autoinjector, so we are excited to be partnering with Crossject to bring this product to patients in need,” said Sean Brynjelsen, CEO of Eton Pharmaceuticals. Patrick Alexandre, CEO of Crossject, added: ‘‘We are proud to announce a sound commercial agreement for ZENEO® Hydrocortisone in the US and Canada with an American leader in adrenal insufficiency. ETON has successfully established strong relations with the patient communities and medical specialists that are its core focus. ZENEO® Hydrocortisone answers a medical need. This strong partnership will contribute to saving lives by bringing to patients and their families a modern autoinjection possibility.’’ “We are delighted about Eton Pharmaceuticals' plans to partner with Crossject to bring this incredibly needed product to patients in the U.S.”, said Dina Matos, Executive Director of CARES Foundation, a leading North American advocacy foundation for patients with congenital adrenal hyperplasia, the most common presentation of adrenal insufficiencies in children. “The challenge for patients and caregivers facing an adrenal crisis is serious; an easy-to-use needleless autoinjector of hydrocortisone will be a game changer for our patients. We welcome this advancement.” ZENEO® is a proprietary needleless device developed and manufactured by Crossject. The pre-filled, single-use device propels medication through the skin in less than a tenth of a second. The device’s compact form factor, simple two-step administration, and needle-free technology make it an ideal delivery system for emergency medications that need to be administered in stressful situations by non-healthcare professionals. Crossject holds more than 400 global patents on the device, including 24 issued in the United States that extend as far as 2037, and has successfully completed bioequivalence and human factor studies with the ZENEO device using various medications. Crossject has developed a proprietary, room-temperature stable liquid formulation of hydrocortisone to be delivered via the ZENEO device. ZENEO hydrocortisone is expected to be the first and only hydrocortisone autoinjector available for patients that require a rescue dose of hydrocortisone. Currently, injectable hydrocortisone is only available in the United States in a lyophilized powder formulation that must be reconstituted and manually delivered via a traditional syringe. Eton expects to submit a New Drug Application for the product to the U.S. Food and Drug Administration in 2023 and plans to request Orphan Drug Designation. In the United States, it is estimated that approximately 100,000 patients currently suffer from adrenocortical insufficiency and are at risk for adrenal crisis. Under the terms of the agreement, Crossject will receive development and regulatory milestone payments from Eton of up to $5.0 million, commercial milestones of up to $6.0 million, and a 10% royalty on net sales of the product. Crossject will be responsible for the management and expense of development, clinical, and manufacturing activities. Eton will be responsible for all regulatory and commercial activities. About Adrenal Crisis Patients with adrenal insufficiency can go into adrenal crisis if their cortisol levels are too low. Adrenal crisis is typically caused by missed doses of maintenance hydrocortisone, trauma, surgery, illness, fever, or major psychological distress. Signs of adrenal crisis include hyperpigmentation, severe weakness, nausea, abdominal pain, and confusion. It is estimated that approximately 8% of adrenal insufficiency patients will report an adrenal crisis in any given year and more than 6% of cases result in death. About Crossject Crossject (ISIN: FR0011716265; Ticker: ALCJ; LEI: 969500W1VTFNL2D85A65) is developing and is soon to market a portfolio of drugs dedicated to emergency situations: epilepsy, overdose, allergic shock, severe migraine and asthma attack. The company’s portfolio currently contains eight products in advanced stages of development, including 7 emergency treatments, 5 of which are intended for life-threatening situations. Thanks to its patented needle-free self-injection system, Crossject aims to become the world leader in self-administered emergency drugs. The company has been listed on the Euronext Growth market in Paris since 2014, and benefits from Bpifrance funding. About Eton Pharmaceuticals Eton Pharmaceuticals, Inc. is an innovative pharmaceutical company focused on developing and commercializing treatments for rare diseases. The company currently owns or receives royalties from three FDA-approved products, including ALKINDI® SPRINKLE, Biorphen®, and Alaway Preservative Free®, and has six additional products that have been submitted to the FDA. Company Contact: David Krempa dkrempa@etonpharma.com 612-387-3740 From https://www.globenewswire.com/news-release/2021/06/15/2247745/0/en/Eton-Pharmaceuticals-Acquires-U-S-and-Canadian-Rights-to-ZENEO-Hydrocortisone-Autoinjector.html

