Tertiary adrenal insufficiency What is Tertiary Adrenal Insufficiency? Tertiary adrenal insufficiency is the third type of adrenal insufficiency. You can learn more about primary (Addison's) and secondary adrenal insufficiency on our "What is Addison's disease and adrenal insufficiency" page. The most common cause of tertiary adrenal insufficiency is exposure to long-term or high-dose glucocorticoid (steriod) therapy. When people are prescribed steroid medication (artificial glucocorticoids) as treatment for conditions such as asthma, skin conditions, arthritis, Crohn's disease or multiple sclerosis, they are taking these steroids for extended periods which can interfere with the normal control mechanisms between the brain and the adrenal glands, known as the hypothalamic-pituitary-adrenal (HPA) axis. The production of cortisol (a steroid hormone, or glucocorticoid) from fully functioning adrenal glands is controlled by two areas of the brain called the hypothalamus and the pituitary gland. Tertiary adrenal insufficiency starts in the hypothalamus, a small area of the brain near the pituitary. The hypothalamus makes corticotropin-releasing hormone (CRH), a hormone that tells the pituitary to make ACTH. When the hypothalamus doesn’t make enough CRH, the pituitary gland doesn’t make enough ACTH. In turn, the adrenal glands don’t make enough cortisol. In summary, the brain thinks that there are too many steroid hormones in the body, and as a result the adrenal glands can go to 'sleep' and stop producing cortisol as they should, and as the body needs to sustain life. When people stop taking artificial glucocorticoids suddenly, their adrenal glands may not return to normal cortisol production, which results in adrenal insufficiency. It is important to emphasise that even if a person stops taking artificial glucocorticoids, they may never recover adrenal function, or it may take many years. If you are learning about tertiary adrenal insufficiency for the first time, watch CoMICs short 3-minute video, made in collaboration with the ADSHG, to give you some background information and context in an easy to understand and accessible format. If you are a healthcare professional, click below to read the joint clinical guidance from the European Society of Endocrinology and Endocrine Society. Watch CoMICs Lite: Glucocorticoid-Induced Adrenal Insufficiency Learn “Diagnosis and Therapy of Glucocorticoid-induced Adrenal Insufficiency. Personal Experience ADSHG member Ruth, an Academic Clinical Psychologist, was given a diagnosis of adrenal insufficiency in 2024 after years of taking Seretide inhalers as treatment for respiratory conditions. She was unaware that there was a risk of her adrenal glands stopping production of cortisol due to her extended use of the steroid medication. Read Ruth's journey to diagnosis Ruth has written an insightful blog post about her journey to diagnosis, and part of her process of adjusting to her new diagnosis of tertiary adrenal insufficiency has been to research it to understand it better. Below, she shares her thorough summary of the existing research around this condition - in her words, 'The Scientific Bit', which makes for a very interesting read. The Scientific Bit Tertiary Adrenal Insufficiency (TAI), also known as Glucocorticoid-Induced Adrenal Insufficiency (GI-AI), is the most common form of adrenal insufficiency. Glucocorticoids (GCs) were first introduced in 1948 and are the most widely used medications worldwide, treating inflammatory and autoimmune diseases and conditions. Tertiary adrenal insufficiency is thought to be highly prevalent in people taking glucocorticoids but remains under-recognised and under-diagnosed. The condition is caused by the effects of all forms of glucocorticoids (e.g. oral, inhaled, etc.) on the function of the adrenal glands, and is linked to the duration of treatment and the dose required. The use of the inhaled glucocorticoids Fluticasone propionate is a particular risk factor, despite there being safer alternatives for the treatment of asthma and COPD. Underreported & Low Rate of Diagnosis The underreporting and low rate of diagnosis is due to a number of factors, including the presentation of vague symptoms and poor education around this condition within the medical profession, including amongst endocrinologists. The symptoms of tertiary adrenal insufficiency can vary from mild fatigue, non-specific abdominal pain and an increased susceptibility to infection, to a life-threatening adrenal crisis. Nevertheless, the risk of glucocorticoid treatments on adrenal function was identified, particularly in the paediatric population, as far back as the early 1990’s, when researchers recommended close liaison between medical teams and endocrinology colleagues. More recent research has again called for greater collaboration, close observation of patients on glucocorticoids, good education for patients, families and healthcare staff, and the use of morning cortisol levels to screen for possible tertiary adrenal insufficiency. Just to demonstrate the scale of the challenge with tertiary adrenal insufficiency, an excellent review published in the BMJ in 2021 demonstrated a 48.7% risk of developing adrenal insufficiency in patients taking oral glucocorticoids, and a 20.3% to 43.7% risk in those using inhaled