CURSO DE MEDICINA

MARIA CLAÚDIA ALBUQUERQUE CASTELO BRANCO

RA: 80122000259

MÓDULO 20: DESORDENS NUTRICIONAIS E METABÓLICAS

AEP’s

Docentes: Dra. Caroline Pellicciari

SANTANA DE PARNAÍBA
2025
 1. ESTUDO DE CASO: ORIENTAÇÃO DE ALIMENTAÇÃO SAUDÁVEL
PARA DIABETES E HIPERTENSÃO
Questão 1.
1. Sobrepeso: com um IMC de 28, essa condição contribui para a resistência à
insulina, o que torna o controle da glicemia mais complicado.
2. Dieta inadequada: a ingestão frequente de alimentos processados, aliada à
dificuldade em preparar refeições saudáveis devido à falta de habilidades culinárias,
à vida solo e à limitação da renda, agrava a situação.
3. Falta de atividade física: a ausência de exercícios regulares prejudica não
apenas o controle do peso, mas também a sensibilidade à insulina e a regulação da
pressão arterial.
5. Tentativas frustradas com dietas da moda: a dificuldade em aderir a essas
dietas levou à desistência, evidenciando a necessidade de um plano alimentar mais
sustentável e que se adapte à sua realidade.

Questão 2.

1. Escolha alimentos naturais: Dê prioridade a opções como arroz, feijão,

legumes, verduras, frango e ovos. Fuja de produtos ultraprocessados que são ricos
em açúcar, sódio e gordura.
2. Facilite o preparo: Cozinhe em maiores quantidades e congele porções
para facilitar o dia a dia.
3. Adapte pratos tradicionais: Mantenha o arroz e feijão na sua
alimentação, mas inclua também saladas e vegetais. Use menos óleo e sal, optando
por temperos naturais.
4. Melhore suas fontes de carboidratos: Sempre que possível, escolha
versões integrais de arroz e pães.
5. Hidrate-se: Beba mais água e evite bebidas açucaradas.
6. Mude gradualmente: Introduza pequenas e consistentes alterações na
sua dieta, evitando dietas restritivas.

Questão 3.
 1. Educação alimentar clara e eficiente: apresentar, de forma prática, como
escolhas alimentares saudáveis propõem benefícios diretos no controle do diabetes e
da hipertensão, conectando esses hábitos ao seu bem-estar e qualidade de vida.
2. Metas pequenas e viáveis: definir objetivos curtos e tangíveis, como reduzir
de maneira gradual o consumo de alimentos processados e aumentar a inclusão de
vegetais nas refeições diárias.
3. Planejamento e organização das refeições: orientar Maria no preparo de
refeições simples em maior quantidade, ensinando-a a congelar porções. Assim, ela
terá fácil acesso a refeições saudáveis, mesmo em dias de baixa disposição.
4. Uso de alimentos acessíveis: mostrar como é possível utilizar ingredientes
comuns e acessíveis, como arroz, feijão e legumes, de maneira equilibrada, sem
necessidade de maiores gastos.
5. Apoio contínuo e acompanhamento: proporcionar suporte regular, seja
através de consultas presenciais ou remotas, para avaliar o progresso, esclarecer
dúvidas e adaptar o plano alimentar sempre que necessário.
6. Encorajamento e motivação: valorizar os pequenos avanços de maria,
estimulando mudanças graduais e sustentáveis, evitando a frustração que pode vir de
dietas restritivas.

Questão 4.

1. Atividade física regular:

- Realizar caminhadas rápidas de 30 minutos, cinco vezes por semana
(totalizando 150 minutos), nas proximidades de casa ou em parques.
- Incluir exercícios de fortalecimento muscular, como agachamentos e
alongamentos, para melhorar a força, o equilíbrio e a sensibilidade à insulina.
2. Planejamento alimentar simples:
- Cozinhar alimentos em maior quantidade, como arroz integral, feijão e
vegetais, e congelar porções para facilitar as refeições durante a semana.
- Criar cardápios práticos e saudáveis a fim de evitar produtos
ultraprocessados.
3. Monitoramento e educação:
- Manter um diário alimentar para rastrear a ingestão de açúcares e sódio,
identificando possíveis excessos.
 - Enfatizar que mudanças graduais tendem a ser mais eficazes do que dietas
restritivas.
4. Apoio profissional:
- Buscar a orientação de nutricionistas e educadores em diabetes para obter
aconselhamentos práticos e personalizados.

5. Liste as fontes consultadas para embasar as respostas.

Silva Júnior WS, Fioretti AMB, Vancea DMM, Macedo CLD, Zagury R. Atividade física
e exercício no pré-diabetes e DM2. Diretriz da Sociedade Brasileira de Diabetes.
Disponível em: https://diretriz.diabetes.org.br/atividade-fisica-e-exercicio-no-pre-
diabetes-e-dm2/?pdf=5742. Acesso em: 01 de março de 2025.

Delmondes EBM, Abreu DS. A Importância da Dietoterapia no controle do Diabetes

Tipo 2 em Adultos: Uma Revisão de Literatura. Id on Line Rev Psic. 2022;16(63):382-
396. DOI: 10.14295/idonline.v16i63.3592. Disponível em:
http://idonline.emnuvens.com.br/id. Acesso em: 20 fev. 2025.

Izar MC, Fonseca FAH, Faludi ÁÁ, Araújo DB. Manejo da hipertensão arterial no
diabetes. Diretriz da Sociedade Brasileira de Diabetes. Última revisão em: 06/01/2022.
Disponível em: https://diretriz.diabetes.org.br/manejo-da-hipertensao-arterial-no-
diabetes/. Acesso em: 01 mar 2025.

Silva CA, Lima WC. Efeito Benéfico do Exercício Físico no Controle Metabólico do
Diabetes Mellitus Tipo 2 à Curto Prazo. Arq Bras Endocrinol Metab. 2002;46(5):550-
556. Disponível em: https://www.scielo.br/j/abem/article/view/157062. Acesso em: 22
fev. 2025.

Ramos S, Campos LF, Baptista DR, Strufaldi M, Gomes DL, Guimarães DB, et al.
Terapia Nutricional no Pré-Diabetes e no Diabetes Mellitus Tipo 2. Diretriz Oficial da
Sociedade Brasileira de Diabetes. 2024. Disponível em:
https://diretriz.diabetes.org.br/terapia-nutricional-no-pre-diabetes-e-no-diabetes-
mellitus-tipo-2/?pdf=8968. Acesso em: 01 de março de 2025.
NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in diabetes prevalence
and treatment from 1990 to 2022: A pooled analysis of 1108 population-representative
studies with 141 million participants. Lancet. 2024;404:2077-93. Disponível em:
https://doi.org/10.1016/S0140-6736(24)00037-6. Acesso em: 01 de março de 2025.

1. REVISÃO DE LITERATURA: TRATAMENTO FARMACOLÓGICO DA

OBESIDADE
USAR ARTIGO: HTTPS://DOI.ORG/10.1093/CVR/CVAC176

A obesidade é uma condição crônica que eleva o risco de desenvolver

doenças como diabetes tipo 2 e complicações cardiovasculares. Entre os
medicamentos analisados – Tirzepatide, Semaglutida e Liraglutida – observamos
variações em seus mecanismos de ação, eficácia, efeitos colaterais e limitações.
Os análogos do GLP-1, Liraglutida e Semaglutida, atuam promovendo a
saciedade, aumentando a secreção de insulina e reduzindo a liberação de glucagon,
o que contribui para um melhor controle glicêmico. Por outro lado, a Tirzepatide, um
agonista dual de GLP-1 e GIP, age nos receptores relacionados a ambos os
hormônios, aumentando a sensação de saciedade, melhorando a sensibilidade à
insulina e favorecendo a redução da gordura corporal.
No que diz respeito ao controle de peso, a Semaglutida mostrou uma perda
média de cerca de 15% (na dosagem de 2,4 mg por semana). A Tirzepatide, por sua
vez, apresentou resultados ainda mais impressionantes, com algumas pessoas
perdendo mais de 20%, superando as expectativas em relação a tratamentos
anteriores. Já a Liraglutida demonstrou uma eficácia menor, com uma perda de peso
em torno de 8 a 10%.
Entre os efeitos colaterais, estão os gastrointestinais, como náuseas, vômitos,
diarreia e constipação, que são comuns entre todos os medicamentos. Vale destacar
que a continuidade do uso é essencial, uma vez que a interrupção do tratamento
normalmente resulta na recuperação do peso perdido.
Diante desse cenário, o Tirzepatide se destaca por sua maior eficácia na
perda de peso, graças à sua ação dual. No entanto, é importante ressaltar que todos
os tratamentos precisam ser mantidos de forma contínua para garantir os resultados
desejados. Os efeitos colaterais gastrointestinais representam um desafio
significativo para a adesão ao tratamento, especialmente entre pacientes com
histórico de problemas digestivos. Assim, são necessários mais estudos para avaliar
os riscos cardiovasculares a longo prazo e para personalizar os tratamentos,
visando melhores resultados.

Figura 1. Comparação entre os medicamentos.

Fonte: Elaborado pela autora (2025).

2. QUIZ DOS PRINCIPAIS TEMAS EM ENDOCRINOLOGIA

1. B)
2. C)
3. D)
4. C)
5. A)
6. B)
7. B)
8. C)
9. B)
10. B)
11. B)
12. B)
13. B)
14. B)
15. C)
16. A)
17. C)
18. D)
 19. B)
20. B)

3. RESOLUÇÃO DE PROTOCOLO CLÍNICO: MANEJO DE DOENÇAS

TIREOIDIANAS NA GESTAÇÃO

Distúrbios tireoidianos durante a Gestação: diagnóstico e classificação

1. Hipotireoidismo na gestação
O hipotireoidismo durante a gestação é definido pela produção insuficiente de
hormônios tireoidianos. O diagnóstico é realizado através de uma combinação de
parâmetros laboratoriais. A seguir, estão distribuídos os critérios de diagnóstico, bem
como as diversas formas de hipotireoidismo.

Tabela 1. Critérios de diagnóstico

CRITÉRIO HIPOTIREOIDISMO HIPOTIREOIDISMO OVERT
DIAGNÓSTICO SUBCLÍNICO
Níveis de TSH Elevados (acima de 2,5 Muito elevados (acima de 10 mUI/L)
mUI/L e < 10 mUI/L.
Níveis de FT4 Limites normais Reduzidos ou abaixo do intervalo de
referência
Características Assintomático ou com Sintomas evidentes de
clínicas sintomas leves hipotireoidismo
Anticorpos Pode estar presente Pode estar presente, relacionado
antitireoidianos (TPOAb, TgAb) com maior risco de complicações e
persistência pós-parto
Fonte: Elaborado pela autora (2025).

• Hipotireoidismo subclínico: nesta condição, os níveis de TSH estão

elevados, enquanto o FT4 se mantém dentro da normalidade. Isso sugere que a
tireoide ainda é capaz de produzir uma quantidade adequada de hormônios, mas a
glândula pituitária tenta compensar uma leve diminuição na produção tireoidiana.
• Hipotireoidismo overt: aqui, tanto os níveis de TSH estão elevados
quanto o FT4 apresenta uma redução. Essa situação indica uma falha na produção
hormonal pela tireoide.
 2. Hipertireoidismo na gestação
O hipertireoidismo durante a gestação é causado pela produção excessiva de
hormônios da tireoide. Para diagnosticar essa condição, são avaliados os níveis de
TSH, FT4, T3 e anticorpos específicos.

Tabela 2. Critérios de diagnóstico

CRITÉRIO DE HIPERTIREOIDISMO GESTACIONAL
DIAGNÓSTICO
Níveis de TSH Suprimidos (geralmente < 0,1 mUI/L)
Níveis de FT4 e T3 Elevados (confirmando hipertireoidismo)
Anticorpos (TRAb) Presença de anticorpos TRAb (indicativo da Doença de
Graves)
Características clínicas Sintomas de hipertireoidismo, como taquicardia e perda
de peso inexplicada
Fonte: Elaborado pela autora (2025).

• Hipertireoidismo Gestacional: Durante o primeiro trimestre da gestação,

é comum que os níveis de TSH estejam baixos como uma resposta fisiológica
normal. No entanto, se esses níveis baixos forem acompanhados por aumentos
em FT4 ou T3, o diagnóstico de hipertireoidismo se confirma. Além disso, a
presença de anticorpos TRAb pode sugerir a Doença de Graves, que é uma das
principais causas do hipertireoidismo durante a gravidez.

3. Disfunção tireoidiana subclínica

A disfunção tireoidiana subclínica se manifesta através de alterações nos níveis
de TSH, enquanto os hormônios tireoidianos, como FT4 e T3, permanecem dentro
dos limites normais.

Tabela 7. Critérios de diagnóstico

CRITÉRIO DISFUNÇÃO TIREOIDIANA SUBCLÍNICA
DIAGNÓSTICO
Níveis de TSH Entre 2,5 e 10 mUI/L
Níveis de FT4 Dentro dos limites normais
 Características Assintomático, mas com risco potencial de complicações
clínicas
Riscos associados Aumento do risco de hipertensão gestacional, parto
prematuro, complicações relacionadas à autoimunidade
Fonte: Elaborado pela autora (2025).

Abordagem inicial para hipotireoidismo e hipertireoidismo em gestantes

1. Hipotireoidismo na gestação
A meta é manter os níveis de TSH abaixo de 2,5 mUI/L, minimizando assim os
riscos tanto para a mãe quanto para o feto.
Início e ajuste da levotiroxina:
- Dosagem inicial: entre 1,6 e 1,8 mcg/kg/dia.
- Ajustes: aumentar a dose conforme necessário, com monitoramento mensal
do tsh até a 16ª semana de gestação.

Monitoramento:
- Frequência: mensal até a 16ª semana, podendo ser reduzido depois, desde
que os níveis estejam estáveis.
- Interpretação: é importante considerar as variações naturais dos níveis de T4
livre, que podem ser influenciadas pela produção da placenta.

2. Hipertireoidismo na gestação
O foco é o controle da produção excessiva de hormônios tireoidianos.

- Uso de antitireoidianos:
- 1º trimestre: optar pelo propiltiouracil (ptu), que é considerado mais seguro
nessa fase.
- 2º trimestre: substituir pelo metimazol (mmi), que oferece maior eficácia e
requer doses menores.

- Monitoramento:
- frequência: avaliação de TSH e T4 livre a cada 1 a 2 semanas no início,
ajustando as doses conforme necessário.
 Monitoramento e Ajustes
- Levotiroxina: aumentar a dose em 20-30% após a confirmação da gravidez,
com acompanhamento mensal do TSH até a 20ª semana.
- Antitireoidianos: monitoramento frequente é essencial para ajustar as doses e
prevenir complicações.

Complicações obstétricas e neonatais

- Pré-eclâmpsia: o risco é maior em casos de hipertireoidismo não controlado.
- Restrição de crescimento fetal: pode ocorrer em ambos os casos, tanto no
hipotireoidismo quanto no hipertireoidismo.
- Parto prematuro: é fundamental controlar a função tireoidiana para reduzir
essa probabilidade.
- Complicações Neonatais: um controle rigoroso da função tireoidiana materna
é crucial para evitar riscos como hipotireoidismo neonatal, taquicardia e baixo peso ao
nascer.

Encaminhamentos para Especialistas

- Endocrinologista:
- Presença de dificuldades no controle tireoidiano.
- Complicações graves da Doença de Graves, como oftalmopatia.
- Nódulos tireoidianos suspeitos (classificação TIRADS 4 ou 5).
- Neonatologista: para monitoramento do recém-nascido em casos de
hipotireoidismo ou hipertireoidismo neonatal, especialmente se houver sinais de
complicações relacionadas à função tireoidiana.
Um manejo adequado, aliado a um monitoramento constante e à colaboração
com neonatologistas, endocrinologistas e obstetras, é fundamental para prevenir
complicações materno-fetais e garantir um acompanhamento eficaz durante a
gestação e no período pós-natal.

Fluxograma 1.
 Fonte: Elaborado pela autora (2025).

Fontes: Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the
American Thyroid Association for the Diagnosis and Management of Thyroid Disease
During Pregnancy and Postpartum. Thyroid. 2017;27(3):315-389.
doi:10.1089/thy.2016.0455. Disponível em: https://www.thyroid.org/professionals/ata-
professional-guidelines/. Acesso em: 03 mar. 2025.

4. CRIAÇÃO DE MATERIAL EDUCATIVO: ENDOCRINOLOGIA DO

CRESCIMENTO INFANTIL E BAIXA ESTATURA

O sistema endócrino desempenha um papel crucial no crescimento e

desenvolvimento do corpo humano, destacando-se a atuação do hormônio do
crescimento (GH) e do fator de crescimento semelhante à insulina (IGF-1). O GH,
secretado pela glândula pituitária anterior, exerce seus efeitos de forma direta nos
tecidos e, indiretamente, por meio do IGF-1, um hormônio produzido, em sua maior
parte, no fígado.

1. A importância do gh e do igf-1 no crescimento ósseo e muscular

O GH atua ligando-se a receptores específicos nas células-alvo, iniciando
uma série de reações intracelulares que promovem a expressão de genes
responsáveis pela produção de proteínas, bem como pela proliferação e
diferenciação celular. No que diz respeito ao crescimento ósseo, o GH exerce uma
ação direta sobre os condrocitos nas placas de crescimento, ou cartilagem epifisária,
estimulando sua mitose e a produção de matriz extracelular, resultando no
alongamento dos ossos longos.
Além disso, o GH estimula o fígado a produzir IGF-1, que potencializa a ação
do GH. O IGF-1 atua sobre vários tipos celulares, como osteoblastos (células
responsáveis pela formação óssea) e mioblastos (células precursoras das fibras
musculares), promovendo a síntese de proteínas e o crescimento celular. Nos ossos,
o IGF-1 impulsiona a ossificação e a mineralização da matriz osteoide, processos
fundamentais para o fortalecimento e desenvolvimento ósseo. No tecido muscular, o
IGF-1 favorece a hipertrofia muscular, estimulando a síntese de proteínas
musculares e a proliferação das células satélites, que são essenciais para a
regeneração e aumento da massa muscular.