— Gradual dose escalation had fewer adverse events, same therapeutic benefit, as quicker increases by Kristen Monaco, Staff Writer, MedPage Today May 27, 2021 A more gradual increase in oral osilodrostat (Isturisa) dosing was better tolerated among patients with Cushing's disease, compared with those who had more accelerated increases, a researcher reported. Looking at outcomes from two phase III trials assessing osilodrostat, only 27% of patients had hypocortisolism-related adverse events if dosing was gradually increased every 3 weeks, said Maria Fleseriu, MD, of Oregon Health & Science University in Portland, in a presentation at the virtual meeting of the American Association of Clinical Endocrinology (AACE). On the other hand, 51% of patients experienced a hypocortisolism-related adverse event if osilodrostat dose was increased to once every 2 weeks. Acting as a potent oral 11-beta-hydroxylase inhibitor, osilodrostat was first approved by the FDA in March 2020 for adults with Cushing's disease who either cannot undergo pituitary gland surgery or have undergone the surgery but still have the disease. The drug is currently available in 1 mg, 5 mg, and 10 mg film-coated tablets. The approval came based off of the positive findings from the complementary LINC3 and LINC4 trials. The LINC3 trial included 137 adults with Cushing's disease with a mean 24-hour urinary free cortisol concentration (mUFC) over 1.5 times the upper limit of normal (50 μg/24 hours), along with morning plasma adrenocorticotropic hormone above the lower limit of normal (9 pg/mL). During the open-label, dose-escalation period, all the participants were given 2 mg of osilodrostat twice per day, 12 hours apart. Over this 12-week titration phase, dose escalations were allowed once every 2 weeks if there were no tolerability issues to achieve a maximum dose of 30 mg twice a day. After this 12-week dose-escalation schedule, additional bumps up in dose were permitted every 4 weeks. The median daily osilodrostat dose was 7.1 mg. The LINC4 trial included 73 patients with Cushing's disease with an mUFC over 1.3 times the upper limit of normal. The 48 patients randomized to receive treatment were likewise started on 2 mg bid of osilodrostat. However, this trial had a more gradual dose-escalation schedule, as doses were increased only every 3 weeks to achieve a 20 mg bid dose. After the 12-week dose-escalation phase, patients on a dose over 2 mg bid were restarted on 2 mg bid at week 12, where dose escalations were permitted once every 3 weeks thereafter to achieve a maximum 30 mg bid dose during this additional 36-week extension phase. Patients in this trial achieved a median daily osilodrostat dose of 5.0 mg. In both studies, patients' median age was about 40 years, the majority of patients were female, and about 88% had undergone a previous pituitary surgery. When comparing the adverse event profiles of both trials, Fleseriu and colleagues found that more than half of patients on the 2-week dose-escalation schedule experienced any grade of hypercortisolism-related adverse events. About 10.2% of these events were considered grade 3. About 28% of these patients had adrenal insufficiency -- the most common hypercortisolism-related adverse event reported. This was a catch-all term that include events like glucocorticoid deficiency, adrenocortical insufficiency, steroid withdrawal syndrome, and decreased cortisol, Fleseriu explained. Conversely, only 27.4% of patients on a 3-week dose escalation schedule experienced a hypercortisolism-related adverse event, and only 2.7% of these were grade 3. No grade 4 events occurred in either trial, and most events were considered mild or moderate in severity. "These adverse events were not associated with any specific osilodrostat dose of mean UFC level," Fleseriu said, adding that most of these events occurred during the initial dose-escalation periods. About 60% and 58% of all