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Adrenal insufficiency

Abstract

Adrenal insufficiency (AI) is a condition characterized by an absolute or relative deficiency of adrenal cortisol production. Primary AI (PAI) is rare and is caused by direct adrenal failure. Secondary AI (SAI) is more frequent and is caused by diseases affecting the pituitary, whereas in tertiary AI (TAI), the hypothalamus is affected. The most prevalent form is TAI owing to exogenous glucocorticoid use. Symptoms of AI are non-specific, often overlooked or misdiagnosed, and are related to the lack of cortisol, adrenal androgen precursors and aldosterone (especially in PAI). Diagnosis is based on measurement of the adrenal corticosteroid hormones, their regulatory peptide hormones and stimulation tests. The goal of therapy is to establish a hormone replacement regimen that closely mimics the physiological diurnal cortisol secretion pattern, tailored to the patient’s daily needs. This Primer provides insights into the epidemiology, mechanisms and management of AI during pregnancy as well as challenges of long-term management. In addition, the importance of identifying life-threatening adrenal emergencies (acute AI and adrenal crisis) is highlighted and strategies for prevention, which include patient education, glucocorticoid emergency cards and injection kits, are described.

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Fig. 1: Adrenal gland hormones.
Fig. 2: Types of adrenal insufficiency.
Fig. 3: The physiological rhythm of cortisol and pharmacokinetic profile of hydrocortisone therapy.
Fig. 4: The renin–angiotensin–aldosterone system.
Fig. 5: Mechanisms underlying Addison disease.
Fig. 6: Adrenal steroidogenesis and 21-hydroxylase deficiency.
Fig. 7: Pathophysiological aspects of adrenal crisis.
Fig. 8: Clinical manifestations of adrenal insufficiency.

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Acknowledgements

S.H. is supported by the Deutsche Forschungsgemeinschaft (DFG) (within the CRC/Transregio 205/1 “The Adrenal: Central Relay in Health and Disease” and HA 6931/3-1). W.A. is supported by the Medical Research Council UK (programme grant G0900567). I.B. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) USA under award K23DK121888. The views expressed are those of the author(s) and not necessarily those of the National Institutes of Health, USA. E.S.H. is supported by K.G. Jebsen Center of Autoimmune Disorders, The Novonordisk Foundation, The Norwegian Research Council. The authors thank S. Aslaksen for her input in creating the figure on mechanisms underlying Addison disease.

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Contributions

Introduction (S.H. and M.Q.); Epidemiology (I.B. and E.S.H.); Mechanisms/pathophysiology (S.H., E.S.H., R.J.R. and M.Q.); Diagnosis, screening and prevention (W.A. and M.Q.); Management (W.A., S.H., M.Q., R.J.R., S.B.-S. and D.J.T.); Quality of life (S.H.); Outlook (S.H., M.Q. and R.J.R.); Overview of Primer (S.H.).

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Correspondence to Stefanie Hahner.

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Competing interests

R.J.R. is a Director of Diurnal group PLC. W.A. served as consultant and clinical investigator for Diurnal Ltd. All other authors declare no competing interests.

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Nature Reviews Disease Primers thanks L. Chan, G. Johannsson, L. Nieman and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Glucocorticoids

A class of corticosteroids that are essential mediators of the stress system and major players in the stress response, that regulate resting homeostasis (metabolism of carbohydrates, proteins and fats) and modulate the immune response.

Mineralocorticoids

A class of corticosteroids involved in the maintenance of the salt and water balance in the body.

Immune checkpoint inhibitors

Drugs typically used in oncology that stimulate antitumour immune response by blocking checkpoint proteins and promoting immune-mediated elimination of tumour cells.

21-Hydroxylase

An enzyme involved in the biosynthesis of cortisol and aldosterone.

Autoimmune polyglandular syndromes

Also known as polyglandular autoimmune syndromes or autoimmune polyendocrine syndromes. These syndromes comprise a heterogeneous group of rare immune-mediated endocrinopathies affecting more than one endocrine organ. Non-endocrine organs may also be involved.

Hypopituitarism

Dysfunction of the pituitary with impaired secretion or a lack of secretion of one or more pituitary hormones.

Macula densa cells

Specialized cells lining the wall of kidney tubules that detect changes in distal tubular fluid composition and transmit signals to the glomerular vascular elements.

Juxtaglomerular cells

Specialized cells in the kidney that synthesize, store and secrete the enzyme renin.

Salt-wasting syndrome

A more severe form of congenital adrenal hyperplasia characterized by insufficient production and action of aldosterone that lead to renal sodium loss and consequent sodium depletion of the body. If undiagnosed, dehydration, hypotension, failure to thrive, hyponatraemia and hyperkalaemia occur within days of birth.

Virilization

A condition in which a female develops masculine characteristics such as excess facial and body hair, acne, increased muscle mass and baldness. Virilization is caused by excess production of endogenous androgens from the adrenals or the ovaries or from exogenous androgen administration.

Precocious pseudopuberty

Partial pubertal development that results from premature appearance of secondary sexual characteristics in prepubertal boys and girls owing to excess production of sex steroids.

Leydig cells

Steroidogenic cells in the testes that produce testosterone upon stimulation by pituitary luteinizing hormone.

Spastic paraparesis

A group of rare hereditary disorders that cause gradual weakness with muscle spasms.

Corticotroph

Cells in the anterior pituitary that produce pro-opiomelanocortin, which undergoes cleavage to form adrenocorticotropic hormone (ACTH) in response to stimulation by hypothalamic corticotropin-releasing hormone.

Adrenarche

Maturation of the zona reticularis of the adrenal resulting in increased production of adrenal androgens.

ACTH 1–24 stimulation test

Also known as the Synacthen test or corticotropin-stimulation test. This test is commonly used for the assessment of adrenal cortisol production. Cortisol serum levels are measured before and 30–60 min after supraphysiological stimulation with synthetic 1–24 ACTH.

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Hahner, S., Ross, R.J., Arlt, W. et al. Adrenal insufficiency. Nat Rev Dis Primers 7, 19 (2021). https://doi.org/10.1038/s41572-021-00252-7

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