Pediatric Adrenal Insufficiency: Challenges and Solutions

Authors NisticĂČ 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

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Daniela NisticĂČ,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 ÎČ -hydroxylase deficiency (11BOHD, 8% of cases), 17α-hydroxylase/17–20 lyase deficiency (17OHD), 3ÎČ-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 ”g/dL (83 nmol/L) best predict AI, while greater than 13 ”g/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 ”g/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 ”g/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 ”g/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 (SynacthenÂź) or cosyntropin (CortrosynÂź) 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 ”g Synacthen vial administration with serum cortisol measurement at baseline and 30 and 60 minutes after. CAI is diagnosed if peak cortisol level is <16 ”g/dL (440 nmol/L), or excluded if >39 ”g/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 ”g 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 ”g55, which is contained in 1 mL of the solution obtained by diluting a 250 ”g vial into 250 mL saline. Serum cortisol level is then measured at baseline and after 30 minutes, resulting in diagnose of CAI if <16 ”g/dL (440 nmol/L), otherwise ruling it out if >22 ”g/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 ”g/Kg human CRH (FerringŸ) 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 ChronocortŸ and PlenadrenŸ. PlenadrenŸ, 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 PlenadrenŸ 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

  1. In neonates and infants CAH is the commonest cause of PAI, causing almost 71.8% of cases.
  2. Adrenoleukodystrophy should be considered in any male with hypoadrenalism.
  3. Unexplained hyponatremia, hyperpigmentation and the loss of pubic and axillary hair should raise the suspicion of AI.
  4. 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.
  5. Patients and parents should be well-trained in adrenal crisis recognition and management.

Disclosure

The authors report no conflicts of interest in this work.

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Home cortisol tests: 3 of the best

Please note that if you buy through links in this article, Medical News Today may earn a small commission. Here’s their process.

Cortisol is a hormone with various functions throughout the body. However, if a person’s body cannot regulate their cortisol levels, it could lead to a serious health condition. In these cases, home cortisol tests may be useful to indicate when someone might need medical attention.

A person sitting at a desk, holding an at-home cortisol test tube, typing on a laptop.

This article discusses:

  • what cortisol is
  • what a home cortisol test is
  • why a person might buy a home cortisol test
  • some home cortisol tests to purchase online
  • when to see a doctor

What is cortisol?

Cortisol is the stress hormone that affects several systems in the body, including the:

The adrenal glands produce cortisol. Most human body cells have cortisol receptors, and the hormone can help in several ways, including:

  • reducing inflammation
  • regulating metabolism
  • assisting with memory formation
  • controlling blood pressure
  • developing the fetus during pregnancy
  • maintaining salt and water balance in the body
  • controlling blood sugar levels

All these functions make cortisol a vital part of maintaining overall health. If the body can no longer regulate cortisol levels, it can lead to several health disorders, such as Cushing’s syndrome and Addison’s disease. Without treatment, these conditions could cause life threatening complications.

The body requires certain cortisol levels during times of stress, such as:

  • in the event of an injury
  • during illness
  • during a surgical procedure

What are home cortisol tests? 

A cortisol test usually involves a blood test. However, some may require saliva and urine samples instead.

There are several home cortisol tests available to purchase over the counter or online. These allow a person to take a sample of blood, urine, or saliva before sending it off for analysis.

After taking a home cortisol test, people can usually receive their results within 2–5 days online or via a telephone call with a healthcare professional.

However, there are currently no studies investigating the reliability of these home cortisol tests. Therefore, people should follow up on their test results with a healthcare professional.

Why and when do people need them? 

A person should take a home cortisol test if they feel they may have a cortisol imbalance.

If cortisol levels are too high, a person may notice the following:

  • rapid weight gain in the face, chest, and abdomen
  • high blood pressure
  • osteoporosis
  • bruises and purple stretch marks
  • mood swings
  • muscle weakness
  • an increase in thirst and need to urinate

If cortisol levels are too low, a person may experience the following symptoms:

  • fatigue
  • loss of appetite
  • unintentional weight loss
  • muscle weakness
  • abdominal pain

Additionally, low cortisol levels may lead to:

A test can help individuals check their cortisol levels. If the test results show these levels are too high or too low, people should seek medical advice.

A cortisol imbalance may be a sign of an underlying condition, which can lead to serious complications without treatment.

If a person cannot carry out a home cortisol test, they should speak to a medical professional who can arrange a cortisol test at a healthcare facility.

What to look for in a home cortisol test

At a clinic or hospital setting, a medical professional will usually take a blood sample and analyze it for an individual’s cortisol levels.

Home cortisol tests involve a person taking a sample of blood, urine, or saliva. There are currently no studies investigating the accuracy of these results.