hypocortisolism-related adverse events occurred during the dose titration period in the 2-week and 3-week dose-escalation schedules, respectively. These events were managed via dose reduction, a temporary interruption in medication, and/or a concomitant medication. Very few patients in either trial permanently discontinued treatment due to these adverse events, Fleseriu noted. "Despite differences in the frequency of dose escalation, the time to first mUFC normalization was similar in the LINC3 and LINC4 studies," she said, adding that "gradual increases in osilodrostat dose from a starting dose of 2 mg bid can mitigate hypocortisolism-related adverse events without affecting mUFC control." "For patients with Cushing's disease, osilodrostat should be initiated at the recommended starting dose with incremental dose increases, based on individual response and tolerability aimed at normalizing cortisol levels," Fleseriu concluded. Kristen Monaco is a staff writer, focusing on endocrinology, psychiatry, and dermatology news. Based out of the New York City office, she’s worked at the company for nearly five years. Disclosures The LINC3 and LINC4 trials were funded by Novartis. Fleseriu reported relationships with Novartis, Recordati, and Strongbridge Biopharma. Primary Source American Association of Clinical Endocrinology Source Reference: Fleseriu M, et al "Effect of dosing and titration of osilodrostat on efficacy and safety in patients with Cushing's disease (CD): Results from two phase III trials (LINC3 and LINC4)" AACE 2021. From https://www.medpagetoday.com/meetingcoverage/aace/92824?xid=nl_mpt_DHE_2021-05-28&eun=g1406328d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=Daily Headlines Top Cat HeC 2021-05-28&utm_term=NL_Daily_DHE_dual-gmail-definition

Some of the latest research advancements in the field of endocrinology presented at the Endocrine Society's virtual ENDO 2021 meeting included quantifying diabetic ketoacidosis readmission rates, hyperglycemia as a severe COVID-19 predictor, and semaglutide as a weight loss therapy. Below are a few more research highlights: More Safety Data on Jatenzo In a study of 81 men with hypogonadism -- defined as a serum testosterone level below 300 ng/dL -- oral testosterone replacement therapy (Jatenzo) was both safe and effective in a manufacturer-sponsored study. After 24 months of oral therapy, testosterone concentration increased from an average baseline of 208.3 ng/dL to 470.1 ng/dL, with 84% of patients achieving a number in the eugonadal range. And importantly, the treatment also demonstrated liver safety, as there were no significant changes in liver function tests throughout the 2-year study -- including alanine aminotransferase (28.0 ± 12.3 to 26.6 ± 12.8 U/L), aspartate transaminase (21.8 ± 6.8 to 22.0 ± 8.2 U/L), and bilirubin levels (0.58 ± 0.22 to 0.52 ± 0.19 mg/dL). Throughout the trial, only one participant had elevation of liver function tests. "Our study finds testosterone undecanoate is an effective oral therapy for men with low testosterone levels and has a safety profile consistent with other approved testosterone products, without the drawbacks of non-oral modes of administration," said lead study author Ronald Swerdloff, MD, of the Lundquist Research Institute in Torrance, California, in a statement. In addition, for many men with hypogonadism, "an oral option is preferred to avoid issues associated with other modes of administration, such as injection site pain or transference to partners and children," he said. "Before [testosterone undecanoate] was approved, the only orally approved testosterone supplemental therapy in the United States was methyltestosterone, which was known to be associated with significant chemical-driven liver damage." Oral testosterone undecanoate received FDA approval in March 2019 following a rocky review history. COVID-19 Risk With Adrenal Insufficiency Alarming new data suggested that children with adrenal insufficiency were more than 23 times more likely to die from COVID-19 than kids without this condition (relative risk 23.68, P<0.0001). This equated to 11 deaths out of 1,328 children with adrenal insufficiency compared with 215 deaths out of 609,788 children without this condition (0.828% vs 0.035%). These young patients with adrenal insufficiency also saw a much higher rate of sepsis (RR 21.68, P<0.0001) and endotracheal intubation with COVID-19 infection (RR 25.45, P<0.00001). Data