2. A influência dos hormônios tireoidianos no desenvolvimento físico e

cognitivo
Os hormônios da tireoide, em especial a triiodotironina (T3) e a tiroxina (T4),
são vitais para o desenvolvimento físico e mental, especialmente na infância. Eles
favorecem o crescimento e a maturação do sistema nervoso central, um aspecto
crucial para um desenvolvimento cognitivo saudável. A deficiência desses hormônios
durante a gestação ou na infância pode resultar em sérias limitações no crescimento
e comprometimentos nas funções cognitivas, como se observa no cretinismo.
Além disso, esses hormônios aceleram o metabolismo celular, promovendo a
captação de oxigênio e nutrientes pelos tecidos, e estimulando a atividade de
enzimas envolvidas no metabolismo energético, processos indispensáveis para o
crescimento. Os hormônios tireoidianos também desempenham uma função
importante no desenvolvimento ósseo, facilitando a conversão dos condrócitos em
osteoblastos, o que contribui para o aumento da densidade óssea e para o
fortalecimento estrutural do esqueleto.

3. A interação de outros hormônios no metabolismo do crescimento: insulina e

cortisol
 A interação entre diferentes hormônios, como a insulina e o cortisol, também
exerce influência significativa no metabolismo do crescimento, adicionando uma
camada de complexidade a esse intrincado sistema regulador.
A insulina e o cortisol exercem funções fundamentais no crescimento e no
metabolismo. A insulina é essencial para o aproveitamento da glicose e a síntese
proteica, facilitando a absorção de glicose e aminoácidos pelas células. Isso não
apenas promove a formação de proteínas, mas também é crucial para o crescimento
de tecidos como músculos e ossos. Além disso, a insulina aumenta a sensibilidade
das células ao IGF-1, potencializando ainda mais seus efeitos no crescimento.
Em contrapartida, o cortisol, um hormônio liberado em resposta ao estresse,
possui uma ação catabólica, podendo levar à degradação de tecidos, especialmente
da musculatura. Apesar de sua importância na regulação do metabolismo
energético, níveis elevados e persistentes de cortisol podem inibir a síntese de
proteínas, resultando em perda muscular e dificultando o crescimento ósseo.
Portanto, é fundamental que exista um equilíbrio entre esses hormônios para
garantir um desenvolvimento físico adequado.

4. Estimativa da estatura alvo genética

A altura final de uma criança, também conhecida como estatura alvo genética,
pode ser estimada a partir da altura dos pais. Para os meninos, a fórmula consiste
na soma das alturas do pai e da mãe, com um acréscimo de 13 cm; já para as
meninas, a abordagem é similar, mas subtraindo-se 13 cm. Essa estimativa reflete a
influência genética sobre a estatura, embora fatores ambientais, como nutrição e
cuidados de saúde, também tenham um papel significativo.

5. Estratégias para promover a saúde endócrina infantil

Uma nutrição adequada é um dos pilares essenciais para o crescimento
saudável das crianças. Uma dieta balanceada, contendo proteínas, vitaminas e
minerais fundamentais, é crucial para um desenvolvimento apropriado. A escassez
de nutrientes pode retardar o crescimento e aumentar o risco de deficiências.
A prática regular de atividades físicas é igualmente relevante, pois o exercício
estimula a liberação de hormônios anabólicos, como o GH e o IGF-1, favorecendo o
crescimento ósseo e muscular. Além disso, a atividade física ajuda a manter o
equilíbrio hormonal e melhora a saúde metabólica de maneira geral.
 Outro aspecto importante é a qualidade do sono, que desempenha um papel
fundamental no crescimento. A secreção de GH ocorre predominantemente durante
o sono profundo, principalmente nas primeiras horas de descanso. Assegurar que as
crianças tenham uma rotina de sono adequada pode maximizar os períodos de
crescimento e recuperação, beneficiando tanto o desenvolvimento físico quanto o
cognitivo.
Essas práticas, aliadas a um acompanhamento médico regular, são
fundamentais para otimizar os processos endócrinos e assegurar um desenvolvimento
saudável e equilibrado.

Fontes:
Silverthorn, D.U. Fisiologia Humana: Uma Abordagem Integrada. 7. ed. São
Paulo: Pearson; 2016.
Tratado de Pediatria. Sociedade Brasileira de Pediatria. Tratado de pediatria.
6ª ed. São Paulo: Manole; 2023.
Hall JE. Guyton & Hall: Tratado de fisiologia médica. 14ª ed. Rio de Janeiro:
Elsevier; 2021.
Vilar L. Endocrinologia clínica. 8ª ed. Rio de Janeiro: Guanabara Koogan; 2024

3. Caso clínicos
a) Caso Clínico 1:

A hipótese diagnóstica sugere baixa estatura constitucional, possivelmente

relacionada a características genéticas familiares, uma vez que tanto os pais quanto
os avós apresentaram estaturas abaixo da média. O paciente demonstra um
crescimento adequado para sua idade, com uma taxa de crescimento que se encaixa
nos padrões normais e sem a presença de sintomas como dor ou atraso puberal. A
estatura-alvo genética estimada é de 166,5 cm, o que está em consonância com o
crescimento do paciente, atualmente situado no percentil 10 para sua faixa etária. No
momento, não é necessário realizar exames laboratoriais, mas recomenda-se um
acompanhamento regular para assegurar o progresso contínuo.

b) Caso Clínico 2
 A hipótese diagnóstica aponta para uma puberdade tardia de origem fisiológica,
possivelmente influenciada por fatores genéticos, considerando o histórico familiar de
puberdade tardia do pai. O paciente apresenta estatura abaixo da média e não
apresenta sinais de puberdade, além de ter uma idade óssea de 10 anos, o que sugere
um atraso no crescimento, mas alinhado com seu padrão genético. A ausência de
sintomas sistêmicos, como fadiga ou dor óssea, e a normalidade nas proporções
corporais fortalecem essa suposição. Recomenda-se a realização de exames
laboratoriais, incluindo a dosagem hormonal, para descartar distúrbios endócrinos. No
entanto, em uma análise preliminar, o quadro parece indicar um atraso puberal
constitucional.

c) Caso Clínico 3

A principal hipótese diagnóstica é a deficiência de hormônio do crescimento

(GH), uma vez que observamos uma baixa estatura persistente, abaixo do percentil 3,
e uma velocidade de crescimento inferior a 4 cm por ano, acompanhada de
características infantis e leve adiposidade abdominal. Essa situação indica um
comprometimento do desenvolvimento adequado para a faixa etária. Para
confirmação do diagnóstico e orientação terapêutica, é essencial realizar exames
laboratoriais, como a dosagem de IGF-1 e testes de estimulação do GH, além de um
acompanhamento clínico regular.

6. ANÁLISE CRÍTICA DE ARTIGO CIENTÍFICO: CRISE ADRENAL

O artigo intitulado "European society of endocrinology and endocrine society

joint clinical guideline: diagnosis and therapy of glucocorticoid-induced adrenal
insufficiency" visa oferecer diretrizes baseadas em evidências para o diagnóstico e
tratamento da insuficiência adrenal induzida pelo uso crônico de glicocorticoides, uma
condição séria que pode afetar pacientes que utilizam essa medicação de forma
prolongada. A relevância clínica do tema é inegável, uma vez que muitos pacientes
em tratamento contínuo, especialmente por condições inflamatórias e autoimunes,
estão vulneráveis ao desenvolvimento da insuficiência adrenal, que pode
desencadear crises adrenais, emergências médicas com potenciais consequências
graves.
 A elaboração dessas diretrizes foi realizada por um grupo de especialistas em
endocrinologia, utilizando a metodologia GRADE para avaliar a qualidade das
evidências disponíveis. A revisão sistemática da literatura revelou que o diagnóstico
pode frequentemente ser realizado com base em sinais clínicos, dispensando a
necessidade de testes dinâmicos. Além disso, o acompanhamento cuidadoso durante
a redução ou interrupção do uso dos glicocorticoides é fundamental para evitar a
ocorrência de crises adrenais.
O artigo se destaca pela colaboração multidisciplinar, que enriqueceu a
abordagem do tema. As diretrizes estão embasadas em uma ampla gama de
evidências clínicas, e suas recomendações foram elaboradas com rigor metodológico,
levando em conta as necessidades específicas de cada paciente. Contudo, uma
limitação significativa reside na qualidade das evidências, frequentemente classificada
como baixa ou muito baixa, o que indica a necessidade de mais pesquisas para validar
as recomendações e aprimorar as estratégias de manejo.
Essas diretrizes têm um impacto considerável na prática clínica, oferecendo um
direcionamento claro para o cuidado e monitoramento de pacientes que utilizam
glicocorticoides por longos períodos. A educação contínua de profissionais de saúde
e dos pacientes sobre os sinais de insuficiência adrenal é crucial para reduzir a
incidência de crises, melhorando os resultados clínicos e a qualidade de vida dos
pacientes. Este estudo representa uma contribuição relevante para o manejo da
insuficiência adrenal induzida por glicocorticoides.
European Journal of Endocrinology, 2024, 190, G25–G51
https://doi.org/10.1093/ejendo/lvae029
Advance access publication 8 May 2024
Clinical Practice Guideline

European Society of Endocrinology and Endocrine Society

Joint Clinical Guideline: Diagnosis and therapy of
glucocorticoid-induced adrenal insufficiency
Felix Beuschlein,1,2,3,*† Tobias Else,4,† Irina Bancos,5,6 Stefanie Hahner,7 Oksana Hamidi,8
Leonie van Hulsteijn,9,10 Eystein S. Husebye,11,12 Niki Karavitaki,13,14,15
Alessandro Prete,13,14,16 Anand Vaidya,17 Christine Yedinak,18 and Olaf M. Dekkers10,19,20

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1
Department of Endocrinology, Diabetology and Clinical Nutrition, University of Zürich (USZ) and University of Zürich (UZH), Zürich,
Switzerland
2
Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität, Munich, Germany
3
The LOOP Zurich Medical Research Center, Zurich, Switzerland
4
Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI 48109, USA
5
Division of Endocrinology, Metabolism, and Nutrition, Mayo Clinic Rochester, MN 55905, US
6
Joint appointment in Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, MN 55905, US
7
Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Germany
8
Division of Endocrinology and Metabolism, University of Texas Southwestern Medical Center, Dallas, Texas, USA
9
European Society of Endocrinology, Bristol, UK
10
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
11
Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway
12
Department of Medicine, Haukeland University Hospital, N-5021 Bergen
13
Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
14
Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
15
Department of Endocrinology, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
16
NIHR Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust,
Birmingham, UK
17
Center for Adrenal Disorders, Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Harvard Medical
School, Boston, MA, USA
18
Department of Neurological Surgery, Oregon Health & Sciences University, Portland, Oregon, USA
19
Department of Endocrinology and Metabolism, Leiden University Medical Center, Leiden, The Netherlands
20
Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark
*Corresponding author: Felix Beuschlein, Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, Raemistrasse 100, CH-8091 Zürich; Switzerland, Email:
[email protected]; phone: +41 44 255 36 25

Abstract
Glucocorticoids are widely prescribed as anti-inflammatory and immunosuppressive agents. This results in at least 1% of the population using
chronic glucocorticoid therapy, being at risk for glucocorticoid-induced adrenal insufficiency. This risk is dependent on the dose, duration and
potency of the glucocorticoid, route of administration, and individual susceptibility. Once glucocorticoid-induced adrenal insufficiency develops
or is suspected, it necessitates careful education and management of affected patients. Tapering glucocorticoids can be challenging when
symptoms of glucocorticoid withdrawal develop, which overlap with those of adrenal insufficiency. In general, tapering of glucocorticoids can
be more rapidly within a supraphysiological range, followed by a slower taper when on physiological glucocorticoid dosing. The degree and
persistence of HPA axis suppression after cessation of glucocorticoid therapy are dependent on overall exposure and recovery of adrenal
function varies greatly amongst individuals. This first European Society of Endocrinology/Endocrine Society joint clinical practice guideline
provides guidance on this clinically relevant condition to aid clinicians involved in the care of patients on chronic glucocorticoid therapy.
Keywords: Adrenal insufficiency, glucocorticoids, steroids, adrenal crisis, substitution therapy, glucocorticoid withdrawal

1. Summary of recommendations quality of evidence behind the recommendations is classified

The recommendations are worded as recommend (strong rec­ as very low (⊕○○○), low (⊕⊕○○), moderate (⊕⊕⊕○),
ommendation) and suggest (weak recommendation). The and strong (⊕⊕⊕⊕). Recommendations that were based on
good clinical practice and experience of the working group
†
F.B. and T.E. are shared first author. members are not formally graded but acknowledged in the

Received: March 14, 2024. Editorial Decision: March 18, 2024. Accepted: March 18, 2024
This article has been co-published with permission in European Journal of Endocrinology and The Journal of Clinical Endocrinology & Metabolism © The
Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Endocrinology. This is an Open Access article distributed under
the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial
re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact
[email protected].
G26 European Journal of Endocrinology, 2024, Vol. 190, No. 5

guideline as ‘good clinical practice’. Recommendations that 2. be tested with a morning serum cortisol. (⊕○○○)
were neither based on evidence or good clinical practice, are • R 2.7 If confirmation of recovery of the HPA axis is de­
not graded at all (also see ‘Methods’ section). sired, we recommend morning serum cortisol as the first
test. The value of morning serum cortisol should be con­
sidered as a continuum, with higher values more indica­
1.1 General recommendations for glucocorticoid
tive of HPA axis recovery. (⊕○○○)
therapy of non-endocrine conditions and
recommendations regarding patient education
As a guide:
• R 1.1 We recommend that, in general, patients on, or ta­
1. we suggest that the test indicates recovery of the HPA axis
pering off glucocorticoids for non-endocrine conditions
if cortisol is >300 nmol/L or 10 μg/dL and glucocorti­
do not need to be evaluated by an endocrinology specialist.
coids can be stopped safely;
• R 1.2 We recommend that clinicians who implement
2. we suggest that if the result is between 150 nmol/L or 5
treatment with glucocorticoids educate patients about
μg/dL and 300 nmol/L or 10 μg/dL, the physiologic gluco­

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various endocrine aspects of glucocorticoid therapy.
corticoid dose should be continued, and the morning cor­
(Good clinical practice)
tisol repeated after an appropriate time period (usually
• R 1.3 We recommend that patients on glucocorticoid
weeks to months);
therapy have access to current up-to-date and appropriate
3. we suggest that if the result is <150 nmol/L or 5 μg/dL,
information about different endocrine aspects of gluco­
the physiologic glucocorticoid dose should be
corticoid therapy. (Good clinical practice)
continued, and the morning cortisol repeated after a
few months.
1.2. Recommendations regarding taper of
• R 2.8 We suggest against routinely performing a
systemic glucocorticoid therapy for non-endocrine
dynamic test for diagnosing adrenal insufficiency in pa­
conditions, diagnosis and approach to
tients tapering or stopping glucocorticoid therapy.
glucocorticoid-induced adrenal insufficiency, and
(⊕○○○)
glucocorticoid withdrawal syndrome
• R 2.9 We suggest awareness of possible glucocorticoid-
induced adrenal insufficiency in patients:
• R 2.1 We suggest not to taper glucocorticoids in patients 1. with current or recent use of non-oral glucocorticoid
on short-term glucocorticoid therapy of <3-4 weeks, irre­ formulations presenting with signs and symptoms in­
spective of the dose. In these cases, glucocorticoids can be dicative of adrenal insufficiency, or
stopped without testing due to low concern for HPA axis 2. using multiple glucocorticoid formulations simultan­
suppression. (⊕○○○) eously, or
• R 2.2 Glucocorticoid taper for patients on long-term gluco­ 3. using high-dose inhaled or topical glucocorticoids, or
corticoid therapy should only be attempted if the under­ 4. using inhaled or topical glucocorticoids for >1 year, or
lying disease for which glucocorticoids were prescribed is 5. who received intra-articular glucocorticoid injections
controlled, and glucocorticoids are no longer required. In in the previous 2 months, or
these cases, glucocorticoids are tapered until approaching 6. receiving concomitant treatment with strong cyto­
the physiologic daily dose equivalent is achieved (e.g., 4-6 chrome P450 3A4 inhibitors.
mg prednisone). (Good clinical practice) • R 2.10 We suggest that patients with current or previous
• R 2.3 We recommend consideration of glucocorticoid glucocorticoid treatment presenting with signs and symp­
withdrawal syndrome that may occur during glucocortic­ toms of exogenous Cushing syndrome are assumed to
oid taper. When glucocorticoid withdrawal syndrome is have glucocorticoid-induced adrenal insufficiency.
severe, glucocorticoid dose can be temporarily increased (Good clinical practice)
to the most recent one that was tolerated, and the dur­
• R 2.11 We suggest that patients aiming to discontinue glu­
ation of glucocorticoid taper could be increased. (Good
cocorticoids, but without recovery of HPA axis in one
clinical practice)
year while on physiologic daily dose equivalent, should
• R 2.4 We recommend against routine testing for adrenal
be evaluated by an endocrinology specialist. We suggest
insufficiency in patients on supraphysiologic doses of glu­
that patients on glucocorticoids and history of adrenal cri­
cocorticoids, or if they are still in need of glucocorticoid
sis should also be evaluated by an endocrinology special­
treatment for the underlying disease. (Good clinical
ist. (Good clinical practice)
practice)
• R 2.12 We recommend against the use of fludrocortisone in
• R 2.5 We suggest that patients taking long-acting gluco­
patients with glucocorticoid-induced adrenal insufficiency.
corticoids (e.g., dexamethasone or betamethasone)
should be switched to shorter-acting glucocorticoids
(e.g., hydrocortisone or prednisone) when long-acting
glucocorticoids are no longer needed. (⊕○○○) 1.3. Recommendations on diagnosis and therapy
• R 2.6 We suggest that patients on a physiologic daily dose of adrenal crisis in patients with
equivalent, and aiming to discontinue glucocorticoid glucocorticoid-induced adrenal insufficiency
therapy, either:
1. continue to gradually taper the glucocorticoid dose, • R 3.1 We recommend that patients with current or
while being monitored clinically for signs and symp­ recent glucocorticoid use who did not undergo biochem­
toms of adrenal insufficiency, or ical testing to rule out glucocorticoid-induced adrenal
Beuschlein et al. G27

insufficiency should receive stress dose coverage when prescription in primary care was found to be 3% with a re­
they are exposed to stress. (Good clinical practice) markably high rate among the elderly of up to 10% during
• R3.1A Oral glucocorticoids should be used in case of mi­ 1999–2015.7
nor stress and when there are no signs of hemodynamic
instability or prolonged vomiting or diarrhea. 3.1 Adverse effects of long-term glucocorticoid
• R3.1B Parenteral glucocorticoids should be used in case therapy
of moderate to major stress, procedures under general
While glucocorticoids are highly effective agents in the treat­
or regional anesthesia, procedures requiring prolonged
ment of autoimmune and inflammatory disorders, they can
avoidance or inability of oral intake, or when there are
cause adverse reactions, particularly when administered at
signs of hemodynamic instability or prolonged vomiting
high doses and/or for a prolonged period. However, even rela­
or diarrhea.
tively low dose (in the range of physiologic daily dose equiva­
• R 3.2 We suggest that in patients with current or recent
lent), long-term glucocorticoid therapy is linked to a range of
glucocorticoid use who did not undergo biochemical test­
adverse outcomes. For instance, a British cohort study involving
ing to rule out glucocorticoid-induced adrenal insuffi­
9,387 patients with rheumatoid arthritis observed over a me­