However, home cortisol tests may be faster and more convenient than making an appointment with a doctor to take a sample.

People may consider several factors when deciding to purchase a home cortisol test, including:

  • Sample type: Some tests require a blood sample, while others need a sample of urine or saliva. With this in mind, a person may wish to buy a product that uses a testing method they are comfortable providing.
  • Test analysis: A person may wish to purchase a product from a company that sends tests to Clinical Laboratory Improvement Amendments (CLIA)-certified labs for analysis. The Food and Drug Administration (FDA), Center for Medicaid Services, and the Centers for Disease Control and Prevention (CDC) regulate these labs to help ensure safety and accuracy.
  • Accuracy: Individuals may wish to speak to a pharmacist or other healthcare professional before purchasing to ensure the test is reliable and accurate.

Products

Several online retailers offer home cortisol tests. It is important to follow all test instructions to ensure a valid result.

Please note, the writer has not tested these products. All information is research-based.

LetsGetChecked – Cortisol Test

This cortisol test uses the finger prick method to draw blood for the sample.

Here are the steps to take and send off a blood sample:

  1. Individuals fill in their details on the collection box and activate their testing kit online at the LetsGetChecked website.
  2. People need to wash their hands with warm soapy water before using an alcohol swab to clean the finger that they will prick.
  3. Once the finger is completely dry, individuals pierce the skin using the lancet in the test kit. A person must wipe away the first drop of blood before squeezing some into the blood collection tube.
  4. After closing the tube, individuals must invert it 5–10 times before placing it in the included biohazard bag, which they then place in the box.

After following these steps, people can send the sample back to LetsGetChecked using the kit’s prepaid envelope. Test results usually come back within 2–5 days.

LetsGetChecked tests samples in the same labs that primary care providers, hospitals, and government schemes use. These labs are CLIA-certified and CAP-accredited.

The company also has a team of nurses and doctors available 24 hours a day, 7 days a week, to offer ongoing support. These healthcare professionals are on hand to discuss a person’s results with them over the phone.

Everlywell At-Home Cortisol Levels Test Kit – Sleep & Stress Test

This Everlywell product uses a urine sample to test a person’s cortisol levels.

The test measures the levels of three hormones in a person’s body: cortisol, cortisone, and melatonin. It also measures a person’s creatinine levels.

There are three steps with this test:

  1. Individuals register their testing kit on Everlywell’s website.
  2. A person follows the instructions carefully to take their urine sample.
  3. Once they have their urine sample, they place it in the prepaid package and send it off to Everlywell’s labs.

Within a few days, individuals will receive their results digitally via the Everlywell website. Medical professionals can also offer helpful insights via their secure platform.

As well as sending a personalized report of each marker, Everlywell also sends detailed information about what the results mean.

The labs where Everlywell tests samples all carry certification with CLIA. The company also ensures that all results are reviewed and certified by independent board-certified physicians within the person’s specific state.SHOP NOW

Healthlabs Cortisol, AM & PM Test

Healthlabs offers a cortisol test that tests a person’s cortisol levels twice — once in the morning and once in the evening.

The company says they do this because a person’s cortisol levels fluctuate throughout the day. Therefore, by testing twice, they can gather information on this fluctuation.

This test uses a blood sample, which a person takes once in the morning and once in the afternoon. They must follow the instructions clearly to ensure they take suitable samples.

The manufacturer says that people should collect a morning sample between 7–9 a.m. and an evening sample between 3–5 p.m.

They then need to send off their sample for analysis. After testing is complete at a CLIA-certified lab, a person will receive their results, which usually takes between 1–2 days. SHOP NOW

When to speak with a doctor

A person should undergo a cortisol test if they believe they may have high or low cortisol levels.

They can do this at home or speak with a medical professional who can carry out the test for them.

People may also wish to seek medical help if they show signs of too much or too little cortisol. This could indicate a potentially serious underlying health issue.

Summary

Cortisol is an important hormone that affects almost all parts of the body. It has many functions, including reducing inflammation, regulating metabolism, and controlling blood pressure.

If a person believes they have high or low cortisol levels, they may wish to take a cortisol test. Usually, these tests take place at a medical practice. However, several home cortisol tests are available to purchase.

A person can take these tests at home by providing a urine, blood, or saliva sample. Once a lab analyzes the test, people usually receive their results within a few days. Individuals should follow up any test results with a healthcare professional. No clinics, no stress. Test your cortisol levels from home

Test your cortisol level from home with LetsGetChecked. Get free shipping, medical support, and results from accredited labs within 2–5 days. Order today for 30% off. LEARN MORE

Last medically reviewed on April 29, 2021 at https://www.medicalnewstoday.com/articles/3-of-the-best-home-cortisol-tests

How does COVID-19 impact the adrenal gland?