for the analysis were drawn from the international TriNetX database, which included patient records of children ages 18 and younger diagnosed with COVID-19 from 60 healthcare organizations in 31 different countries. "It's really important that you take your hydrocortisone medications and start stress dosing as soon as you're sick," study author Manish Raisingani, MD, of the University of Arkansas for Medical Sciences and Arkansas Children's in Little Rock, explained during a press conference. "This will help prevent significant complications due to COVID-19 or any other infections. A lot of the complications that we see in kids with adrenal insufficiency are due to inadequate stress dosing of steroids." And with kids starting to return back to in-person schooling, "parents should also be reeducated about using the emergency injections of hydrocortisone," Raisingani added. He noted that the COVID-19 complication rates were likely so high in this patient population because many had secondary adrenal insufficiency due to being on long-term, chronic steroids. Many also had comorbid respiratory illnesses, as well. Cushing's Death Risk In a systematic review and meta-analysis of 87 studies -- including data on 17,276 patients with endogenous Cushing's syndrome -- researchers found that these patients face a much higher death rate than those without this condition. Overall, patients with endogenous Cushing's syndrome faced a nearly three times higher mortality ratio (standardized mortality ratio 2.91, 95% CI 2.41-3.68, I2=40.3%), with those with Cushing's disease found to have an even higher mortality risk (SMR 3.27, 95% CI 2.33-4.21, I2=55.6%). And those with adrenal Cushing's syndrome also saw an elevated death risk, although not as high as patients with the disease (SMR 1.62, 95% CI 0.08-3.16, I2=0.0%). The most common causes of mortality among these patients included cardiac conditions (25%), infection (14%), and cerebrovascular disease (9%). "The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism, and good infection control, and emphasize the need to achieve disease remission, normalizing cortisol levels," said lead study author Padiporn Limumpornpetch, MD, of the University of Leeds in England, in a statement. From https://www.medpagetoday.com/meetingcoverage/endo/91808

Adrenal insufficiency increases the risk for severe outcomes, including death, 23-fold for children who contract COVID-19, according to a data analysis presented at the ENDO annual meeting. “Adrenal insufficiency in pediatrics does increase risk of complications with COVID-19 infections,” Manish Gope Raisingani, MD, assistant professor in the department of pediatrics in the division of pediatric endocrinology at Arkansas Children's Hospital, University of Arkansas for Medical Sciences, told Healio. “The relative risk of complications is over 20 for sepsis, intubation and mortality, which is very significant.” Source: Adobe Stock Using the TriNetX tool and information on COVID-19 from 54 health care organizations, Raisingani and colleagues analyzed data from children (aged 0-18 years) with COVID-19; 846 had adrenal insufficiency and 252,211 did not. The mortality rate among children with adrenal insufficiency was 2.25% compared with 0.097% for those without, for a relative risk for death of 23.2 (P < .0001) for children with adrenal insufficiency and COVID-19. RRs for these children were 21.68 for endotracheal intubation and 25.45 for sepsis. “Children with adrenal insufficiency should be very careful during the pandemic,” Raisingani said. “They should take their steroid medication properly. They should also be appropriately trained on stress steroids for infection, other significant events.” From https://www.healio.com/news/endocrinology/20210321/severe-covid19-risks-greatly-increased-for-children-with-adrenal-insufficiency