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ciency and present with hemodynamic instability,
dian of 8 years (with an average prednisone dosage of 5.8 mg/
vomiting, or diarrhea, the diagnosis of adrenal crisis
day for approximately 9.5 months) exhibited elevated rates of
should be considered irrespective of the glucocorticoid
conditions such as diabetes, osteoporosis, fractures, hyperten­
type, mode of administration, and dose; patients with sus­
sion, thrombotic events, gastrointestinal complications, and
pected adrenal crisis should be treated with parenteral
increased mortality, compared to those not treated with gluco­
glucocorticoids and fluid resuscitation. (Good clinical
corticoids.8 Of note, these observations may be confounded by
practice)
the underlying disease severity. Additional studies have corro­
borated these findings, linking even low dose glucocorticoid
use (prednisone 2.5–7.5 mg/day) to increased risks of cardio­
2. Introduction vascular disease,9 severe infections,10 hypertension,11 dia­
At least 1% of the population use chronic glucocorticoid ther­ betes,12 osteoporosis and fractures,13,14 and increased overall
apy as anti-inflammatory and immunosuppressive agents.1–3 mortality with concurrent type 2 diabetes mellitus.15 While
Virtually every discipline of medicine applies glucocorticoids the absolute risk elevations were relatively modest, the impli­
via multiple modes of administration (including oral, inhaled, cations are significant given the extensive patient population
intranasal, intra-articular, topical, and intravenous), and exposed to low dose glucocorticoids.15
frequently for prolonged duration. Suppression of the
hypothalamic-pituitary-adrenal (HPA) axis is an inevitable ef­ 3.2 Pathophysiology of glucocorticoid-induced
fect of chronic exogenous glucocorticoid therapy and recovery adrenal insufficiency
of adrenal function varies greatly amongst individuals.
Glucocorticoids suppress HPA axis activity by inhibiting
Glucocorticoid-induced adrenal insufficiency necessitates
the production of corticotropin-releasing hormone (CRH)
careful education and management, and in the rare cases of
by the hypothalamus and adrenocorticotropic hormone
adrenal crisis, prompt diagnosis and therapy.4 Considering
(ACTH) by the pituitary. Inhibition of CRH and ACTH
the widespread use of glucocorticoids and the risk for
induced by exogenous glucocorticoids is similar to the mecha­
glucocorticoid-induced adrenal insufficiency, the present clin­
nisms involved in the physiologic cortisol negative feedback.16
ical practice guideline provides guidance on this clinically rele­
Prolonged duration of supraphysiologic glucocorticoid ther­
vant condition to aid the endocrinology specialists, as well as
apy often leads to a reduction in the overall responsiveness
general practitioners and other specialists involved in the care
of the anterior pituitary gland. In rodent models, glucocorti­
of these patients.
coids exert pro-apoptotic effects on the pituitary gland17 and
promote protein degradation as represented by Crooke’s hya­
line in corticotroph cells.18 This ultimately results in atrophy
3. Epidemiology of glucocorticoid therapy of the adrenal cortex. Conversely, following withdrawal of
Since their first description in the late 1940s,5 glucocorticoids glucocorticoids, there is resurgence of ACTH stimulation of
have remained cornerstone agents in treating a wide array of the adrenal cortex. In most instances, the adrenal cortex will
medical conditions, ranging from autoimmune diseases, in­ recover and produce adequate levels of cortisol. Despite these
flammatory disorders and severe allergic reactions to the pre­ adaptive responses, the time to full biochemical and clinical
vention of transplant rejection and as antineoplastic agents for restitution of the HPA axis is highly variable.
hematologic neoplasias. Earlier studies estimated that the Any glucocorticoid dose above the physiologic daily dose
prevalence of oral glucocorticoid use was approximately 1% equivalent can potentially lead to suppression of the HPA
in the United Kingdom and the United States adult popula­ axis. The degree and persistence of HPA axis suppression after
tions.1–3 Based on a population of more than 65,000 patients cessation of glucocorticoid therapy are dependent on overall
registered with general practitioners in 1995 in the United exposure, which, amongst other factors, is determined by po­
Kingdom, continuous (> 3 months) oral glucocorticoids tency of the glucocorticoid (Table 1), glucocorticoid dose,
were prescribed for 0.5% of the total population and 1.4% length of therapy, and individual susceptibility. Notably, any
of patients age 55 years or older.6 Additional data from the route of administration has the potential of HPA axis suppres­
United Kingdom showed an increase of long-term glucocortic­ sion, including oral, topical, inhaled, intra-nasal, intravenous
oid prescriptions between 1989 and 2008 from 0.59% to and intra-articular administration.
0.79% of adult patients.1 In a population-based study from With regards to glucocorticoid therapy, immunosuppres­
Denmark, the annual prevalence of systemic glucocorticoid sive and anti-inflammatory doses considerably exceed the
G28 European Journal of Endocrinology, 2024, Vol. 190, No. 5

Table 1: Pharmacologic characteristics of commonly prescribed systemic glucocorticoids74,131–134

Glucocorticoids Approximate Glucocorticoid potency Plasma Biological Therapeutic indications

equivalent dosea (relative to hydrocortisone)a,b half-life half-life (hours)a
(min)a,c
Short-acting glucocorticoids with lower potency
Hydrocortisone 20 mg 1.0 90-120 8-12 Adrenal insufficiency replacement
Cortisone acetate 25 mg 0.8 80-120 8-12 Adrenal insufficiency replacement
Deflazacort 7.5 mg 1.0 70-120 Not defined Duchenne muscular dystrophy
Intermediate-acting glucocorticoids with moderate potency
Prednisone 5 mg 4.0 60 12-36 Anti-inflammatory,
immunosuppressant;
Adrenal insufficiency replacement
Prednisolone 5 mg 4.0 115-200 12-36 Anti-inflammatory,
immunosuppressant;
Adrenal insufficiency replacement

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Triamcinolone 4 mg 5.0 30 12-36 Anti-inflammatory,
immunosuppressant
Methylprednisolone 4 mg 5.0 180 12-36 Anti-inflammatory,
immunosuppressant
Long-acting glucocorticoids with highest potency
Dexamethasone 0.5 mg 30-60 200 36-72 Anti-inflammatory,
immunosuppressant;
Usually reserved for short-term use
in severe, acute conditions.
Betamethasone 0.5 mg 25-40 300 36-72 Anti-inflammatory,
immunosuppressant;
Usually reserved for short-term use
in severe, acute conditions.
a
These are estimates based on historically accepted conversion factors and should be seen as a guide only. There can be considerable variation depending on
factors such as route of administration, the individual patient’s metabolism and susceptibility.
b
Glucocorticoid potency equivalences apply to oral and/or intravenous administration. Mineralocorticoid effects are not considered.
c
Plasma half-life does not reflect the biological half-life.

equivalent of endogenous cortisol production and, therefore, of this biochemical glucocorticoid-induced adrenal insuffi­
invariably result in HPA axis suppression. While tapering glu­ ciency was not established. In the above-mentioned meta-
cocorticoids within the supraphysiologic dose range, patients analysis, ten of the 74 included studies also assessed symptoms
can develop glucocorticoid withdrawal syndrome, which of adrenal insufficiency (although not systematically scored) in
manifests with clinical features similar to those of adrenal in­ a total of 521 patients.19 Of these 521 patients, 98 patients had
sufficiency. However, symptoms due to adrenal insufficiency biochemical evidence of adrenal insufficiency. Ten of them
are much more likely to develop when overall total daily (10%) reported symptoms. However, 88 (90%) did not report
glucocorticoid dose is below physiologic levels, or levels re­ any symptoms indicating that clinical symptoms are not specific
quired for an adequate stress response. and do not correlate well with biochemical findings.
A Danish self-controlled case series including 286,680
persons who discontinued prolonged (≥3 months) oral gluco­
3.3 Epidemiology of glucocorticoid-induced corticoid treatment, assessed the presence of clinical conse­
adrenal insufficiency and associated morbidity and quences of glucocorticoid-induced adrenal insufficiency after
mortality glucocorticoid cessation.20 Comparing the discontinuation
A meta-analysis of the risk of developing biochemical period with the reference period (the period before treatment
glucocorticoid-induced adrenal insufficiency stratified by gluco­ started), increased incidence rate ratios of clinical indicators
corticoid route of administration showed pooled percentages of of adrenal insufficiency were found: 2.5 (95% CI 1.4-4.3)
4.2% (95% CI 0.5–28.9) for nasal administration, 48.7% (95% for hypotension, 1.7 (95% CI 1.6-1.9) for gastrointestinal
CI 36.9-60.6) for oral use, and 52.2% (95% CI 40.5–63.6) for symptoms, 2.2 (95% CI 0.7-7.3) for hypoglycemia, and 1.5
intra-articular administration.19 The risk also varied when (95% CI 1.1-2.0) for hyponatremia.
stratified for the underlying disease and increased with higher Only a few studies report on the incidence of adrenal crisis
dose (low dose 2.4% (95% CI 0.6 –9.3) to high dose 21.5% in patients with glucocorticoid-induced adrenal insufficiency.
(95% CI 12.0–35.5)) and longer treatment duration (1.4% In a United States survey reporting on self-perceived determi­
(95% CI 0.3–7.4) (<28 days) to 27.4% (95% CI 17.7–39.8) nants of health in patients with adrenal insufficiency, a median
(>1 year)) in patients with asthma. Since an estimated minimum of 0 (IQR 0-0.33) adrenal crises per person-year since diagno­
of 1% of adult populations (United States and United Kingdom) sis were reported in glucocorticoid-induced adrenal insuffi­
use oral glucocorticoids at any given time1–3, this would imply ciency, compared to 0.07 (IQR 0-0.25) in primary adrenal
several million people are at risk of developing glucocorticoid- insufficiency and 0 (IQR 0-0.14) in secondary adrenal insuffi­
induced adrenal insufficiency in these countries alone. ciency.21 A Dutch study found an incidence rate of 15.1 (95%
It must be taken into consideration that in most of the studies CI 11.0–19.9) per 100 person-years in 28 patients with
the diagnosis of glucocorticoid-induced adrenal insufficiency glucocorticoid-induced adrenal insufficiency, compared to
was based on biochemical testing, whereas the clinical relevance 5.2 (95% CI 4.3– 6.3) in 111 patients with primary adrenal
Beuschlein et al. G29

insufficiency and 3.6 (95% CI 3.1– 4.1) in 319 patients with (15-25 mg hydrocortisone, 4-6 mg prednisone or prednis­
secondary adrenal insufficiency.22 These outcomes must be in­ olone, 3-5 mg methylprednisone, 0.25-0.5 mg dexa­
terpreted cautiously however because of the few subjects with methasone). Endogenous production of cortisol is
glucocorticoid-induced adrenal insufficiency and possible se­ estimated to be 9-10 mg/day. The above mentioned doses
lection bias. In this study, the presence of comorbidities (in­ are based on an estimate of bioavailability
cluding neurologic, cardiac and malignant diseases) was the • Supraphysiologic glucocorticoid therapy: Any dose
most important risk factor for developing adrenal crisis. Of greater than physiologic daily dose equivalent (see above)
note, in six patients with glucocorticoid-induced adrenal in­ • Short-term glucocorticoid therapy: Any glucocorticoid
sufficiency, adrenal crisis was precipitated by a reduction in therapy of less than 3-4 weeks duration
glucocorticoid dose. There were 20 deaths in the total cohort, • Long-term glucocorticoid therapy: Glucocorticoid ther­
but none was reported as related to adrenal crisis. apy greater than 3-4 weeks duration with glucocorticoid
In the European Adrenal Insufficiency Registry which in­ doses greater than physiologic daily dose equivalent of
cluded 1233 patients with secondary adrenal insufficiency fol­ hydrocortisone (15-25 mg hydrocortisone, 4-6 mg pred­
lowed for 5 years, 18 deaths were reported.23 The Registry nisone or prednisolone, 3-5 mg methylprednisone,

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included various etiologies of adrenal insufficiency and the per­ 0.25-0.5 mg dexamethasone)
centage of patients with their condition attributed to exogenous • Glucocorticoid taper: Taper of glucocorticoid therapy
glucocorticoids could not be ascertained [personal communica­ dose, initially guided by the management of the under­
tion with the author]. Only one of the 26 deaths was clearly at­ lying disease (= therapeutic taper), and later by the man­
tributed to an adrenal crisis and this death occurred in a patient agement of glucocorticoid withdrawal and adrenal
with glucocorticoid-induced adrenal insufficiency [data re­ insufficiency (= endocrine taper)
trieved after contacting the author].23 A retrospective cohort • Glucocorticoid withdrawal syndrome: Symptoms expe­
study from the United Kingdom including 70,638 oral gluco­ rienced when lowering glucocorticoid dose within the
corticoid users found a sharp increase in the incidence of mor­ supraphysiologic glucocorticoid dose range, that are not
tality during the first 2 months after glucocorticoid cessation, due to the underlying disease for which the glucocorti­
which then rapidly decreased after the first 3 months. Whilst coids were initially prescribed for and per definition not
only 13 subjects had their cause of death recorded as adrenal in­ due to untreated adrenal insufficiency, as the total gluco­
sufficiency, the relationship with glucocorticoid cessation raises corticoid daily dose is still supraphysiologic
the suspicion of possible undiagnosed adrenal crises.24
The use of supraphysiologic glucocorticoids (prednisone Glucocorticoid doses vary based on glucocorticoid agent and
equivalent dose > 5 mg daily) has been associated with a high­ are defined as physiologic within the lower and upper ranges to
er risk of all-cause mortality (adjusted hazard ratio of 1.97 illustrate the inter-individual differences. In the recommenda­
(95% CI 1.81–2.15) in rheumatoid arthritis patients,25 with tions, prednisone and prednisolone are used interchangeably.
increasing risk with higher current daily and cumulative
doses.24,26 This association was not observed with daily gluco­
corticoid doses below 5 mg prednisone equivalent.25,27 4. Methods
Estimates from these studies have to be interpreted cautiously 4.1 Guideline working group
because of potential underlying confounding factors such as This joint clinical guideline was initiated and developed on
underlying disease and disease severity.25 behalf of The European Society of Endocrinology (ESE) and
The Endocrine Society (ES). The chairs of the working group,
3.4 Definitions Felix Beuschlein (ESE) and Tobias Else (ES), were appointed
by the ESE Clinical Committee and ES Clinical Guidelines
We recognize that there is great inter-individual variation in
Subcommittee, respectively. Olaf Dekkers served as the
responses to glucocorticoids, likely affecting the risk for
methodology lead, Christine Yedinak as Endocrine Nurses
glucocorticoid-induced adrenal insufficiency. Consequently,
Society Representative and Alessandro Prete as ESE Young
glucocorticoid exposure should be considered as a multidi­
Endocrinologists and Scientists representative. The other mem­
mensional risk factor, including dose and frequency, adminis­
bers were suggested by the chairs and approved by the ESE
tration mode, duration of therapy, potency of glucocorticoid,
Clinical Committee and ES Clinical Guidelines Subcommittee,
and individual susceptibility. Glucocorticoid exposure via oral
including Irina Bancos, Stefanie Hahner, Oksana Hamidi,
administration that poses risk for adrenal insufficiency, is ex­
Eystein S. Husebye, Niki Karavitaki and Anand Vaidya.
pected to at least exceed both of the following thresholds:
Leonie van Hulsteijn joined the guideline working group for
methodology support. Prior to the process, all participants
• Duration of glucocorticoid therapy to pose risk for ad­ completed conflict of interest forms (see Supplementary
renal insufficiency – 3-4 weeks, or greater Table 1). The process was approved by the ESE Executive
• Dose of glucocorticoid therapy to pose risk for adrenal in­ Committee and ES Society Board of Directors.
sufficiency – any dose greater than daily hydrocortisone There were several virtual working group meetings and one
equivalent of 15-25 mg (4-6 mg prednisone or prednisolone, in-person meeting, and the working group communicated by
3-5 mg methylprednisone, 0.25-0.5 mg dexamethasone) email in between meetings.
The following defined terms will be used in the remainder of
these guidelines: 4.2 Target groups
This guideline was developed for health care professionals
• Physiologic daily dose equivalent: Daily glucocorticoid who see adult patients with long-term supraphysiologic gluco­
dose equivalent to average daily cortisol production corticoid exposure and who seek guidance for glucocorticoid
G30 European Journal of Endocrinology, 2024, Vol. 190, No. 5

taper and evaluation of these patients’ adrenal function. The 5. Results of the systematic reviews
guideline served as a source document for the preparation of
5.1 Clinical questions, eligibility criteria, and
a patient information leaflet and educational material pub­
definition of endpoints
lished on the ESE and ES websites, to empower patients and
glucocorticoid prescribing clinicians. At the start of the guideline process, the working group
formulated clinical questions regarding evaluation of adrenal
function and treatment of patients after long-term supraphy­
4.3 Aims siologic glucocorticoid exposure. The clinical questions that
The overall purpose of this guideline is to provide clinicians formed the basis for the systematic reviews are summarized
with practical guidance on the evaluation of adrenal function in Supplementary Table 2.
of adult patients with long-term supraphysiologic gluco­ Eligible articles were required to present data on adult patients
corticoid therapy and for supplementation therapy in case (≥18 years). Articles presenting data on glucocorticoid-induced
of glucocorticoid-induced adrenal insufficiency. In clinical adrenal insufficiency based on biochemical testing were included
practice, both the recommendations and the clinical judg­ based on the use of the high-dose (250 μg) short ACTH