This month marks a little over one year since the first surge of COVID-19 across the United States. April is also Adrenal Insufficiency Awareness month, a good time to review the data on how COVID-19 infection can impact the adrenal glands.

The adrenal glands make hormones to help regulate blood pressure and the ability to respond to stress. The hormones include steroids such as glucocorticoid (cortisol), mineralocorticoid (aldosterone), and forms of adrenaline known as catecholamines (norepinephrine, epinephrine, and dopamine). The activity of the adrenal gland is controlled through its relationship with the pituitary gland (the master regulator of hormones in the body).

Some common adrenal diseases include the following:

  • Addison’s Disease (where the body attacks the adrenal glands making them dysfunctional)
  • Hyperaldosteronism
  • Cushing’s Syndrome
  • Pheochromocytoma
  • Adrenal Nodules/Masses (termed incidentaloma)
  • Congenital adrenal hyperplasia

COVID-19 was found in the adrenal and pituitary glands of some patients who succumbed to the illness, suggesting that these organs might be among the targets for infection.  One of the first highly effective therapies for COVID-19 infection was the use of IV steroid (dexamethasone) supplementation in hospitalized patients in patients requiring oxygen.

A focused search of COVID-19-related health literature shows 85 peer-reviewed papers that have been published in medical literature specifically on the adrenal gland and COVID-19. This literature focuses on three phases of COVID infection that may impact the adrenal gland: the acute active infection phase, the immediate post-infection phase, and the long-term recovery phase.

Medical research has identified that during the acute active infection, the adrenal system is one of the most heavily affected organ systems in the body in patients who have COVID-19 infection requiring hospitalization. In these cases, supplementation with the steroid dexamethasone serves as one of the most powerful lifesaving treatments.

Concern has also been raised regarding the period of time just after the acute infection phase – particularly, the development of adrenal insufficiency following cases of COVID-19 hospitalizations. Additionally, some professional societies recommend that for patients who have adrenal insufficiency and are on adrenal replacement therapy, they be monitored closely post-COVID-19 vaccine for the development of stress-induced adrenal insufficiency.

In mild-to-moderate COVID-19 cases, there does not seem to be an effect on adrenaline-related hormones (norepinephrine, epinephrine, dopamine). However, in cases of severe COVID-19 infection triggering the development of shock, patients will need supplementation with an infusion of catecholamines and a hormone called vasopressin to maintain their blood pressure.

Finally, some studies have addressed the concern of adrenal insufficiency during the long-term recovery phase. Dr Sara Bedrose, adrenal endocrine specialist at  Baylor College of Medicine, indicates that studies which included adrenal function in COVID survivors showed a large percentage of patients with suboptimal cortisol secretion during what is called ACTH stimulation testing.

Results indicated that most of those cases had central adrenal insufficiency. It was concluded that adrenal insufficiency might be among the long-term consequences of COVID-19 and it seemed to be secondary to pituitary gland inflammation (called hypophysitis) or due to direct hypothalamic damage. Long-term follow-up of COVID 19 survivors will be necessary to exclude a gradual and late-onset adrenal insufficiency.

Some patients who have COVID-19 will experience prolonged symptoms. To understand what is happening to them, patients may question whether or not they have a phenomenon called adrenal fatigue. This is a natural question to ask, especially after having such a severe health condition. A tremendous amount of resources are being developed to investigate the source and treatment of the symptoms, and this work has only just begun.

However, adrenal fatigue is not a real medical diagnosis. It’s a term to describe a group of signs and symptoms that arise due to underactive adrenal glands. Current scientific data indicate that adrenal fatigue is not in and of itself a medical disease – although a variety of over-the-counter supplements and compounded medications may be advocated for in treatment by alternative medicine/naturopathic practitioners.

My takeaway is that we have learned a great deal about the effects COVID-19 infection has on the adrenal glands. Long-term COVID-19 remains an area to be explored –  especially in regards to how it may affect the adrenal glands.

-By Dr. James Suliburk, associate professor of surgery in the Division of Surgical Oncology and section chief of endocrine surgery for the Thyroid and Parathyroid Center at Baylor College of Medicine

From https://blogs.bcm.edu/2021/04/22/how-does-covid-19-impact-the-adrenal-gland/

New study identifies the main genetic causes of autoimmune Addison’s disease

Novel genetic associations could pave the way for early interventions and personalized treatment of an incurable condition.

Scientists from the University of Bergen (Norway) and Karolinska Institutet (Sweden) have discovered the genes involved in autoimmune Addison’s disease, a condition where the body’s immune systems destroys the adrenal cortex leading to a life-threatening hormonal deficiency of cortisol and aldosterone.