Patients with adrenal insufficiency may have higher rates of cardiovascular events due to the presence of cardiovascular comorbidities, shows a study published in The Journal of Clinical Endocrinology and Metabolism. Led by Kanchana Ngaosuwan, MD, PhD, of Imperial College London, UK, the authors of this population-based matched cohort study also found that cerebrovascular events were independently increased in patients with secondary adrenal insufficiency, particularly in those treated with irradiation therapy. Cardiovascular mortality, specifically from ischemic heart disease, was higher regardless of having secondary adrenal insufficiency or primary adrenal insufficiency (Addison’s disease). Adrenal insufficiency occurs when the adrenal glands fail to produce adequate glucocorticoids. In Addison’s disease, it arises from the adrenal glands, but in secondary adrenal insufficiency, it occurs as a result of a pituitary or hypothalamic condition. Glucocorticoid replacement therapy is usually the first line of defense, but the treatment is associated with a number of adverse events, such as cardiovascular disease. Ischemic heart disease is the leading cause of death for patients with Addison’s disease. Data from this study was sourced from the Clinical Practice Research Datalink which collected information from 15,354,125 individuals living in the United Kingdom between 1987 and 2017. Data from patients prescribed glucocorticoid prescriptions for adrenal insufficiency (primary: n=2,052; secondary: n=3,948) and random age and gender matched controls (primary: n=20,366; secondary: n=39,134) were assessed for comorbidities and clinical outcomes. Patients and controls had previous cardiovascular disease (17.5% vs 11.2%), diabetes (10.4% vs 4.8%), hypertension (22.1% vs 13.6%), dyslipidemia (20.5% vs 5.0%), and 19.6% and 4.9% of patients and controls were taking statins, respectively. Composite cardiovascular events occurred at a rate of 31.4 (95% CI, 29.6-33.3) per 1,000 person-years among the patients and 24.4 (95% CI, 23.9-24.9; P <.0001) per 1,000 person years among the controls. Stratified by adrenal insufficiency subtype, after correcting for cofounders, patients with primary (adjusted hazard ratio [aHR], 1.08; 95% CI, 0.96-1.22) and secondary (aHR, 1.10; 95% CI, 1.01-1.19) adrenal insufficiency were at marginally increased risk for composite cardiovascular events. Cerebrovascular disease occurred at a rate of 10.4 (95% CI, 9.5-11.5) per 1.000 person years among the patients and 7.2 (95% CI, 7.0-7.5; P <.0001) per 1,000 person years among the controls. Only patients with secondary adrenal insufficiency were at increased risk for cerebrovascular disease (aHR, 1.53; 95% CI, 1.34-1.74). All patients had increased risk for hospitalization due to cardiovascular diseases (aHR, 1.41; 95% CI, 1.28-1.55) and only the patients with secondary adrenal insufficiency were more likely to be hospitalized with cerebrovascular disease (aHR, 1.63; 95% CI, 1.28-2.08). Patients had increased rates of cardiovascular mortality compared with controls (9.9 vs 6.4 per 1,000 person years; P <.0001). Both patients with primary (aHR, 1.58; 95% CI, 1.19-2.10) and secondary (aHR, 1.23; 95% CI, 0.99-1.52) insufficiency were at increased risk for cardiovascular mortality. Risk for cerebrovascular mortality was elevated for patients with secondary insufficiency (aHR, 1.14; 95% CI, 0.78-1.67). Stratified by secondary insufficiency, age, and sex, women (aHR, 1.18; 95% CI, 1.04-1.31; P =.016) and patients who were less than 50 years old (aHR, 1.58; 95% CI, 1.22-2.03; P <.0001) were at increased risk for composite cardiovascular events. Similarly, patients 50 years old or younger were at increased risk for cerebrovascular disease (aHR, 3.67; 95% CI, 2.60-5.17; P <.0001). These data may be limited by the cohort imbalance of disease risk factors, although the investigators corrected for these features, some residual biases may remain. While further study is needed to assess changes in treatment approaches, the authors suggested that “these findings support further optimization of glucocorticoid replacement in conjunction with cardio protective interventions in patients with adrenal insufficiency.” Reference Ngaosuwan K, Johnston D G, Godsland I F, et al. Cardiovascular disease in patients with primary and secondary adrenal insufficiency and the role of comorbidities. J Clin Endocrinol Metab. 2021;dgab063. doi:10.1210/clinem/dgab063. From https://www.endocrinologyadvisor.com/home/topics/cardiovascular-and-metabolic-disorders/adrenal-insufficiency-associated-with-increased-cvd-and-cerebrovascular-disease/