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ment of treating physicians should be taken into account. (1-24)-test (also referred by brand names as Synacthen or cosyn­
Recommendations are not meant to replace clinical acumen tropin test), since these tests are widely used in clinical practice.
and may need adaptation to local circumstances. During this test, 250 μg of synthetic ACTH (ACTH (1-24), or
another corticotropic agent), is administered intravenously. To
determine adrenal response to synthetic ACTH, serum cortisol
4.4 Summary of methods used for guideline levels are measured 30 and 60 minutes after administration. In
development primary and secondary adrenal insufficiency, peak cortisol levels
The methods used for establishing the guideline have < 500 nmol/L (<18.1 μg/dL), depending on assay, are indicative
been described in detail previously.28,29 In short, Grading of adrenal insufficiency.33,34 Since the population under study
of Recommendations, Assessment, Development, and was assessed for glucocorticoid insufficiency, the definition of
Evaluation (GRADE) was used as a methodological basis. a positive test was based on cut-off values provided in the indi­
The first step was to define the clinical questions (see below) vidual articles. For clinical question I (incidence and predictors
followed by systematic literature searches. We estimated an of recovery of HPA axis function in patients with glucocortic­
average effect for specific outcomes where possible and rated oid-induced adrenal insufficiency), the number of persons with
the quality of the evidence behind the recommendations as recovery of HPA axis at re-testing (numerator) and the total
very low (⊕○○○), low (⊕⊕○○), moderate (⊕⊕⊕○), or number of persons with glucocorticoid-induced adrenal insuffi­
strong (⊕⊕⊕⊕). Not all recommendations were formally ciency tested at baseline (denominator) were used to estimate
graded (see below). the incidence of recovery.
Considered for the recommendations were the quality of the We did not include case reports or case series, which are
evidence, the balance of desirable and undesirable outcomes, more prone to selection and publication bias; only studies re­
and individual values and preferences (patient preferences, porting a population of ten or more patients were eligible. In
goals for health, costs, management inconvenience, feasibility case of multiple studies describing the same cohort, the study
of implementation).28,30 The recommendations are worded as comprising the highest number of subjects was included.
‘recommend’ (strong recommendation) or ‘suggest’ (weak rec­ Eligible studies were restricted to languages familiar to the au­
ommendation). The meaning of a strong recommendation is thors (English, French, German, Dutch and Spanish). Authors
that all reasonably informed persons (clinicians, policy makers were contacted for clarification when reported data were not
and patients) would want the management in accordance with sufficient for accurate data extraction.
the recommendation, while for a weak recommendation, most
persons would still act in accordance with the guideline, but a 5.2 Description of search and selection of literature
substantial number would not.31 Formal evidence syntheses PubMed, MEDLINE, Embase, Web of Science, and Cochrane
were performed and graded only for recommendations ad­ Library were searched with the help of a specialized librarian
dressing our initial clinical questions (see ‘Clinical questions, to identify potentially relevant studies. The literature searches
eligibility criteria, and definition of endpoints’ section). for questions I-Ia, II and III were performed in January 2023,
Recommendations that were based on good clinical practice February 2023 and March 2023, respectively. Searches can be
and experience of the working group members are not formal­ found in Appendix 1 (see section on supplementary materials
ly graded,32 but acknowledged in the guideline as ‘good clin­ given at the end of this guideline).
ical practice’. Recommendations that were neither based on All studies obtained from the searches were entered into ref­
evidence or good clinical practice, are not graded at all. erence manager software (EndNote X20, Clarivate Analytics,
Consensus was reached upon discussion; minority positions Philadelphia, PA) and title and abstract were screened.
were considered in the rationale behind recommendations. Potentially relevant studies were retrieved for detailed assess­
ment. References of included studies were assessed for add­
itional relevant articles.
4.5 Review process For question I and sub-question Ia (incidence and predictors
A draft of the guideline was reviewed by four experts in the of recovery of HPA axis function in patients with
field (see ‘Acknowledgments’ section) and was distributed glucocorticoid-induced adrenal insufficiency), we used data
to all ESE and ES members for commenting. All comments from the study by Broersen et al.19. In this systematic review
and suggestions were then discussed and implemented as published in 2015, the risk of adrenal insufficiency following
thought appropriate by the guideline working group (see use of various types of glucocorticoids for several underlying
Supplementary Table 9). diseases was reported. This systematic review included 17
Beuschlein et al. G31

publications in which patients had been retested for adrenal the studies by Baek and Leong was based on results of bio­
insufficiency. Given this existing review, an original search chemical testing, while signs and symptoms of adrenal insuf­
as described above was performed from February 2014 on­ ficiency were not reported. It is thus uncertain whether this
wards, identifying 373 additional papers. After detailed as­ biochemical glucocorticoid-induced adrenal insufficiency
sessment, three manuscripts were included reporting data on was of clinical relevance. The study by Menzies-Gow re­
recovery of the HPA axis. ported no adrenal crises, or (serious) adverse events related
For clinical question II (optimal tapering scheme in patients to adrenal insufficiency.
no longer requiring chronic glucocorticoid treatment), 873 pa­ Studies assessing recovery of HPA axis function through
pers were identified, of which five were included. For clinical measurement of morning cortisol or low-dose 1 µg ACTH
question III (diagnostic accuracy of morning cortisol vs. 250 (1-24)-test were not formally included in the systematic re­
μg ACTH(1-24)-test), three of the 843 identified papers were view (see ‘Clinical questions, eligibility criteria, and defin­
included. ition of endpoints’), but reported recovery incidence rates
of 17% to 100% within a range of 4 days to 3 years38–45.
It is plausible that in studies reporting recovery at re-testing

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5.3 Summary and interpretation of evidence from already after a couple of days, initial cortisol levels may
the systematic reviews have represented adrenal suppression due to remaining circu­
Clinical question I: What is the incidence of recovery of HPA lating long-acting exogenous glucocorticoids rather than true
axis function in patients with glucocorticoid-induced ad­ adrenal insufficiency.
renal insufficiency? Clinical sub-question Ia: Which clinical/biochemical pa­
Broersen et al. performed a meta-analysis on eleven out of rameters predict recovery of HPA axis function in patients
seventeen studies re-testing patients for biochemical adrenal with glucocorticoid-induced adrenal insufficiency?
insufficiency for which results could be categorized in short- Both studies included for clinical question I also assessed
term (defined as less than 4 weeks) high-dose glucocorticoid predictors of recovery of adrenal function.35,36 In the study
therapy re-testing after 4 weeks (six studies), and long-term by Baek et al., patients recovering adrenal function had higher
(>1 year) medium-dose glucocorticoid therapy re-testing after cortisol increments during the first ACTH (1-24)-test than
6 months (five studies).19 Included articles had to use a cutoff patients without recovery (219 vs. 99 nmol/L (10.3 vs. 6.7
value for serum cortisol of ≤ 500 nmol/L (18 μg/dL) or higher μg/dL), OR 1.58 per μg/dL increase in cortisol, 95%CI
(e.g. ≤ 550 nmol/L or 19.8 μg/dL) or 11-deoxycortisol of ≤ 1.02-2.46) when adjusting for confounders, basal cortisol
200 nmol/L (7.2 μg/dL) after the metyrapone test to diagnose concentration and basal ACTH levels.35 In the study by
adrenal insufficiency. Pooled analysis of studies in the first Leong et al., patients recovering adrenal function had higher
group (141 patients), demonstrated a decrease in adrenal in­ ambulatory morning cortisol values in between retesting
sufficiency from 38.7% after cessation of glucocorticoid ther­ with ACTH (1-24)-test than patients not recovering (286 vs.
apy to 14.9% after 4 weeks. Pooled analysis of studies in the 186 nmol/L (7.9 vs. 3.6 μg/dL), OR 1.02 per μg/dL increase
second group (174 patients) indicated a decrease in adrenal in­ in cortisol, 95%CI 1.01-1.04).36 There were no studies assess­
sufficiency from 56.4% at baseline to 25.3% after 6 months. ing clinical parameters predicting HPA axis recovery.
Three additional studies assessing recovery of HPA axis Clinical question II: What is the optimal tapering scheme in
function in a total of 202 patients with glucocorticoid-induced patients no longer requiring chronic glucocorticoid treatment
adrenal insufficiency were included based on the search for the underlying condition?
from February 2014 onwards35–37. The description of the Four randomized-controlled trials were included46–49, and
GRADE evidence can be found in Supplementary Table 3 one single-arm study.37 The GRADE table is shown in
and details of included studies in Supplementary Table 4. The Supplementary Table 5, and details of the studies are shown
Menzies-Gow study assessed adrenal function in patients with in Supplementary Table 6. Three studies compared the effects
severe eosinophilic asthma after achieving a stable predniso(­ of a tapering scheme of glucocorticoids vs. placebo after short-
lo)ne dosage of 5 mg/day for four weeks. In the studies term use of high dose glucocorticoids in a total of 135 patients
by Baek and Leong, included patients displayed large clinical with multiple sclerosis, asthma, or chronic obstructive pul­
variability with respect to underlying disease and mean gluco­ monary disease exacerbation.46,48,49 One study compared
corticoid treatment dose and duration before diagnosis of the effects of tapering vs. continuing glucocorticoids after
glucocorticoid-induced adrenal insufficiency were not de­ long-term use in patients with rheumatoid arthritis who
scribed. Adrenal function was assessed using the 250 μg achieved remission or low disease activity,47 so only data of
ACTH (1-24)-test in all studies. Except for the Menzies-Gow the patient group tapering glucocorticoids (n = 131) were con­
study, timing of re-testing was not standardized. In the study sidered. The last study evaluated the effectiveness and safety of
by Baek et al., in 58.8% of patients adrenal function recovered a rapid, individualized steroid-reduction algorithm after bera­
after a median of 16 months.35 In the study by Leong et al, lizumab initiation in 598 patients with severe, eosinophilic
60.6% of patients showed recovered adrenal function, with a asthma.37 Although adrenal function was not the primary
median recovery time of 24 months.36 In the study by endpoint of included studies, Burmester et al. predefined
Menzies-Gow et al., 10% of patients showed recovered ad­ symptomatic adrenal insufficiency as one of their secondary
renal function after 3 months.37 Although these data are outcomes, and Menzies-Gow et al. as a safety outcome, and
based on a limited number of patients with a low quality of from the three other studies data on (serious) adverse events
evidence (i.e., certainty in these estimates) due to heterogen­ and hospital readmission were used as a proxy for symptom­
eity and a serious risk of bias, the data suggest that adrenal atic adrenal insufficiency/adrenal crisis. The data showed no
function can recover in a time frame from a few months to symptomatic adrenal insufficiency and no clinical events re­
up to 4 years in some cases. It must be emphasized that the lated to potential adrenal insufficiency during follow-up in
diagnosis of glucocorticoid-induced adrenal insufficiency in all five studies.
G32 European Journal of Endocrinology, 2024, Vol. 190, No. 5

Although the total number of included patients is relatively Rationale

small and there is heterogeneity due to various underlying dis­ Despite their efficacy as anti-inflammatory and immunosup­
eases, results from the included studies suggest that it is often pressive agents, chronic use of glucocorticoids can induce
safe to stop glucocorticoids abruptly after short-term use of manifestations of Cushing syndrome, along with concomitant
high dose glucocorticoids. After long-term use of glucocorti­ central and later permanent adrenal insufficiency (suppression
coids, more rapid tapering of glucocorticoids when on a supra­ of the entire HPA axis).53 For this reason, clinicians prescrib­
physiologic dosing, followed by a slower taper when on ing glucocorticoids for non-endocrine reasons are advised to
physiologic glucocorticoid dosing, appears to be a safe strat­ employ the lowest effective dose and duration of therapy
egy.37,47 There were no studies identified comparing different and consider tapering glucocorticoid doses when treatment
tapering schemes. is no longer necessary for the underlying condition.
Clinical question III: What is the diagnostic accuracy of a Given the widespread use of glucocorticoids, it is imperative
morning cortisol value vs. 250μg ACTH (1-24)-test in diag­ that treating physicians of any discipline be well-versed in the
nosing glucocorticoid-induced adrenal insufficiency? clinical consequences of long-term supraphysiologic gluco­
Three studies were included50–52. The GRADE evidence table corticoid therapy and the prevention, diagnosis, and treatment

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is shown in Supplementary Table 7, and details of the studies are of glucocorticoid-induced adrenal insufficiency. It is equally
shown in Supplementary Table 8. All studies assessed the diag­ critical to recognize signs and symptoms of adrenal insuffi­
nostic performance of a morning serum cortisol value vs. 250 ciency and be experienced in methods to taper and/or stop glu­
µg ACTH (1-24)-test. Of note, in the studies of Sagar et al. cocorticoids once their pharmacologic effects are no longer
and Sbardella et al. ACTH (1-24) was administered intramuscu­ required.
larly or intravenously, and results could not be stratified for The management of glucocorticoid therapy is considered a
intravenous ACTH (1-24) only. Both studies measured cortisol general medical skill that should be managed by the prescrib­
by immunoassay. In the study by Sagar et al., 100% of patients ing clinician, also taking into consideration the underlying dis­
with morning cortisol < 100 nmol/L (<3.6 μg/dL) failed ACTH ease as a determinant of tapering speed. Furthermore, the
(1-24)-test, while all patients with morning cortisol affected number of patients (at least 1% of the general popu­
>350 nmol/L (>12.6 μg/dL) passed ACTH (1-24)-test51 (see lation) is too large with too few endocrinology providers to
Supplementary Table 8 for cut-off values for ACTH perform consultations for each instance of glucocorticoid ta­
(1-24)-testing in included studies). The results of the study by pering. When prescribing clinicians decide that glucocorticoid
Sbardella et al. showed that morning cortisol ≥336 nmol/L therapy is no longer required, they should educate their patient
(≥12.1 μg/dL) had a specificity of 100% for predicting a normal on methods to taper the dose, symptoms of adrenal insuffi­
ACTH (1-24)-test, and morning cortisol ≤124 nmol/L (≤4.5 ciency and appropriate responses, and proceed to wean the
μg/dL) was 100% sensitive for predicting failure.52 Positive dose (Table 2). In the vast majority of cases, glucocorticoid
and negative predictive values were not reported. Debono taper does not cause any clinical endocrine concerns. In rare
et al. found that a baseline serum cortisol >310 nmol/L (>11.2 cases, however, when long-term supraphysiologic glucocortic­
μg/dL) measured by immunoassay excluded glucocorticoid- oid therapy has resulted in prolonged suppression of HPA axis
induced adrenal insufficiency with a sensitivity of 98% and a (greater than 1 year), or when patients experience adrenal cri­
negative predictive value of 97% (data retrieved after contacting ses, referral to or consultation with an endocrine specialist
the authors).50 A baseline serum cortisol < 152 nmol/L (<5.5 μg/ should be considered (see recommendation 2.11). However,
dL) confirmed glucocorticoid-induced adrenal insufficiency with it should be recognized that endocrinology providers have
a specificity of 97% and a positive predictive value of 95%. no specialized diagnostic approaches or therapies to facilitate
For serum cortisol measured by LC-MS/MS, a value unique care of glucocorticoid tapering. In this regard, the edu­
> 327 nmol/L (>11.8 μg/dL) resulted in a sensitivity of cation and approach to stopping glucocorticoid therapy is a
98% and a negative predictive value of 99% for excluding general medical process that every clinician who prescribes
glucocorticoid-induced adrenal insufficiency, and a value glucocorticoids should be familiar with.
<152 nmol/L (<5.5 μg/dL) resulted in a specificity of 98%
and a positive predictive value of 99% for confirming
glucocorticoid-induced adrenal insufficiency. • R 1.2 We recommend that clinicians who implement
The quality of evidence was moderate due to applicability treatment with glucocorticoids educate patients about
concerns and the numbers were too small to draw firm conclu­ various endocrine aspects of glucocorticoid therapy.
sions on the value of morning cortisol as stand-alone test (Good clinical practice)
to diagnose glucocorticoid-induced adrenal insufficiency.
Importantly, test results of both serum cortisol and 250 µg Rationale
ACTH(1-24)-test were not related to clinical endpoints such Clinicians prescribing long-term supraphysiologic gluco­
as adrenal crisis. corticoid therapy should actively educate their patients about
the potential development of adverse manifestations associ­
6. Recommendations ated with exogenous Cushing syndrome during extended
use. Furthermore, patients need to be informed about the risks
6.1. General recommendations for glucocorticoid of adrenal insufficiency, especially when tapering glucocortic­
therapy of non-endocrine conditions and oid medication below the physiologic daily dose equivalent
recommendations regarding patient education (see Definitions section). Clinicians should also provide com­
prehensive guidance on the importance of stress dosing with
• R 1.1 We recommend that, in general, patients on, or ta­ glucocorticoids. (see recommendation 3.1). Informing pa­
pering off glucocorticoids for non-endocrine conditions tients of the adverse effects of glucocorticoids and methods
do not need to be evaluated by an endocrinology specialist. to monitor and mitigate these outcomes is crucial to enhancing
Beuschlein et al. G33

Table 2: Overview of topics prescribing clinicians should discuss with patients when prescribing oral glucocorticoids.