Groundbreaking study

The rarity of Addison’s disease has until now made scanning of the whole genome for clues to the disease’s genetic origins difficult, as this method normally requires many thousands of study participants. However, by combining the world’s two largest Addison’s disease registries, Prof. Eystein Husebye and his team at the University of Bergen and collaborators at Karolinska Institutet in Sweden (prof. KĂ€mpe) were able to identify strong genetic signals associated with the disease. Most of them are directly involved in the development and functioning of the human immune system including specific molecular types in the so-called HLA-region (this is what makes matching donors and recipients in organ transplants necessary) and two different types of a gene called AIRE (which stands for AutoImmune REgulator).

AIRE is a key factor in shaping the immune system by removing self-reacting immune cells. Variants of AIRE, such as the ones identified in this study, could compromise this elimination of self-reacting cells, which could lead to an autoimmune attack later in life.

Knowing what predisposes people to develop Addison’s disease opens up the possibilities of determining the molecular repercussions of the predisposing genetic variation (currently ongoing in Prof. Husebye’s lab). The fact that it is now feasible to map the genetic risk profile of an individual also means that personalised treatment aimed at stopping and even reversing the autoimmune adrenal destruction can become a feasible option in the future.

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Contact information:

Professor at the University of Bergen, Eystein Husebye – Eystein.Husebye@uib.no – cell phone +47 99 40 47 88

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

From https://www.eurekalert.org/pub_releases/2021-02/tuob-nsi021221.php

Earwax may reveal how stressed you are

How stressed are you? Your earwax could hold the answer.

A new method of collecting and analyzing earwax for levels of the stress hormone cortisol may be a simple and cheap way to track the mental health of people with depression and anxiety.

Cortisol is a crucial hormone that spikes when a person is stressed and declines when they’re relaxed. In the short-term, the hormone is responsible for the “fight or flight” response, so it’s important for survival. But cortisol is often consistently elevated in people with depression and anxiety, and persistent high levels of cortisol can have negative effects on the immune system, blood pressure and other bodily functions.

There are other disorders which involve abnormal cortisol, including Cushing’s disease (caused by the overproduction of cortisol) and Addison’s disease (caused by the underproduction of cortisol). People with Cushing’s disease have abnormal fat deposits, weakened immune systems and brittle bones. People with Addison’s disease have dangerously low blood pressure.

There are a lot of ways to measure cortisol: in saliva, in blood, even in hair. But saliva and blood samples capture only a moment in time, and cortisol fluctuates significantly throughout the day. Even the experience of getting a needle stick to draw blood can increase stress, and thus cortisol levels. Hair samples can provide a snapshot of cortisol over several months instead of several minutes, but hair can be expensive to analyze — and some people don’t have much of it.

AndrĂ©s Herane-Vives, a lecturer at University College London’s Institute of Cognitive Neuroscience and Institute of Psychiatry, and his colleagues instead turned to the ear. Earwax is stable and resistant to bacterial contamination, so it can be shipped to a laboratory easily for analysis. It also can hold a record of cortisol levels stretching over weeks.

But previous methods of harvesting earwax involved sticking a syringe into the ear and flushing it out with water, which can be slightly painful and stressful. So Herane-Vives and his colleagues developed a swab that, when used, would be no more stressful than a Q-tip. The swab has a shield around the handle, so that people can’t stick it too far into their ear and damage their eardrum, and a sponge at the end to collect the wax.

In a small pilot study, researchers collected blood, hair and earwax from 37 participants at two different time points. At each collection point, they sampled earwax using a syringe from one ear, and using the new self-swab method from the other. The researchers then compared the reliability of the cortisol measurements from the self-swab earwax with that of the other methods.

They found that cortisol was more concentrated in earwax than in hair, making for easier analysis. Analyzing the self-swabbed earwax was also faster and more efficient than analyzing the earwax from the syringe, which had to be dried out before using. Finally, the earwax showed more consistency in cortisol levels compared with the other methods, which were more sensitive to fluctuations caused by things like recent alcohol consumption. Participants also said that self-swabbing was more comfortable than the syringe method.

The researchers reported their findings Nov. 2 in the journal Heliyon. Herane-Vives is also starting a company called Trears to market the new method. In the future, he hopes that earwax could also be used to monitor other hormones. The researchers also need to follow up with studies of Asian individuals, who were left out of this pilot study because a significant number only produce dry, flaky earwax as opposed to wet, waxy earwax.

“After this successful pilot study, if our device holds up to further scrutiny in larger trials, we hope to transform diagnostics and care for millions of people with depression or cortisol-related conditions such as Addison’s disease and Cushing syndrome, and potentially numerous other conditions,” he said in a statement.

Originally published in Live Science.

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