A retrospective cohort study was performed to compare mortality risk and causes of death in adrenal insufficiency with an individually-matched reference population. Researchers examined 6,821 patients with adrenal insufficiency (primary, 2052; secondary, 3948) and 6,7564 individually-matched controls (primary, 20366; secondary, 39134). It was shown that in adrenal insufficiency, mortality was elevated, particularly primary, even with individual matching, and was found early in the disease course. The data demonstrated that cardiovascular disease was the major cause but mortality from infection was also high. The adrenal crisis was a common contributor. The outcomes suggested that early education for prompt treatment of infections and avoidance of adrenal crisis hold the potential to decrease mortality. The Journal of Clinical Endocrinology & Metabolism, dgab096, https://doi.org/10.1210/clinem/dgab096 Abstract Context Mortality data in patients with adrenal insufficiency are inconsistent, possibly due to temporal and geographical differences between patients and their reference populations. Objective To compare mortality risk and causes of death in adrenal insufficiency with an individually-matched reference population. Design Retrospective cohort study. Setting UK general practitioner database (CPRD). Participants 6821 patients with adrenal insufficiency (primary, 2052; secondary, 3948) and 67564 individually-matched controls (primary, 20366; secondary, 39134). Main outcome measures All-cause and cause-specific mortality; hospital admission from adrenal crisis. Results With follow-up of 40799 and 406899 person-years for patients and controls respectively, the hazard ratio (HR; [95%CI]) for all-cause mortality was 1.68 [1.58 - 1.77]. HRs were greater in primary (1.83 [1.66 - 2.02]) than in secondary (1.52 [1.40 - 1.64]) disease; (HR; primary versus secondary disease, 1.16 [1.03 - 1.30]). The leading cause of death was cardiovascular disease (HR 1.54 [1.32-1.80]), along with malignant neoplasms and respiratory disease. Deaths from infection were also relatively high (HR 4.00 [2.15 - 7.46]). Adrenal crisis contributed to 10% of all deaths. In the first two years following diagnosis, the patients’ mortality rate and hospitalisation from adrenal crisis were higher than in later years. Conclusion Mortality was increased in adrenal insufficiency, especially primary, even with individual matching and was observed early in the disease course. Cardiovascular disease was the major cause but mortality from infection was also high. Adrenal crisis was a common contributor. Early education for prompt treatment of infections and avoidance of adrenal crisis hold potential to reduce mortality. PDF available at https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/clinem/dgab096/6141434?redirectedFrom=fulltext

The treatment of adrenal insufficiency with hydrocortisone granules in children with congenital adrenal hyperplasia (CAH) was associated with an absence of adrenal crises and normal growth patterns over a 2-year period, according to study findings published in The Journal of Clinical Endocrinology and Metabolism. The study included a total of 17 children with CAH and 1 child with hypopituitarism. All included participants were <6 years old who were receiving current adrenocortical replacement therapy, including hydrocortisone with or without fludrocortisone. Hydrocortisone medications used in this population were converted from pharmacy compounded capsules to hydrocortisone granules without changing the dose. These study participants were followed by study investigators for 2 years. Glucocorticoid replacement therapy was given three times a day for a median treatment duration of 795 days. Treatment was adjusted by 3 monthly 17-hydroxyprogesterone (17-OHP) profiles in children with CAH. There were a 150 follow-up visits throughout the study. At each visit, participants underwent assessments that measured hydrocortisone dose, height, weight, pubertal status, adverse events, and incidence of adrenal crisis. A total of 40 follow-up visits had changes in hydrocortisone doses based on salivary measurements (n=32) and serum 17-OHP levels (n=8). At time of study entry, the median daily doses of hydrocortisone were 11.9 mg/m2 for children between the ages of 2 to 8 years, 9.9 mg/m2 for children between 1 month and 2 years, and 12.0 mg/m2 for children <28 days of age. At the end of the study, the respective doses for the 3 age groups were 10.2, 9.8, and 8.6. The investigators observed no trends in either accelerated growth or reduced growth; however, 1 patient with congenital renal hypoplasia and CAH did show reduced growth. While 193 treatment-emergent adverse events, including pyrexia, gastroenteritis, and viral upper respiratory tract infection, were reported in 14 patients, there were no observed adrenal crises. Limitations of this study included the small sample size as well as the relatively high drop-out rate of the initial sample. The researchers concluded that “hydrocortisone granules are an effective treatment for childhood adrenal insufficiency providing the ability to accurately prescribe pediatric appropriate doses.” Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures. Reference Neumann U, Braune K, Whitaker MJ, et al. A prospective study of children 0-7 years with CAH and adrenal insufficiency treated with hydrocortisone granules. Published online September 4, 2020. J Clin Endocrinol Metab. doi:10.1210/clinem/dgaa626