Considerations Eligible Patients Timing Comments

Risk for developing All patients on long-term At the time of initiation There are many sequelae of exogenous Cushing
exogenous Cushing supraphysiologic glucocorticoid syndrome. Patients should be educated on
syndrome therapy the most common and clinically significant,
Risk for developing including weight gain, sarcopenia,
chronic adrenal hyperglycemia, hypertension, bone
insufficiency demineralization.
Even transient adrenal insufficiency requires
education to raise awareness for the need to
stress dose when appropriate
Education on stress Patients on long-term supraphysiologic At least at the time when Dedicated education should be provided to
dosing strategies glucocorticoid therapy who have dosing approaches a prepare patients with confirmed, or likely,
Education on injectable reduced dosing to physiologic, or physiologic range. adrenal insufficiency for routine and
emergency subphysiologic, levels. emergent stress dosing.

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glucocorticoid
administration
Glucocorticoid Patients on long-term supraphysiologic At the time Some patients on long term supraphysiologic
withdrawal syndrome glucocorticoid therapy who are ready glucocorticoid tapering glucocorticoid therapy experience
to begin tapering the dose. begins symptoms as the doses are tapered.

the beneficial aspects of glucocorticoid therapy while minimiz­ taper is low but increases with the cumulative number of
ing the undesired adverse events and risks thereof. Education risk factors including glucocorticoid potency, administration
on stress and emergency dosing can prevent symptoms of ad­ route, dose and treatment duration. (Table 3).
renal insufficiency and hospitalizations for adrenal crises. The educational content and timing of education delivery
Lastly, all patients initiating a glucocorticoid taper should should be individualized to each patient. This relates to ad­
be educated on the possibility of glucocorticoid withdrawal verse effects of glucocorticoid therapy, symptoms of with­
syndrome.53 The symptoms of glucocorticoid withdrawal drawal and adrenal crisis and means to prevent and treat
have substantial overlap with symptoms of adrenal insuffi­ adrenal crisis. Patients at low risk for developing adrenal in­
ciency and in some cases a disease flare, and can impede sufficiency or adrenal crisis may not require substantial educa­
the tapering of glucocorticoids (see recommendation 2.3). tion when initiated on glucocorticoid therapy. In contrast,
Anticipation of these potential symptoms can increase patients with a moderate-to-high number of risk factors
awareness and minimize the need for urgent care. should receive more intensive education to minimize the risk
of adverse outcomes. They may require multiple, well-timed
trainings that should be reinforced until their glucocorticoid
• R 1.3 We recommend that patients on glucocorticoid
therapy is discontinued (Table 2).
therapy have access to current up-to-date and appropriate
information about different endocrine aspects of gluco­
corticoid therapy. (Good clinical practice)
6. 2. Recommendations regarding taper of
systemic glucocorticoid therapy for non-endocrine
Rationale
conditions, diagnosis and approach to
Empowering patients with knowledge of the benefits and
glucocorticoid-induced adrenal insufficiency, and
risks of glucocorticoid therapy is critical.54 Patients require in­
glucocorticoid withdrawal syndrome
formation in an age, education level, and learning style-
appropriate format, along with access to supportive social re­
sources such as family members or care providers and • R 2.1 We suggest not to taper glucocorticoids in patients
disease-oriented support groups. We recommend the inclusion on short-term glucocorticoid therapy of <3-4 weeks, irre­
of at least one family member or primary caregiver in all edu­ spective of the dose. In these cases, glucocorticoids can be
cation sessions.55 stopped without testing due to low concern for HPA axis
Patient education and empowerment to adjust glucocortic­ suppression. (⊕○○○)
oid doses according to stressors are essential to prevent severe
symptoms of adrenal insufficiency and adrenal crisis.56 Rationale:
Confidence in self-management to prevent adrenal crisis Short-term glucocorticoid therapy is commonly used for
was demonstrated to be low in a large study that surveyed pa­ conditions such as exacerbation of asthma, chronic obstruct­
tients with adrenal insufficiency, including patients with ive lung disease, inflammatory bowel disease, allergic skin re­
glucocorticoid-induced adrenal insufficiency.21 Poor disease actions, and rheumatoid arthritis. In a United States insurance
knowledge and lack of awareness of adrenal insufficiency sub­ database study of 1.5 million adults, 21% had received at least
type diagnosis were associated with higher rates of adrenal cri­ one course of oral glucocorticoids during the last three years,
sis. Standardized patient education programs for patients and with a median dose of 20 mg prednisone equivalent and a me­
their relatives proved to be useful for sustainably improving dian duration of 6 days.59 A starting dose of 50 mg of prednis­
the level of knowledge regarding the prevention of adrenal cri­ one tapering to zero within 5-7 or 10-14 days are typical
sis, as well as self-confidence in dealing with the disease.57,58 treatment regimens for exacerbation of asthma (Global
The risk for developing adrenal insufficiency and the poten­ Strategy for Asthma Management and Prevention. www.
tial for adrenal crisis during glucocorticoid treatment and ginasthma.org/2023-gina-main-report).
G34 European Journal of Endocrinology, 2024, Vol. 190, No. 5

Table 3: Risk factors for developing adrenal insufficiency, and susceptibility to adrenal crisis, during glucocorticoid therapy and withdrawal from therapy.

Factors Risk for Adrenal Insufficiency and Crisis

Low Moderate High
Glucocorticoid potency Hydrocortisone Prednisone Dexamethasone
Cortisone acetate Prednisolone Betamethasone
Deflazacort Methylprednisolone Fluticasone
Triamcinolone
Administration Route Nasal Inhaled Systemic (oral, intramuscular,
Topical intravenous)
Ophthalmic Intra-articular
Concurrent use of differently
administered glucocorticoid
Dose Low Medium High
Duration of use < 3-4 weeks 3-4 weeks-3 months > 3 months
Body Mass Index135

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Normal Overweight Obese
Age63 Younger adults Older adults

There is no evidence that such short treatment periods lead Table 4. Suggested tapering regimen depending on glucocorticoid dose
to clinically relevant suppression of HPA axis, although there
Patient’s current daily Suggested prednisone Time
is lack of large high-quality studies. Suppression as evaluated prednisone equivalent decrements interval
by a 1µg ACTH (1-24)-test has been reported.41 However, this dose
test is less validated than a 250 µg ACTH (1-24)-test and
should be interpreted with caution.60 While adrenal insuffi­ >40 mg 5-10 mg decrease Every
week
ciency is unlikely after short-term glucocorticoid therapy,
20-40 mg 5 mg decrease Every
clinicians should be aware that even short-term glucocorticoid week
treatment can lead to complications such as increased inci­ 10-20 mg 2.5 mg decrease Every 1-4
dence of sepsis, gastrointestinal bleeding, thromboembolism, weeks
and fractures.59,61 5-10 mg 1 mg decrease Every 1-4
weeks

• R 2.2 Glucocorticoid taper for patients on long-term gluco­ 5 mg In absence of clinical symptoms Every 4
corticoid therapy should only be attempted if the under­ or negative testing for adrenal weeks
insufficiency continue
lying disease for which glucocorticoids were prescribed is 1 mg decrease
controlled, and glucocorticoids are no longer required. In (if low dosage prednisolone
these cases, glucocorticoids are tapered until approaching preparations are not available,
the physiologic daily dose equivalent is achieved (e.g., 4-6 alternative: 20 mg
mg prednisone). (Good clinical practice) hydrocortisone with 5 mg
decrease)

Rationale
Glucocorticoids should only be tapered if the underlying dis­ It is helpful to consider the likelihood of adrenal insuffi­
ease no longer requires glucocorticoid therapy. In general, gluco­ ciency and the risk of underlying disease flare before planning
corticoid taper can be faster and in larger decrements if the total further tapering. It is also important to consider the underlying
daily glucocorticoid dose is high (e.g., greater than 30 mg of comorbidities and evaluate concurrent drugs that could im­
prednisone). As the total daily glucocorticoid dose is approach­ pact glucocorticoid metabolism and overall glucocorticoid ex­
ing the physiologic daily dose equivalent (greater than equivalent posure. Although lacking systematic evidence, empirically, the
of 15-25 mg hydrocortisone, 4-6 mg prednisone, see Table 1), patient’s previous history of success or failure of glucocortic­
the taper should be slower and with smaller decrements oid taper may also help design the most effective glucocortic­
(Table 4). In certain patients with glucocorticoid-induced com­ oid taper. Additional factors that may impact the risk of
plications, such as uncontrolled hypertension and hypergly­ adrenal insufficiency include inter-individual variability of
cemia, glucocorticoid-induced psychosis, or herpetic keratitis, glucocorticoid pharmacodynamics and pharmacokinetics. A
a more rapid glucocorticoid taper towards physiologic daily study examining oral and intravenous methylprednisolone
dose equivalent may be required. The pre-test probability of ad­ found that 20% of individuals demonstrated increased clear­
renal atrophy and concurrent adrenal insufficiency is high for ance of methylprednisolone.62 In general, older individuals
patients taking long-term supraphysiologic glucocorticoid have reduced drug clearance,63 despite a small sample size in
doses; adrenal function testing is unnecessary until a physiologic these studies, data suggest a considerable and multifactorial
glucocorticoid dose is achieved. inter-individual variability in what would be considered a
HPA recovery is possible once the glucocorticoid therapy physiological glucocorticoid dose.
has been tapered to a near-physiologic daily dose (e.g.
4-6 mg prednisone). At this time, taper or assessment for
HPA recovery could be performed unless glucocorticoids at • R 2.3 We recommend consideration of glucocorticoid
this dose are required for control of the underlying condition withdrawal syndrome that may occur during glucocortic­
(for example transplant, or polymyalgia rheumatica). oid taper. When glucocorticoid withdrawal syndrome is
Beuschlein et al. G35

Table 5. Clinical features of adrenal insufficiency, glucocorticoid withdrawal syndrome and common underlying conditions.

Glucocorticoid withdrawal syndrome Adrenal insufficiency Underlying condition for which

glucocorticoids were initially
prescribed
Symptoms General malaise, fatigue, nausea, muscle General malaise, fatigue, nausea, Depending on condition (e.g. joint pain
and joint pain, sleep disturbances, mood muscle and joint pain in rheumatoid arthritis). Common
change overlapping symptoms (general
malaise, fatigue)
Signs Cushingoid features common, especially Weight loss (*), hypotension, Disease-specific signs reappear
earlier in the glucocorticoid taper orthostasis
Timing of At any point during glucocorticoid taper, Only when not treated with optimal At any point during glucocorticoid
symptoms and usually when prednisone is decreased glucocorticoid therapy taper if the underlying condition is
signs <15 mg/day. (subphysiologic glucocorticoid dose, sub-optimally controlled with a
occurrence Higher risk with long-term increased glucocorticoid non-glucocorticoid agent
supraphysiologic glucocorticoid therapy requirements due to sickness)

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Biochemistry Normal electrolytes Hyponatremia, hypoglycemia Biomarkers of disease activity
Glucocorticoid-induced hyperglycemia (sedimentation rate, disease-specific
may be present biomarkers)
HPA axis Testing is not recommended Initially, low ACTH and cortisol Not applicable
If tested, ACTH and cortisol are usually Later in recovery: normal-elevated
undetectable ACTH, low cortisol
Risk of adrenal Unlikely, if glucocorticoids are Yes, if not optimally treated with Not applicable
crisis administered (as patients with glucocorticoid therapy
glucocorticoid withdrawal syndrome
also have adrenal insufficiency)

(*) weight loss due to resolving GC induced Cushing syndrome should be considered.
General remarks: Patients with glucocorticoid-induced adrenal insufficiency may be asymptomatic at baseline conditions but can develop symptoms – from mild to
life-threatening adrenal crisis – when exposed to potential triggers (see Table 9). When present, symptoms of adrenal insufficiency are often non-specific and can
overlap with those of the disease for which glucocorticoids are prescribed. Recurrence of underlying autoimmune diseases can occur during tapering of exogenous
glucocorticoids. Signs and symptoms of adrenal insufficiency can overlap with those of glucocorticoid withdrawal syndrome, which arises from the discontinuation
of rapid tapering of glucocorticoid therapy in patients who developed a tolerance to supraphysiologic glucocorticoid levels. In patients on glucocorticoids close to
the physiological range, adrenal insufficiency and glucocorticoid withdrawal syndrome cannot be distinguished with complete accuracy.

severe, glucocorticoid dose can be temporarily increased severity and duration of glucocorticoid withdrawal, but sys­
to the most recent one that was tolerated, and the dur­ tematic studies are lacking. In a recent study investigating
ation of glucocorticoid taper could be increased. (Good glucocorticoid withdrawal syndrome in patients following
clinical practice) curative surgery for endogenous hypercortisolism, symptoms
of glucocorticoid withdrawal syndrome included arthralgias,
Rationale myalgias, weakness, fatigue, sleep disturbances, and mood
Glucocorticoid withdrawal syndrome occurs due to depend­ changes in up to 50% of patients.65 Symptoms are thought
ence on supraphysiologic glucocorticoids while decreasing the to occur due to an abrupt decrease in glucocorticoid exposure
dose of glucocorticoids64–66. Patients should be informed that leading to an increase in inflammatory cytokines.67 Symptoms
glucocorticoid withdrawal symptoms are expected to occur of glucocorticoid withdrawal syndrome overlap with those
during the glucocorticoid dose reduction and what the differ­ seen in patients with untreated or not optimally treated ad­
ences are between glucocorticoid withdrawal syndrome, ad­ renal insufficiency (Table 5),21 and most patients with gluco­
renal insufficiency, and underlying disease flare. It should be corticoid withdrawal syndrome do have concomitant
emphasized that an insufficient glucocorticoid supply is not ex­ adrenal insufficiency.66 Since symptoms of adrenal insuffi­
pected to occur when the glucocorticoid dose is greater than ciency and glucocorticoid withdrawal significantly overlap,
the physiologic daily dose equivalent. As exceptions, it should good clinical guidance to differentiate between those is to con­
be noted that the glucocorticoid requirement may be signifi­ sider the total daily dose of glucocorticoids with high doses
cantly higher in the case of critical illness or that glucocorticoid making adrenal insufficiency less likely. For example, a patient
absorption is not guaranteed in gastroenteritis. Many of the treated for several months with prednisone 20-40 mg might
symptoms of the withdrawal syndrome are nonspecific and experience glucocorticoid withdrawal symptoms, but con­
overlap with symptoms of the underlying disease, especially cerns for spontaneous symptoms and signs of adrenal insuffi­
in inflammatory musculoskeletal disorders. Managing gluco­ ciency are only a concern once the taper reaches 5-7.5 mg
corticoid withdrawal syndrome and glucocorticoid taper in The overall duration, type, and daily dose of glucocorticoid
these patients may be especially challenging. Patients should used should be considered when designing a glucocorticoid
be educated on symptoms of glucocorticoid withdrawal to taper. Patients treated with higher glucocorticoid doses, long-
avoid anxiety related to unexpected symptoms or reactive, un­ acting glucocorticoids, and for a longer duration of time are
necessary, or excessive increase in glucocorticoids. likely to have more glucocorticoid withdrawal symptoms.
Glucocorticoid withdrawal syndrome is reported to occur Patients with features of exogenous Cushing syndrome are
in 40-67% of patients tapering glucocorticoids following more likely to have a challenging glucocorticoid taper course
curative adrenalectomy in adrenal Cushing syndrome.66 because of glucocorticoid withdrawal syndrome (Table 5).
Duration of exogenous glucocorticoid use, glucocorticoid Slow decrease in glucocorticoid dose is the only known
dose and type, and individual susceptibility likely impact the intervention that may help prevent severe glucocorticoid
G36 European Journal of Endocrinology, 2024, Vol. 190, No. 5

withdrawal symptoms. In patients following a curative sur­ cortisone acetate to promote recovery of the HPA axis. For pa­
gery for endogenous hypercortisolism65 baseline clinical se­ tients on non-oral glucocorticoids, e.g. inhaled steroids, in
verity score was associated with the severity of whom there is a concern for glucocorticoid-induced adrenal in­
glucocorticoid withdrawal, and symptoms worsened once to­ sufficiency, a switch to short-acting oral glucocorticoids would
tal daily glucocorticoid dose reached below 30 to 35 mg of be appropriate when non-oral glucocorticoids or no longer
hydrocortisone equivalent (e.g. 7.5 prednisone). Clinical se­ needed. Prednisone and hydrocortisone have a wider variety
verity was calculated based on the presence of physical fea­ of available doses and allow for a more gradual taper in smaller
tures and comorbidities potentially related to glucocorticoid decrements, thus potentially enabling HPA axis to recover.74,75
excess, and may also be applied in patients treated with supra­ For replacement of adrenal insufficiency, prednisone is usually
physiologic glucocorticoids when deciding on the rapidity of provided as single morning dose, whereas due to shorter half-
glucocorticoid taper, with slower taper in patients with high life hydrocortisone and cortisone acetate are divided into 2-3
clinical severity score, and a more rapid taper in patients doses with higher doses given in the morning and subsequent
with lower clinical severity score. In a patient with severe doses given at lunch and late afternoon if applicable.33
glucocorticoid withdrawal syndrome despite a slower gluco­ Currently, the optimal type and dose of glucocorticoids to use

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corticoid taper, increasing the glucocorticoid dose temporarily during the taper has not been established. There is also a lack of
to the most recent dose prior to onset of glucocorticoid with­ reliable data comparing different strategies and tapering regi­
drawal syndrome will usually alleviate the symptoms. mens vary widely in clinical practice. Moreover, there is no
compelling evidence to switch intermediate-acting glucocorti­
• R 2.4 We recommend against routine testing for adrenal coids such as prednisone to hydrocortisone or cortisone acetate
insufficiency in patients on supraphysiologic doses of glu­ to further promote the recovery of the HPA axis. The evidence
cocorticoids, or if they are still in need of glucocorticoid of the effect of different types and dosages of glucocorticoid
treatment for the underlying disease. (Good clinical taper on the timing of HPA axis recovery and possible symp­
practice) toms of glucocorticoid withdrawal remain limited and incon­
clusive.66,73,76–78 Consequently, an individualized approach
to glucocorticoid taper is possible and necessary.
Rationale
If the glucocorticoid dose is in the supraphysiologic range,
suppression of the HPA axis is expected and it is unnecessary • R 2.6 We suggest that patients on a physiologic daily dose
to test adrenal function. Similarly, testing is unnecessary in pa­ equivalent, and aiming to discontinue glucocorticoid
tients unable to stop glucocorticoid treatment, for example pa­ therapy, either:
tients with organ transplants and in cases of polymyalgia 1. continue to gradually taper the glucocorticoid dose,
rheumatica. These patients should be educated on manage­ while being monitored clinically for signs and symp­
ment of glucocorticoid-induced adrenal insufficiency (see sec­ toms of adrenal insufficiency, or
tion R.3). 2. be tested with a morning serum cortisol.
(⊕○○○)
• R 2.5 We suggest that patients taking long-acting gluco­
corticoids (e.g., dexamethasone or betamethasone) During the initial glucocorticoid tapering, ACTH and corti­
should be switched to shorter-acting glucocorticoids sol levels remain suppressed. When the dose of glucocorticoid
(e.g., hydrocortisone or prednisone) when long-acting therapy is lowered, the hypothalamus and pituitary gland start
glucocorticoids are no longer needed. (⊕○○○) to recover, resulting in increased production of ACTH. ACTH
increase can promote the recovery of adrenal function leading
Rationale to an increase and recovery in cortisol. Complete recovery of
The use of long-acting glucocorticoids with higher gluco­ cortisol production can remain impaired in a minority of pa­
corticoid potency predisposes to a more pronounced suppres­ tients53,79–81 (Figure 1).
sion of HPA axis and subsequent adrenocortical function There is no compelling evidence to guide optimal tapering.
impairment. This is due to the continuous and non-circadian Discontinuation of long-term glucocorticoid therapy necessi­
glucocorticoid effect of these drugs, especially when adminis­ tates a cautious approach due to an increased risk of adrenal
tered systemically (Table 1). insufficiency, though the risk of clinically relevant adrenal cri­
Long-acting glucocorticoids such as dexamethasone or beta­ sis is generally low. Although glucocorticoid dose and treat­
methasone, even in physiologic daily dose equivalent, are more ment duration are associated with the development of
likely to cause HPA axis suppression, exogenous Cushing syn­ adrenal insufficiency, predicting the risk of adrenal insuffi­
drome, and glucocorticoid withdrawal syndrome when being ciency remains challenging. A uniform approach to tapering
tapered.19,68–72 HPA axis recovery is impossible in the setting the glucocorticoid dose has not yet been established and there
of continuous administration of long-acting glucocorticoids. is a lack of sufficient data on this topic (see Clinical question
In contrast, intermediate- or short-acting glucocorticoids – II). While some authors recommend a rapid reduction of the
which have both a shorter biological half-life and lower gluco­ glucocorticoid dose to slightly above physiologic daily dose
corticoid potency – are more likely to allow HPA recovery, pro­ equivalent (e.g. 7.5 mg prednisone), followed by a further re­
vided that they are not administered at nighttime, when they duction in smaller steps, others prefer testing of HPA axis to
can more pronouncedly inhibit ACTH production and the guide further tapering or immediate discontinuation, if nor­
early-morning rise of endogenous cortisol.73,74 mal adrenocortical function is demonstrated. An ongoing
If treatment with long-acting glucocorticoids is no longer randomized controlled clinical trial (TOASST) is testing
needed, we recommend changing to shorter-acting formula­ abrupt cessation vs. gradual tapering once a dose of prednis­
tions such as prednisone, prednisolone, hydrocortisone, or one 7.5 mg is achieved.82
Beuschlein et al. G37

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Figure 1: Schematic representation of HPA axis recovery following discontinuation of supraphysiologic glucocorticoid therapy (adapted from: Prete and
Bancos 202153).

Once glucocorticoids are tapered down to physiologic As a guide:

replacement doses, the panel suggests two possible approaches
for the discontinuation of glucocorticoid therapy (Figure 2).
Selecting one approach over the other might be driven 1. we suggest that the test indicates recovery of the HPA
by patient-related aspects including co-morbidities, co- axis if cortisol is >300 nmol/L or 10 μg/dL and glucocor­
medication, age and pre-test probability for adrenal insuffi­ ticoids can be stopped safely;
ciency or by the medical context such as training and 2. we suggest that if the result is between 150 nmol/L or
experience of the treating clinician or accessibility to labora­ 5 μg/dL and 300 nmol/L or 10 μg/dL, the physiologic
tory diagnostics. There are no studies showing the superiority glucocorticoid dose should be continued, and the morn­
of any of these approaches in terms of clinical outcomes or ing cortisol repeated after an appropriate time period
cost-benefit. (usually weeks to months);
Patients may gradually taper glucocorticoids while being 3. we suggest that if the result is <150 nmol/L or 5 μg/dL,
cautiously monitored for clinical manifestations of adrenal in­ the physiologic glucocorticoid dose should be continued,
sufficiency. If the patient experiences signs and symptoms of and the morning cortisol repeated after a few months.
adrenal insufficiency, glucocorticoid regimen should be re­
started and not discontinued until recovery of HPA axis is Rationale
documented. If the patient does not experience any symptoms, Due to the ease/convenience of testing, experience and valid­
the tapering proceeds until glucocorticoid discontinuation. ation, a morning serum cortisol level (measured between 8:00
Alternatively, patients may undergo testing with a morning and 9:00 AM, after holding glucocorticoid dose for at least
serum cortisol (sample collected between 8:00 and 9:00 AM) 24 hours) is the recommended test to examine for recovery of
for the determination of HPA axis recovery (R 2.7). If adrenal HPA axis following glucocorticoid therapy (see also results of
insufficiency is documented, exogenous glucocorticoid should Clinical Question III). The test should be done only after reach­
not be reduced below the lower end of physiologic replace­ ing the range of a physiologic equivalent daily dose (e.g., pred­
ment dose ranges to ensure adequate replacement for adrenal nisone 4-6 mg daily or hydrocortisone 15-25 mg total daily
insufficiency, yet still providing a stimulus for HPA-axis recov­ dose, see Definitions). Several other approaches to HPA axis as­
ery.20 Patients should be retested according to recommenda­ sessment exist, including measurement of waking salivary cor­
tions in 2.7. and further significant dose reduction should tisone, morning DHEA-S measurement, 250 µg ACTH
only occur with indication of HPA-axis recovery. (1-24)-test, overnight metyrapone test and insulin tolerance
test.34 However, the literature comparing different tests for ad­
renal insufficiency in the context of glucocorticoid use is very
• R. 2.7 If confirmation of recovery of the HPA axis is de­ limited; importantly, test results are hardly related to clinically
sired, we recommend morning serum cortisol as the first relevant outcomes (see section 3). Assessment should be done at
test. The value of morning serum cortisol should be con­ least 24 hours after the last dose of glucocorticoids (excluding
sidered as a continuum (Considering this continuum, sug­ dexamethasone). It should be emphasized that biochemical test­
gested cut-offs in moll/l and μg/dL are not exact ing for adrenal insufficiency is sensitive, but not specific.
conversions but have been rounded to improve clinical Persistence of biochemical suppression or insufficient recovery
applicability in an international context), with higher val­ of HPA axis is a prerequisite for clinical adrenal insufficiency,
ues more indicative of HPA axis recovery. (⊕○○○) yet even amongst those patients with biochemical insufficiency,
G38 European Journal of Endocrinology, 2024, Vol. 190, No. 5

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Figure 2: Proposed approach to systemic glucocorticoid discontinuation.

the risk for clinically meaningful adrenal insufficiency and ad­ guide: < 150 nmol/L (5μg/dL)) are very likely to have persistent
renal crisis remains very low. Due to the low prevalence of clin­ adrenal insufficiency.83 In such cases, dynamic testing is unlikely
ically relevant adrenal insufficiency despite the high prevalence to be useful. We recommend that these patients continue with
of biochemical adrenal insufficiency following a glucocorticoid physiologic daily dose equivalent glucocorticoid replacement
taper, testing can provide a safeguard in identifying those less at aiming for the lowest safe dose and undergo repeat morning cor­
risk but is not a prerequisite for continued tapering. tisol testing until recovery occurs. As a general guide, the gluco­
Although proposing a serum cortisol cut-off of 300 nmol/L corticoid dose should provide sufficient replacement, but also a
(10 μg/dL) as a guide, the panel suggests that the value of serum sufficient stimulus for recovery (meaning avoiding any over-
cortisol is considered as a continuum, rather than an arbitrary replacement). Frequency of repeat measuring may range be­
cut-off, with higher values more likely to indicate HPA axis re­ tween 1 to 6 months, depending on the dose and length of gluco­
covery. Patients with very low morning cortisol levels (as a corticoid therapy and the prior trajectory of cortisol values.
Beuschlein et al. G39

In patients with higher serum cortisol levels but below the time of HPA axis recovery, suggesting that duration of
300 nmol/L (10 μg/dL), HPA axis recovery is possible. In adrenal cortex atrophy impacts androgen recovery.93
such cases, we suggest that the most cost-effective and prac­ A promising alternative is waking salivary cortisone or cor­
tical strategy is that these patients continue with physiologic tisol.50 This non-invasive and practical ambulatory test holds
daily dose equivalent glucocorticoid replacement and have the promise of replacing in-hospital assessments to test for ad­
morning serum cortisol re-checked every few weeks until re­ renal insufficiency, but is currently not widely available.
covery occurs. If cortisol levels remain between 150 nmol/L
(5 μg/dL) and 300 nmol/L (10 μg/dL), dynamic testing can • R. 2.8 We suggest against routinely performing a dynamic
be considered. test for diagnosing adrenal insufficiency in patients taper­
In a study of patients with suspected primary or secondary ing or stopping glucocorticoid therapy. (⊕○○○)
adrenal insufficiency, morning cortisol ≥354 nmol/L (12.8
μg/dL) predicted normal adrenal function with 100% sensitiv­
Rationale
ity.84 One might also extrapolate some of the cut-off values
Morning cortisol measurement can serve as a simple ap­
from experiences with therapy of endogenous Cushing syn­
proach to HPA axis assessment, obviating the need for other

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drome. In patients recovering from endogenous hypercortiso­
tests in many patients (see recommendation 2.7)94–96.
lism, morning cortisol ≥276 nmol/L (10.0 μg/dL) was
However, if cortisol remains indeterminate (see 2.7), dynamic
associated with no reported symptoms of glucocorticoid with­
testing can be considered. The decision to carry out dynamic
drawal syndrome or instances of adrenal crisis.66 Given these
testing should consider the test’s availability, feasibility, costs
considerations, and the fact that there is substantial variability
and regional accessibility. There is no evidence that a specific
in the calibration between different cortisol assays, we con­
test in the context of glucocorticoid treatment is superior.
sider cortisol values greater than 300 nmol/L (10 μg/dL) as a
Dynamic testing options include 250 µg ACTH (1-24) and,
reasonable threshold to indicate recovery of HPA function fol­
less commonly, overnight metyrapone97 and insulin tolerance
lowing glucocorticoid-induced adrenal insufficiency.
tests. The 250µg ACTH (1-24) test only examines the direct re­
When interpreting the values of morning cortisol measure­
sponse of the adrenal gland to supraphysiologic ACTH stimu­
ment, it has to be taken into account that several factors can af­
lation. In primary and secondary adrenal insufficiency, a peak
fect the results. Cortisol production is affected by the
cortisol level <500 nmol/L (<18.1 μg/dL), depending on assay,
sleep-awake cycle, with cortisol secretion reaching its peak just
at 30 or 60 minutes is indicative of adrenal insufficiency.33,34 As
minutes before waking up. Thus, morning serum cortisol can ap­
suppression of the HPA axis subsequently results in adrenocort­
pear falsely low in individuals with disrupted circadian rhythm
ical atrophy with impaired cortisol response, the test may yield
(e.g., night shift workers, jet lag, and severe insomnia).33 In add­
less reliable results in patients on shorter duration of gluco­
ition, serum cortisol concentrations can be elevated in patients
corticoid therapy.34 The overnight metyrapone stimulation
with elevated cortisol-binding globulin, such as seen during
test and insulin tolerance test are more labor-intensive and
pregnancy and in women on oral estrogens.85,86 By contrast, se­
can be associated with significant adverse effects. They assess
rum cortisol concentrations can be decreased in patients with
the entire HPA axis, but head-to-head studies comparing differ­
low albumin and cortisol binding globulin, as in hypoalbumine­
ent dynamic tests in this patient population are lacking.
mic states (such as advanced cirrhosis, nephrotic syndrome, and
Furthermore, most of the published studies using dynamic test­
malnutrition), and prolonged critical illness.87,88
ing to diagnose glucocorticoid-induced adrenal insufficiency
The interpretation of serum cortisol varies depending on the
rely on ACTH (1-24) stimulation. The panel suggests against
assays used. Available techniques for measuring serum cortisol
the use of the 1 µg ACTH (1-24) test since it does not provide
listed from least to most accurate methods are immunoassays
better diagnostic accuracy than the standard 250 µg and there
using polyclonal antibodies, immunoassays using more specific
are no commercially available preparations of 1 µg ACTH
monoclonal antibody to cortisol, and liquid chromatography-
(1-24).33,98 If dynamic testing is employed, it should be done
tandem mass spectrometry.52,89,90 For example, in a large study
after holding any glucocorticoid therapy for at least 24 hours
of patients undergoing 250 µg ACTH (1-24)-test, baseline cor­
to avoid interference in steroid measurements.
tisol that excluded adrenal insufficiency varied between 336
(12.2 μg/dL) and 506 nmol/L (18.3 μg/dL) when measured by
three different immunoassays.52 Most prior studies utilized dif­ • R. 2.9 We suggest awareness of possible glucocorticoid-
ferent forms of immunoassays, rather than mass spectrometry- induced adrenal insufficiency in patients:
based assays. Therefore, it is important to point out that, ideal­ 1. with current or recent use of non-oral glucocorticoid
ly, physicians should be familiar with cut-off values used in their formulations presenting with signs and symptoms in­
laboratories. dicative of adrenal insufficiency, or
Concomitant measurement of baseline DHEAS was re­ 2. using multiple glucocorticoid formulations simultan­
ported to have a good diagnostic accuracy in making a diagno­ eously, or
sis of secondary adrenal insufficiency, including those with 3. using high dose inhaled or topical glucocorticoids, or
glucocorticoid-induced adrenal insufficiency.91,92 Data on 4. using inhaled or topical glucocorticoids for >1 year, or
DHEAS use to diagnose recovery from glucocorticoid-induced 5. who received intra-articular glucocorticoid injections
adrenal insufficiency are scarce, but suggest that normaliza­ in the previous 2 months, or
tion of cortisol secretion occurs prior to normalization of 6. receiving concomitant treatment with strong cyto­
DHEAS, making it a less favorable laboratory value to detect chrome P450 3A4 inhibitors.
adrenal axis recovery. In one study of 32 patients with his­
tory of endogenous Cushing syndrome, patients with Rationale
ACTH-independent Cushing syndrome had lower DHEAS Glucocorticoid-induced adrenal insufficiency can occur
than patients with ACTH-dependent Cushing syndrome at with any glucocorticoid formulation99 (Table 6) and there is
G40 European Journal of Endocrinology, 2024, Vol. 190, No. 5

Table 6: Non-oral glucocorticoid formulations and risk of glucocorticoid-induced adrenal insufficiency