Adults with adrenal insufficiency who are adequately treated and trained display the same incidence of COVID-19-suggestive symptoms and disease severity as controls, according to a presenter. “Adrenal insufficiency is supposed to be associated with an increased risk for infections and complications,” Giulia Carosi, a doctoral student in the department of experimental medicine at Sapienza University of Rome, said during a presentation at the virtual European Congress of Endocrinology Annual Meeting. “Our aim was to evaluate the incidence of COVID symptoms and related complications in this group.” In a retrospective, case-control study, Carosi and colleagues evaluated the incidence of COVID-19 symptoms and complications among 279 adults with primary or secondary adrenal insufficiency (mean age, 57 years; 49.8% women) and 112 adults with benign pituitary nonfunctioning lesions without hormonal alterations, who served as controls (mean age, 58 years; 52.7% women). All participants lived in the Lombardy region of northern Italy. Participants completed a standardized questionnaire by phone on COVID-19-suggestive symptoms, such as fever, cough, myalgia, fatigue, dyspnea, gastrointestinal symptoms, conjunctivitis, loss of smell, loss of taste, upper respiratory tract symptoms, thoracic pain, headaches and ear pain. Patients with primary or secondary adrenal insufficiency were previously trained to modify their glucocorticoid replacement therapy when appropriate. From February through April, the prevalence of participants reporting at least one symptom of viral infection was similar between the adrenal insufficiency group and controls (24% vs. 22.3%; P = .788). Researchers observed “highly suggestive” symptoms among 12.5% of participants in both groups. No participant required hospitalization and no adrenal crisis was reported. Replacement therapy was correctly increased for about 30% of symptomatic participants with adrenal insufficiency. Carosi noted that few nasopharyngeal swabs were performed (n = 12), limiting conclusions on the exact infection rate (positive result in 0.7% among participants with adrenal insufficiency and 0% of controls; P = .515). “We can conclude that hypoadrenal patients who have regular follow-up and trained about risks for infection and sick day rules seem to present the same incidence of COVID-19 symptoms and the same disease severity as controls,” Carosi said. As Healio previously reported, there is no evidence that COVID-19 has a more severe course among individuals with primary and secondary adrenal insufficiency; however, those with adrenal insufficiency are at increased risk for respiratory and viral infections, and patients experiencing major inflammation and fever are at risk for life-threatening adrenal crisis. In a position statement issued by the American Association of Clinical Endocrinologists in March, researchers wrote that people with adrenal insufficiency or uncontrolled Cushing’s syndrome should continue to take their medications as prescribed and ensure they have appropriate supplies for oral and injectable steroids at home, with a 90-day preparation recommended. In the event of acute illness, those with adrenal insufficiency are instructed to increase their hydrocortisone dose per instructions and call their health care provider for more details. Standard “sick day” rules for increasing oral glucocorticoids or injectables would also apply, according to the statement. From https://www.healio.com/news/endocrinology/20200910/no-increased-covid19-risk-with-adequately-treated-adrenal-insufficiency