Prevalence of Factors increasing the Strategies to mitigate the risk of

glucocorticoid-induced risk of glucocorticoid-induced glucocorticoid-induced adrenal
adrenal insufficiencya adrenal insufficiency insufficiencyd
Inhaled • Overall: 7.8% (CI 4.2-13.9) • Treatment with high dosesb for prolonged • Use the lowest effective
glucocorticoids • Short-term use (<1 month): periods glucocorticoid dose for the
1.4% (CI 0.3-7.4) • Use of fluticasone propionate shortest period
• Medium-term use (1-12 • Concomitant use of other glucocorticoid • Use spacers and mouth rinsing
months): 11.9% (CI 5.8-23.1) formulations (e.g., oral glucocorticoids in • Consider alternative
• Long-term use (>12 months): chronic obstructive pulmonary disease or glucocorticoids to fluticasone
27.4% (CI 17.7-39.8) nasal glucocorticoids for rhinitis/nasal propionate
• Low dose use: 2.4% (0.6-9.3) polyposis) • Avoid co-administration with
• Intermediate dose use: 8.5% • Lower body mass index strong cytochrome P450 3A4
(4.2-16.8) • Higher compliance with treatment inhibitorsc
• High doseb use: 21.5% • Concomitant treatment with strong

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(12.0-35.5) cytochrome P450 3A4 inhibitorsc (e.g.,
medications containing ritonavir;
antifungal drugs for acute allergic
bronchopulmonary aspergillosis)
Intra-articular 52.2% (40.5-63.6) • Repeated injections over a short period • Reduce the number of injections, if
glucocorticoids (<3 months) possible
• Simultaneous injections of multiple joints • Space out injections by at least 3-4
• Use of high glucocorticoid doses months, if possible
• Inflammatory arthropathies • Triamcinolone hexacetonide may
• Concomitant use of other glucocorticoid carry a lower risk of systemic
formulations absorption than triamcinolone
• Concomitant treatment with strong acetonide
cytochrome P450 3A4 inhibitorsc • Avoid co-administration with
strong cytochrome P450 3A4
inhibitorsc
Percutaneous 4.7% (CI 1.1-18.5) • Long-term use of high-potency • Use the smallest effective quantity
(topical) glucocorticoids on large surface areas or for the shortest period
glucocorticoids areas of increased absorption (e.g. • Use lower potency
mucosa) glucocorticoids, if possible
• Prolonged use on inflamed skin with • Avoid co-administration with
impaired barrier function strong cytochrome P450 3A4
• Occlusive dressings inhibitorsc
• Use on mucous membranes, eyelids, and
scrotum
• Concomitant use of other glucocorticoid
formulations
• Concomitant treatment with strong
cytochrome P450 3A4 inhibitorsc
Intra-nasal 4.2% (CI 0.5-28.9) • Long-term use • Use the lowest effective
glucocorticoids • Concomitant use of other glucocorticoid glucocorticoid dose for the
formulations shortest period
• Concomitant treatment with strong • Avoid co-administration with
cytochrome P450 3A4 inhibitorsc strong cytochrome P450 3A4
inhibitorsc
a
Based on a systematic review and meta-analysis of studies assessing the prevalence of biochemical impairment of the HPA axis, regardless of clinical
correlates.19 Systematic data on the prevalence of signs and symptoms of adrenal insufficiency are lacking.
b
High doses of commonly prescribed inhaled glucocorticoids in adults are:
• Fluticasone propionate >500 μg/day
• Beclometasone dipropionate (standard particle inhalers) > 1000 μg/day
• Beclometasone dipropionate (extra fine particle inhalers) > 400 μg/day
• Budesonide >800 μg/day
• Ciclesonide >320 μg/day
• Fluticasone furoate >200 μg/day
• Mometasone furoate standard particle >400 μg/day
These doses are expressed as total daily doses and should be seen as a guide only. Doses are based on information from manufactures’ summaries of
product characteristics, Global Initiative for Asthma (2023), and the British National Formulary.
c
Strong inhibitors include boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, idelalisib, indinavir, itraconazole, ketoconazole, lopinavir,
mifepristone, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole.
d
Suggested strategies include consideration of reduced doses, frequencies, and alternative treatments, but sufficient control of the underlying
glucocorticoid dependent disease remains paramount
Abbreviations: CI, confidence interval; HIV, human immunodeficiency virus.
Beuschlein et al. G41

no established safe level of dose exposure.19 Published studies are expected during that time frame, and recovery can be con­
provide some guidance on the overall degree of risk in patients firmed in the following 4 weeks. Evidence regarding epidural
treated with glucocorticoids. However, establishing the risk glucocorticoid injections is also very limited but patients receiv­
on an individual basis is challenging and relies on clinical judg­ ing multiple injections and higher doses appear to carry a higher
ment. We suggest that some groups of non-oral glucocorticoid risk of glucocorticoid-induced adrenal insufficiency111–114.
users carry a higher risk, although evidence is limited. Most glucocorticoids are metabolized by the hepatic cyto­
We suggest that glucocorticoid-induced adrenal insuffi­ chrome P450 3A4 (CYP3A4). Strong CYP3A4 inhibitors –
ciency should be suspected in patients with current or recent which include food ingredients such as grapefruit juice, several
use of non-oral glucocorticoid formulations presenting with antibiotics, antifungals, and the protease inhibitor ritonavir
signs and symptoms indicative of adrenal insufficiency among others – have been shown to significantly increase
(Table 5). Manifestations of adrenal insufficiency are often circulating concentrations of glucocorticoids and hence sub­
non-specific and can overlap with other conditions including stantially increase the risk of suppressing HPA axis. Several
those for which glucocorticoids were prescribed. It is therefore cases of exogenous Cushing syndrome linked to oral and
imperative that healthcare professionals maintain a high de­ non-oral glucocorticoid formulations in patients using strong

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gree of suspicion for the presence of adrenal insufficiency. CYP3A4 inhibitors have been published.103,104 Ritonavir is
Patients receiving multiple types of glucocorticoids (e.g., the most commonly reported offending medication, used as
oral and inhaled) are more susceptible to developing part of antiviral combinations to treat HIV infection, hepatitis
glucocorticoid-induced adrenal insufficiency, reflecting the cu­ C infection, and COVID-19.
mulative risk of systemic absorption and impact on the HPA
axis. Pooled data from 11 studies on 354 patients found a • R. 2.10 We suggest that patients with current or previous
risk of 42.7% (95%CI 28.6-58.0).19 glucocorticoid treatment presenting with signs and symp­
In patients treated with inhaled glucocorticoids, the risk cor­ toms of exogenous Cushing syndrome are assumed
relates directly with treatment dose and duration. A total of to have glucocorticoid-induced adrenal insufficiency.
21.5% (95%CI 12.0-35.5) of patients using high doses of in­ (Good clinical practice)
haled glucocorticoids53 and 27.4% (95%CI 17.7-39.8) of those
treated for more than 1 year were found to have biochemical evi­
Rationale
dence of glucocorticoid-induced adrenal insufficiency19
Patients with a history of glucocorticoid treatment/exposure
(Table 6). A Canadian study found only 392 hospital admissions
presenting with manifestations of Cushing syndrome (Table 7)
due to glucocorticoid-induced adrenal insufficiency over a
should be assumed to have a fully suppressed HPA axis and
15-year period among adults receiving inhaled glucocorti­
managed accordingly. Exogenous Cushing syndrome can occur
coids.100 Patients using higher daily doses and cumulative yearly
with any glucocorticoid formulation and can take several
doses had an almost twofold higher risk of hospital admission
months to resolve after the glucocorticoid daily dose is de­
than those with lower exposure.100 A study focusing on the gen­
creased to physiological range.115,116 Morning cortisol meas­
eral practice records of 2.4 million people in the UK identified
urement can differentiate those with adrenal insufficiency
only 31 cases of established glucocorticoid-induced adrenal in­
(suppressed cortisol level) or identify those with recovering ad­
sufficiency linked to inhaled glucocorticoids.101 However, the
renal axis, but persistence of cushingoid features.
same study also found a very low prevalence of
glucocorticoid-induced adrenal insufficiency in patients on oral
glucocorticoids, suggesting that this problem is largely unrecog­ • R. 2.11 We suggest that patients aiming to discontinue
nized or under-reported.101 Of note, among all inhaled gluco­ glucocorticoids, but without recovery of HPA axis in
corticoids fluticasone propionate is most frequently associated one year while on physiologic daily dose equivalent,
with the development of symptomatic glucocorticoid-induced should be evaluated by an endocrinology specialist. We
adrenal insufficiency and exogenous Cushing syn­ suggest that patients on glucocorticoids and history of ad­
drome.95,99,102–106 This is potentially linked to its pharmacokin­ renal crisis should also be evaluated by an endocrinology
etics (long half-life of 14.4 hours) and pharmacodynamics specialist. (Good clinical practice)
(binding affinity to the glucocorticoid receptors 18 times that
of dexamethasone).107 Regarding intranasal glucocorticoid Rationale
use, the risk of glucocorticoid-induced adrenal insufficiency is Prior studies have shown that adrenal insufficiency may last
low for short-term use at the recommended doses (Table 6). even up to 2-4 years after glucocorticoid cessation, owing to
However, several intra-nasal glucocorticoids have high bioavail­ slow recovery of adrenal cortisol production.35,42,117–119
ability and glucocorticoid receptor binding affinity, which can Persistent impairment of cortisol secretion beyond four years
result in significant systemic exposure after prolonged use.108 suggests that recovery of adrenal function is very unlikely and
Robust evidence about the impact of intra-articular long-term glucocorticoid replacement should be contin­
glucocorticoid injections on the HPA axis is lacking. ued.94,119 Additional regular testing beyond four years may
Glucocorticoids can be detected in the urine for months after in­ not be helpful but can be considered on a case-by-case basis.
jections109,110 suggesting prolonged systemic absorption.19 We The panel suggests that patients with persistent adrenal
suggest that patients are monitored for signs and symptoms of insufficiency while on physiologic daily dose equivalent of
adrenal insufficiency and that healthcare professionals have a glucocorticoids for longer than one year should be evaluated
low threshold for testing especially within 2 months by an endocrinology specialist to assess for underlying causes
of injections and in patients who receive simultaneous or of adrenal insufficiency other than glucocorticoid-induced
multiple injections over a short period. Commonly used adrenal insufficiency (e.g., pituitary causes). The panel sug­
intra-articular glucocorticoid preparations often lead to a sup­ gests that patients who experience an adrenal crisis while on
pression of 4 weeks and therefore low morning cortisol values glucocorticoids should be evaluated by an endocrinology
G42 European Journal of Endocrinology, 2024, Vol. 190, No. 5

Table 7: Signs and symptoms of glucocorticoid-induced (exogenous) prevent adrenal crises and their negative sequelae (Figure 3).
Cushing syndrome Potential adrenal insufficiency and the need for stress dosing
Symptoms Muscle weakness should be considered even after discontinuation of gluco­
Sleep disturbances (insomnia) corticoid therapy and replacement, particularly in those pa­
Increased appetite tients that had not undergone biochemical testing to confirm
Mood and cognitive disturbances (irritability, recovery of the HPA-axis. Based on a retrospective analysis
impaired memory, depression) mortality is increased particularly in the immediate period
Signs Proximal muscle weakness and wasting
Excess weight gain and central obesity
following the cessation of glucocorticoid therapy.24
Supraclavicular and dorsocervical fat Therefore, patients with current or recent glucocorticoid
accumulation use who did not undergo biochemical testing to rule out
Facial and upper neck plethora with facial glucocorticoid-induced adrenal insufficiency who are under
rounding minor stress (e.g., fever, infection requiring antibiotics,
Skin atrophy with easy bruising, red stretchmarks, physical trauma, significant emotional stress) not leading to
and poor wound healing
Acne
hemodynamic instability and with no evidence of oral gluco­

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Menstrual irregularities in women. corticoid malabsorption (vomiting, diarrhea) or are undergo­
Other Cardiometabolic risk factors (hypertension, ing a surgical procedure under local anesthesia will require
manifestations dysglycemia, dyslipidemia, hypercoagulability) coverage with stress dose of oral glucocorticoids (as a general
Osteoporosis and fragility fractures guide, see Table 8). The recommended stress dose of hydro­
Hypogonadism, reduced libido, and reduced cortisone is the same as for patients with primary or secondary
fertility
adrenal insufficiency of other etiology: patients should receive
double the physiologic replacement dose (i.e., hydrocortisone
specialist. Patients with adrenal insufficiency for more than 40 mg daily, usually split in three doses 20 mg on rising, 10 mg
one year should be treated with standard replacement doses 12 midday, 10 mg 5pm).120 In patients using other gluco­
of hydrocortisone or prednisone (Table 1). Furthermore, it is corticoid formulations, a dose equivalent to 40 mg hydrocor­
necessary to provide education to these patients regarding the tisone is suggested and this regime needs to be offered for the
adjustment of glucocorticoid substitution therapy doses dur­ duration of the stress period e.g., prednisone 10 mg total daily
ing stressful situations to prevent adrenal crises or to manage dose to be given in one or two divided doses (as a general
them33 (see Section 3). guide, see Table 8). Particularly for patients undergoing sur­
gery under general or regional anesthesia associated with
long recovery time, parenteral stress doses of hydrocortisone
• R 2.12 We recommend against the use of fludrocortisone in
or equivalent doses of other glucocorticoids such as methyl­
patients with glucocorticoid-induced adrenal insufficiency.
prednisolone or dexamethasone are recommended (as a gen­
eral guide, see Table 8). We base our suggested stress-dose
Rationale
glucocorticoid regimens on clinical practice and the guidelines
Secretion of the mineralocorticoid aldosterone is largely
from the Association of Anaesthetists, the Royal College of
regulated by the renin-angiotensin system and potassium lev­
Physicians, the Endocrine Society and the Society for
els. Accordingly, mineralocorticoid function is expected to
Endocrinology UK.33,121 However, we acknowledge that in
be preserved in glucocorticoid-induced adrenal insufficiency,
the absence of robust evidence and head-to-head comparison
as in other forms of secondary or tertiary adrenal insufficiency.
of different glucocorticoid regimens, practices vary consider­
Substitution therapy with fludrocortisone is not indicated.
ably among centers and lower doses are also routinely used
in patients under moderate or major stress.122
6.3 Recommendations on diagnosis and therapy of
adrenal crisis in patients with
glucocorticoid-induced adrenal insufficiency • R. 3.2 – We suggest that in patients with current or recent
glucocorticoid use who did not undergo biochemical test­
ing to rule out glucocorticoid-induced adrenal insuffi­
• R. 3.1 We recommend that patients with current or recent
ciency and present with hemodynamic instability,
glucocorticoid use who did not undergo biochemical test­
vomiting, or diarrhea, the diagnosis of adrenal crisis
ing to rule out glucocorticoid-induced adrenal insuffi­
should be considered irrespective of the glucocorticoid
ciency should receive stress dose coverage when they are
type, mode of administration, and dose; patients with sus­
exposed to stress. (Good clinical practice)
pected adrenal crisis should be treated with parenteral
• R.3.1A Oral glucocorticoids should be used in case of mi­
glucocorticoids and fluid resuscitation. (Good clinical
nor stress and when there are no signs of hemodynamic
practice)
instability or prolonged vomiting or diarrhea.
• R.3.1B Parenteral glucocorticoids should be used in case
of moderate to major stress, procedures under general or Rationale
regional anesthesia, procedures requiring prolonged Adrenal crisis (also known as acute adrenal insufficiency or
avoidance or inability of oral intake, or when there are Addisonian crisis) can occur in patients taking oral supraphy­
signs of hemodynamic instability or prolonged vomiting siologic doses of glucocorticoids, if drug availability suddenly
or diarrhea. decreases (e.g. missed doses, gastroenteritis). It is a life-
threatening emergency that must be promptly recognized
Rationale and treated. Therefore, timely therapy is essential and takes
As discussed in sections R1.2, R1.3, and R3.2, patients need precedence over the evaluation for other causes of symptoms
to be educated on stress dosing of glucocorticoids aiming to that are in accordance with adrenal crisis. Adrenal crisis is
Beuschlein et al. G43

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Figure 3: Management of patients at risk of or with diagnosed glucocorticoid-induced adrenal insufficiency with suspected adrenal crisis or during
exposure to stress

characterized by the inability of the adrenal cortex to produce glucocorticoids such as methylprednisolone or dexamethasone;
enough cortisol to respond appropriately to stressors such as head-to-head comparison data of different treatment strategies
infections, trauma, and surgery (Table 9). The pathophysi­ for adrenal crisis are lacking. Any identifiable potential triggers
ology of adrenal crisis is complex and not fully understood, (e.g., infections, trauma) should be treated where possible.
but it is invariably characterized by volume depletion and vas­ Short-term administration of parenteral glucocorticoids at the
oplegia resulting in hypotension and – if left untreated – shock recommended doses is safe; hence, treatment should be initiated
and eventually death.123,124 Adrenal crisis can occur not only even if an adrenal crisis diagnosis is eventually ruled out.
in patients treated with oral glucocorticoids but also in pa­ Evidence regarding the incidence of adrenal crisis in patients
tients receiving only inhaled,105,125 topical,126 intra- with glucocorticoid-induced adrenal insufficiency is limited (see
articular,127 or other glucocorticoid formulations.128 This introduction). Some data suggest that the risk is low considering
highlights the potential clinical risks associated with the unto­ the relatively small number of hospital admissions for adrenal
ward systemic absorption of non-oral glucocorticoids. As crisis recorded in patients on long-term glucocorticoids.124
mentioned above, adrenal crisis should be considered in pa­ The preserved aldosterone production and some residual corti­
tients in the period immediately following cessation of gluco­ sol production in glucocorticoid-induced adrenal insufficiency
corticoid therapy. may explain these observations. One study found a higher inci­
Adrenal crisis is a clinical diagnosis and should be suspected dence of adrenal crisis – precipitated by infections in about half
in patients with current or recent use of any glucocorticoid for­ of cases – in patients with established glucocorticoid-induced
mulation presenting with hypotension, collapse, or acute ab­ adrenal insufficiency compared to other causes of adrenal insuf­
dominal symptoms (Table 9). Hyponatremia may also ficiency,22 but this was not observed in other studies.21
be associated. A high degree of clinical suspicion is para­ A significant proportion of patients with glucocorticoid-
mount, as patients may not have been tested for suspected induced adrenal insufficiency may be undiagnosed; as such,
glucocorticoid-induced adrenal insufficiency prior to the acute adrenal insufficiency symptoms and adrenal crisis can
event and adrenal crisis may be the first manifestation of the be missed. A population-based study found an increased
disease. Treatment must not be delayed by laboratory or im­ incidence of potential manifestations of untreated adrenal in­
aging investigations. If an established or impending adrenal sufficiency (hypotension, gastrointestinal symptoms, hypo­
crisis is suspected, the patient should immediately receive glycemia, and hyponatremia) after discontinuation of
an injection of 100 mg hydrocortisone intravenously or long-term oral glucocorticoids.20 Individuals exposed to in­
intramuscularly followed by rapid volume resuscitation with fections – common triggers of adrenal insufficiency symp­
intravenous administration of 0.9% saline solution (or toms – and older individuals taking higher glucocorticoid
equivalent).33 Patients with confirmed adrenal crisis should doses for longer periods prior to discontinuation carried a
be maintained on hydrocortisone at a dose of 200 mg hydro­ higher risk of developing these manifestations.20 Another
cortisone per 24 hours (preferably by continuous intravenous study found a sharp mortality increase in the first 3-6 months
infusion, alternatively by intravenous or intramuscular injec­ after cessation of long-term oral glucocorticoids.24 Whilst it
tion of 50 mg hydrocortisone every 6 hours) until clinical recov­ is not possible to establish how many deaths were due to un­
ery and further guidance by an endocrinology specialist.33,129 In recognized adrenal crisis, these data highlight the need for
patients with very high body weight, higher doses might be con­ close clinical monitoring of patients coming off long-term
sidered. Some centers use equivalent parenteral doses of other glucocorticoid therapy.24,125
G44 European Journal of Endocrinology, 2024, Vol. 190, No. 5

Table 8: Suggested glucocorticoid regimens in patients at risk of or with diagnosed glucocorticoid-induced adrenal insufficiency during exposure to stress

General considerations Examples Suggested regimen

Minor stress If the patient is already taking • Illness requiring bed rest If not on daily glucocorticoids: give
hydrocortisone ≥40 mg daily • Illness with fever (out of hospital) hydrocortisone 40 mg total daily dose,
prednisone ≥10 mg daily, or • Illness requiring treatment with to be given in three divided doses (e.g.,
dexamethasone ≥1 mg daily, there is antibiotics (out of hospital) 20 mg on rising, 10 mg 12 midday,
typically no need to increase the dose • Significant emotional stress (e.g., 10 mg 5pm). Continue for 2-5 days until
unless there are signs of hemodynamic bereavement) well (or for the duration of antibiotic
instability. treatment).
If on hydrocortisone <40 mg total daily
dose: increase to 40 mg total daily dose, to
be given in three divided doses (e.g., 20 mg
on rising, 10 mg 12 midday, 10 mg 5pm).
Continue for 2-5 days until well (or for the
duration of antibiotic treatment).

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If on prednisone <10 mg total daily dose:
increase to 10 mg total daily dose, to be
given in one or two divided doses.
Continue for 2-5 days until well (or for the
duration of antibiotic treatment).
If on dexamethasone <1 mg total daily
dose: increase to 1 mg once daily.
Continue for 2-5 days until well.
Minor surgery including any procedure If not on daily glucocorticoids: give oral
requiring local anesthesia hydrocortisone 40 mg total daily dose,
to be given in three divided doses (e.g.,
20 mg one hour prior to the procedure,
10 mg six hours after the procedure,
10 mg after a further six hours).
Continue glucocorticoids in patients
who remain unwell after the procedure
until clinically stable.
If on hydrocortisone <40 mg total daily
dose: increase to 40 mg total daily dose, to
be given in three divided doses (e.g., 20 mg
one hour prior to the procedure, 10 mg six
hours after the procedure, 10 mg after a
further six hours). Continue increased
dose in patients who remain unwell after
the procedure until clinically stable.
If on prednisone <10 mg total daily dose:
increase to 10 mg total daily dose, to be
given one hour prior to the procedure.
Continue increased dose in patients who
remain unwell after the procedure until
clinically stable.
If on dexamethasone <1 mg total daily
dose: increase to 1 mg total daily dose, to
be given one hour prior to the procedure.
Continue increased dose in patients who
remain unwell after the procedure until
clinically stable.
Bowel procedures not carried out under If not on daily glucocorticoids: give
general anesthesia hydrocortisone 20 mg total daily dose,
to be given in three divided doses (e.g.,
10 mg one hour prior to the procedure,
5 mg six hours after the procedure, 5 mg
after a further six hours).
If on daily glucocorticoids: continue
normal glucocorticoid dose. Give an
equivalent I.V. dose if prolonged nil by
mouth.
Moderate If the patient is already taking Severe intercurrent illness, for example: For patients with persistent vomiting or
and major hydrocortisone ≥200 mg daily, diarrhea who are well enough to remain
stress prednisone ≥50 mg daily, or • Persistent vomiting or diarrhea from out of hospital: Hydrocortisone 100 mg
dexamethasone ≥6-8 mg daily, there is gastro-intestinal illness. I.M. injection immediately, which can
typically no need to increase the dose • Infection requiring hospital be repeated after 6 hours if needed. If
In patients with suspected reduced admission or I.V. antibiotics (e.g., symptoms do not resolve or
absorption (persistent vomiting or sepsis). hemodynamic instability develops,
diarrhea), nil by mouth, or unable to take admit to hospital for I.V. urgent
(continued)
Beuschlein et al. G45

Table 8: Continued

General considerations Examples Suggested regimen

tablets, give stress-dose glucocorticoids • Acute trauma resulting in significant glucocorticoid and fluid administration.
I.V. or I.M. blood loss or hospital admission. Patients requiring hospital admission:
High body weight can be taken into Hydrocortisone 100 mg I.V. bolus or I.M.
consideration as a factor indicating higher injection immediately, followed by
dosage requirements. immediate initiation of a continuous
infusion of hydrocortisone 200 mg over
24 h. If a continuous infusion is not
feasible, give hydrocortisone 50 mg I.V.
boluses every 6 hours. The duration and
dose of the glucocorticoid regimen
thereafter must be individualized based on
the stressor type and the patient’s clinical
status.

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Surgery or any procedure requiring Intra-operative regimen: Hydrocortisone
general or regional anesthesia with 100 mg I.V. bolus at induction, followed
anticipated short recovery time and no by immediate initiation of a continuous
nil by mouth infusion of hydrocortisone 200 mg over
24 h. If a continuous infusion is not
feasible, give hydrocortisone 50 mg I.V.
boluses every 6 hours.
Postoperative regimen: Resume oral
glucocorticoids at an increased dose for
48 h (e.g., hydrocortisone 40 mg/daily in
three divided doses; prednisone 10 mg/
daily in one or two divided doses;
dexamethasone 1 mg once daily) and then
resume the pre-surgical dose. In case of
post-operative complications (e.g.,
significant pain, infections), maintain an
increased oral dose or give stress-dose
glucocorticoids I.V. as clinically
appropriate.
Surgery (including cesarean section) or any Intra-operative regimen: Hydrocortisone
procedure requiring general or regional 100 mg I.V. bolus at induction, followed
anesthesia with nil by mouth or by immediate initiation of a continuous
expected long recovery time infusion of hydrocortisone 200 mg over
24 h. If a continuous infusion is not
feasible, give hydrocortisone 50 mg I.V.
boluses every 6 hours.
Postoperative regimen: Continuous
infusion of hydrocortisone 200 mg over
24 h while the patient is nil by mouth. If a
continuous infusion is not feasible, give
hydrocortisone 50 mg I.V. boluses every
6 hours. If the post-operative period is
uncomplicated and once the patient can
eat, resume oral glucocorticoids at an
increased dose for 48 h (e.g.,
hydrocortisone 40 mg/daily in three
divided doses; prednisone 10 mg/daily in
one or two divided doses; dexamethasone
1 mg once daily) and then resume the
pre-surgical dose. In case of post-operative
complications (e.g., significant pain,
infections), maintain an increased oral
dose or give stress-dose glucocorticoids
I.V. as clinically appropriate.
Labor and vaginal delivery Hydrocortisone 100 mg I.V. bolus at onset
of labor, followed by immediate
initiation of a continuous infusion of
hydrocortisone 200 mg over 24 h. If a
continuous infusion is not feasible, give
hydrocortisone 50 mg I.V. boluses every
6 hours.

Adrenal crisis prevention is one of the main goals of the and symptoms, possible precipitating factors (see recommen­
management of any patient with adrenal insufficiency and is dations 1.2 and 1.3, Table 9), when and how to increase
achieved through regular patient education about its signs glucocorticoid dose (sick day rules), and the provision of
G46 European Journal of Endocrinology, 2024, Vol. 190, No. 5

Table 9: Signs and symptoms of adrenal crisis and potential precipitating factors
General considerations • Patients present with a shock out of proportion to the severity of the trigger, if a trigger is
identified (see below).
• The shock is typically resistant to inotropes and fluid resuscitation if the adrenal crisis is
not recognized and promptly treated with parenteral glucocorticoids.
• Risk factors for adrenal crises include a history of previous adrenal crises, older age (>65
years), adolescence and transition from pediatric to adult care, and a higher comorbidity
burden.
• Glucocorticoid tapering down and discontinuation are crucial times, as
glucocorticoid-induced adrenal insufficiency can become clinically apparent.
Diagnosis Hypotension or hypovolemic shock.
plus at least one of the following:
• Nausea or vomiting.
• Severe fatigue.
• Fever.
• Impaired consciousness (incl. lethargy, confusion, somnolence, collapse, delirium, coma,

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and seizures).
Possible laboratory abnormalities (not required for • Hyponatremia (typically with raised urinary sodium).
the diagnosis) • Hyperkalemia.
• Signs of volume depletion (e.g., raised urea and creatinine).
• Hypoglycemia.
• Lymphocytosis.
• Eosinophilia.
Factors that can trigger an adrenal crisis or elicit Common to all patients with adrenal insufficiency:
symptoms of adrenal insufficiency
• Infections (including gastrointestinal, genitourinary, respiratory, and sepsis)
• Acute illness (including fever)
• Physical trauma
• Surgery or other procedures requiring general, regional, or local anesthesia
• Bowel procedures requiring laxatives/enema
• Labor and delivery
• Dental procedures
• Severe stress and pain (including severe anxiety and bereavement)
• Strenuous exercise

Specific to patients with glucocorticoid-induced adrenal insufficiency:

• Abrupt glucocorticoid withdrawal in subjects on long-term treatment

• Glucocorticoid tapering below physiological replacement doses
• Switch between different types, formulations, and doses of inhaled glucocorticoids,
which can lead to considerable variability of glucocorticoid systemic absorption
• Initiation of strong cytochrome P450 3A4 inducers, which leads to increased liver
metabolism of several glucocorticoids. Strong inducers include apalutamide,
carbamazepine, enzalutamide, fosphenytoin, lumacaftor, lumacaftor-ivacaftor,
mitotane, phenobarbital, phenytoin, primidone, and rifampicin.

patient-held prompts to healthcare professionals should they low or very low. Therefore, future epidemiology research
become seriously ill or unconscious (e.g., ESE steroid emer­ needs to define the true risk of clinical adrenal crisis and
gency card: A Standardised European Emergency Card for adrenal insufficiency. Additional data regarding morbid­
Patients with Adrenal Insufficiency | ESE (ese-hormones. ity and mortality of glucocorticoid-induced adrenal insuf­
org)).120,130 When compared to other adrenal insufficiency ficiency is required to understand the associated health
etiologies, patients with an established diagnosis of risk, which will ultimately define the approach to care
glucocorticoid-induced adrenal insufficiency were found to for patients tapering long-term glucocorticoid therapy.
be less aware of their diagnosis, to engage less with preventa­ • There is a need for further definition of risk factors con­
tive strategies (possession of emergency injectable hydrocorti­ tributing to the development and susceptibility of adrenal
sone, wearing medical alert gear), experienced considerably insufficiency, such as genetic predisposition, environmen­
more delays during emergency treatment for adrenal crises, tal influences, concurrent medication and underlying dis­
and generally had more difficulty in managing their condition ease for which glucocorticoid therapy is initiated for.
with poorer self-perceived health.21 These observations high­ • Biomedical and psychosocial research into understanding
light the need for prevention strategies and education of pa­ of glucocorticoid withdrawal is warranted, ideally pro­
tients and healthcare professionals alike. viding clinical scoring systems or biomarkers, in order
to better differentiate glucocorticoid withdrawal from
glucocorticoid-induced adrenal insufficiency.
7. Future research
• Established dynamic tests for glucocorticoid-induced ad­
renal insufficiency identify a relatively large proportion
• Evidence for the majority of above recommendations re­ of patients with biochemical HPA axis insufficiency fol­
garding glucocorticoid-induced adrenal insufficiency is lowing glucocorticoid therapy, yet there is only a very
Beuschlein et al. G47

low reported number of patients that develop clinical evi­ 6. Walsh LJ, Wong CA, Pringle M & Tattersfield AE. Use of oral cor­
dence of adrenal insufficiency and only an exceedingly ticosteroids in the community and the prevention of secondary
low number of patients develop adrenal crisis. Therefore, osteoporosis: a cross sectional study. Bmj 1996 313 344-346.
more specific and predictive tests and follow-up parame­ 7. Laugesen K, Jørgensen JOL, Sørensen HT & Petersen I. Systemic
glucocorticoid use in Denmark: a population-based prevalence
ters (including salivary cortisol and potentially continuous
study. BMJ Open 2017 7 e015237.
monitoring of interstitial cortisol) are needed to identify at-
8. Wilson JC, Sarsour K, Gale S, Pethö-Schramm A, Jick SS & Meier
risk patients who would benefit from dedicated preventive CR. Incidence and Risk of Glucocorticoid-Associated Adverse
intervention. Effects in Patients With Rheumatoid Arthritis. Arthritis Care
• More research is needed aiming to identify glucocorticoids Res (Hoboken) 2019 71 498-511.
retaining immunosuppressive and anti-inflammatory prop­ 9. Spivey CA, Griffith J, Kaplan C, Postlethwaite A, Ganguli A &
erties, but having less effect on HPA axis suppression and Wang J. A Retrospective Analysis of Corticosteroid Utilization
an improved adverse effect profile. In addition, the explor­ Before Initiation of Biologic DMARDs Among Patients with
ation of other therapeutic strategies, such as concurrent Rheumatoid Arthritis in the United States. Rheumatol Ther
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be entertained. 10. George MD, Baker JF, Winthrop K, Hsu JY, Wu Q, Chen L, Xie F,
• There is a need for a harmonization of cortisol assays. Yun H & Curtis JR. Risk for Serious Infection With Low-Dose
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immunoassays, usually overestimating true cortisol val­
11. Costello RE, Yimer BB, Roads P, Jani M & Dixon WG.
ues due to varying degrees of cross-reactivity with other
Glucocorticoid use is associated with an increased risk of hyper­
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lows for a specific measurement of cortisol. Future re­ 12. Lillegraven S, Greenberg JD, Reed GW, Saunders K, Curtis JR,
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urement for routine cortisol measurements. rheumatoid arthritis. PLoS One 2019 14 e0210459.
13. Kim D, Cho SK, Park B, Jang EJ, Bae SC & Sung YK.
Glucocorticoids Are Associated with an Increased Risk for
Acknowledgments Vertebral Fracture in Patients with Rheumatoid Arthritis. J
Rheumatol 2018 45 612-620.
The authors of the guideline would like to thank and acknow­ 14. Cheng TT, Lai HM, Yu SF, Chiu WC, Hsu CY, Chen JF & Chen
ledge Johannes Bijlsma (rheumatologist, The Netherlands), YC. The impact of low-dose glucocorticoids on disease activity,
Maria Fleseriu (MD, FACE, Oregon Health &Science bone mineral density, fragility fractures, and 10-year probability
University, Portland, Oregon, United States), Jens Otto Lunde of fractures in patients with rheumatoid arthritis. J Investig Med
Jørgensen (endocrinologist, Aarhus University, Denmark) and 2018 66 1004-1007.
John Newell-Price (endocrinologist, University of Sheffield, 15. Costello RE, Marsden A, Movahedi M, Lunt M, Humphreys JH,
United Kingdom) for their expert review. We are also grateful Emsley R & Dixon WG. The effect of glucocorticoid therapy on
for all the valuable and critical comments of members of the mortality in patients with rheumatoid arthritis and concomitant
type II diabetes: a retrospective cohort study. BMC Rheumatol
European Society of Endocrinology and the Endocrine
2020 4 4.
Society. The comments of the reviewers as well as our responses
16. Drouin J, Trifiro MA, Plante RK, Nemer M, Eriksson P & Wrange
are available in Supplementary Table 9. O. Glucocorticoid receptor binding to a specific DNA sequence is
In addition, the authors would like to thank J.W. Schoones required for hormone-dependent repression of pro-opiomelanocortin
for his help in conducting the literature searches. gene transcription. Mol Cell Biol 1989 9 5305-5314.
17. Nolan LA & Levy A. Anterior pituitary trophic responses to dexa­
methasone withdrawal and repeated dexamethasone exposures.
Funding J Endocrinol 2001 169 263-270.
This guideline was sponsored by the European Society of 18. Marin F, Cheng Z & Kovacs K. Ubiquitin immunoreactivity in
Endocrinology. corticotrophs following glucocorticoid treatment and in pituitary
adenomas. Arch Pathol Lab Med 1993 117 254-258.
19. Broersen LH, Pereira AM, Jørgensen JO & Dekkers OM. Adrenal
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