With the novel COVID-19 virus continuing to spread, it is crucial to adhere to the advice from experts and the Centers for Disease Control and Prevention (CDC) to help reduce risk of infection for individuals and the population at large. This is particularly important for people with adrenal insufficiency and people with uncontrolled Cushing’s Syndrome. Studies have reported that individuals with adrenal insufficiency have an increased rate of respiratory infection-related deaths, possibly due to impaired immune function. As such, people with adrenal insufficiency should observe the following recommendations: Maintain social distancing to reduce the risk of contracting COVID-19 Continue taking medications as prescribed Ensure appropriate supplies for oral and injectable steroids at home, ideally a 90-day preparation In the case of hydrocortisone shortages, ask your pharmacist and physician about replacement with different strengths of hydrocortisone tablets that might be available. Hydrocortisone (or brand name Cortef) tablets have 5 mg, 10 mg or 20 mg strength In cases of acute illness, increase the hydrocortisone dose per instructions and call the physician’s office for more details Follow sick day rules for increasing oral glucocorticoids or injectables per your physician’s recommendations In general, patients should double their usual glucocorticoid dose in times of acute illness In case of inability to take oral glucocorticoids, contact your physician for alternative medicines and regimens If experiencing fever, cough, shortness of breath or other symptoms, call both the COVID-19 hotline (check your state government website for contact information) and your primary care physician or endocrinologist Monitor symptoms and contact your physician immediately following signs of illness Acquire a medical alert bracelet/necklace in case of an emergency Individuals with uncontrolled Cushing’s Syndrome of any origin are at higher risk of infection in general. Although information on people with Cushing’s Syndrome and COVID-19 is scarce, given the rarity of the condition, those with Cushing’s Syndrome should strictly adhere to CDC recommendations: Maintain social distancing to reduce the risk of contracting COVID-19 If experiencing fever, cough, shortness of breath or other symptoms, call both the COVID-19 hotline (check your state government website for contact information) and your primary care physician or endocrinologist In addition, people with either condition should continue to follow the general guidelines at these times: Stay home as much as possible to reduce your risk of being exposed When you do go out in public, avoid crowds and limit close contact with others Avoid non-essential travel Wash your hands with soap and water regularly, for at least 20 seconds, especially before eating or drinking and after using the restroom and blowing your nose, coughing or sneezing If soap and water are not readily available, use an alcohol-based sanitizer with at least 60% alcohol Cover your nose and mouth when coughing or sneezing with a tissue or a flexed elbow, then throw the tissue in the trash Avoid touching your eyes, mouth or nose when possible From https://www.aace.com/recent-news-and-updates/aace-position-statement-coronavirus-covid-19-and-people-adrenal

Along with all of you, NADF is monitoring this outbreak by paying close attention to CDC and FDA updates. We have also asked our Medical Advisor to help answer your important questions as they come up. We asked Medical Director Paul Margulies, MD, FACE, FACP to help us with this question: Question: Does Adrenal Insufficiency cause us to have a weakened immune system and therefore make us more susceptible? Response: Individuals with adrenal insufficiency on replacement doses of glucocorticoids do not have a suppressed immune system. The autoimmune mechanism that causes Addison’s disease does not cause an immune deficiency that would make one more likely to get an infection. The problem is with the individual’s ability to deal with the stress of an infection once it develops. Those with adrenal insufficiency fall into that category. When sick with a viral infection, they can have a more serious illness, and certainly require stress dose steroids to help to respond to the illness. If someone with adrenal insufficiency contracts the coronavirus, it is more likely to lead to the need for supportive care, including hospitalization. This information from the CDC Website provides important information regarding Prevention & Treatment. You can find this information here: https://www.cdc.gov/coronavirus/2019-ncov/about/prevention-treatment.html From https://www.nadf.us/