glucocorticoids, particularly when used for more than a year and used alongside oral steroids (a common combination for the treatment of asthma). Excellent guidelines for the identification and treatment of potential tertiary adrenal insufficiency in patients taking glucocorticoids are available (see BMJ 2021 and the joint clinical guidance from the European Society of Endocrinology and Endocrine Society), and my own experience indicates a shift in approach to patients with a history of taking Fluticasone propionate. However, diagnosis remains a challenge as few people present with obvious signs or symptoms, and those that do are considered to be the “tip of the iceberg”. The danger of missing possible tertiary adrenal insufficiency is that infections, surgery or severe stress can trigger a life-threatening adrenal crisis in those undiagnosed. Diagnosis, Treatment and (potential) Recovery When tertiary adrenal insufficiency is identified, through morning cortisol levels and subsequent Short Synacthen Test, guidelines suggest different levels of treatment with replacement glucocorticoids (e.g. hydrocortisone or prednisolone) depending on an individual’s level of adrenal function. They also suggest education for patients and relatives on replacement glucocorticoid dose, emergency injections and sick day rules. There are also clear guidelines on how to manage the dosage of glucocorticoids required to treat the initial illness or condition that required glucocorticoids in the first place. These guidelines consider whether the condition is acute or long-term and recommend caution when tapering glucocorticoid doses, due to the effects on the adrenal glands. Ultimately, tapering the dose of glucocorticoids aims to assist in the recovery of adrenal function. So, the science is clear. The impact of glucocorticoids on adrenal function has been known for more than 30 years. The higher the dose and the longer the use of glucocorticoids, the more likely it is that someone will develop tertiary adrenal insufficiency. Those on one of the most common forms of asthma inhalers are particularly at risk. Almost 50% of people using oral or inhaled glucocorticoids will develop tertiary adrenal insufficiency, and up to 7% of people with tertiary adrenal insufficiency will never recover normal adrenal function. Reading the papers and summarising the information has been both enlightening and difficult. The risks of glucocorticoids have been known for a long time, and liaison between teams of specialists and endocrinologists has been recommended repeatedly, as has the utilisation of morning cortisol (in my experience a very simple test to have done) to pick up patients at risk. These factors have made me question why more hasn’t been done to address this issue and identify those at risk. This is particularly the case given the continued use of Fluticasone propionate, a particular risk for the development of tertiary adrenal insufficiency. It certainly leaves me with strong feelings as I adjust to my own diagnosis and my personal experience of tertiary adrenal insufficiency. What I hope going forward is that clinicians prescribing glucocorticoids consider the risks to adrenal function and form partnerships with endocrinology teams. That they assess each patient’s risk of developing tertiary adrenal insufficiency, and utilise morning cortisol tests to screen people. It is fantastic that charities such as the ADSHG continue to raise awareness, as, inevitably, there will be an increase in the number of patients diagnosed with tertiary adrenal insufficiency going forward. References Kate Davies (2023) Understanding tertiary adrenal insufficiency. Journal of Pediatric Nursing 69 (2023) 121–122. https://doi.org/10.1016/j.pedn.2023.02.012 Stefanie Hahner, Christine Spinnler, Martin Fassnacht, Stephanie Burger-Stritt, Katharina Lang, Danijela Milovanovic, Felix Beuschlein, Holger S. Willenberg, Marcus Quinkler, and Bruno Allolio (2015) High Incidence of Adrenal Crisis in Educated Patients With Chronic Adrenal Insufficiency: A Prospective Study. J Clin Endocrinol Metab 100: 407–416, 2015 Birgit Harbeck, Swantje Brede, Claudia Witt, Sven Süfke, Hendrik Lehnert and Christian Haas (2015) Glucocorticoid replacement therapy in adrenal insufficiency — a challenge to physicians? Endocrine Journal 2015, 62 (5), 463-468 J. Holme, J.W. Tomlinson, R.A. Stockley, P.M. Stewart, N. Barlow and A.L. Sullivan (2008) Adrenal suppression in bronchiectasis and the impact of inhaled corticosteroids. Eur Respir J 2008; 32: 1047–1052 DOI: 10.1183/09031936.00016908 Mathis Komminoth, Marc Y. Donath, et al (2023) Glucocorticoid withdrawal and glucocorticoid-induced adrenal insufficiency: Study protocol of the randomized controlled «TOASST” (Taper Or Abrupt Steroid STop) multicentre trial. https://doi.org/10.1371/journal.pone.0281585 Alessandro Prete & Irina Bancos (2021) Glucocorticoid induced adrenal insufficiency. BMJ 2021;374:n1380 http://dx.doi.org/10.1136/bmj.n1380 Rebecca Sagar, Sarah Mackie, Ann W. Morgan, Paul Stewart, Afroze Abbas (2020) Evaluating tertiary adrenal insufficiency in rheumatology patients on long-term systemic glucocorticoid treatment. Clinical Endocrinology. 2021;00:1–10. DOI: 10.1111/cen.14405 Vishnu Sannarangappa and Ryan Jalleh (2014) Inhaled Corticosteroids and Secondary Adrenal Insufficiency. The Open Respiratory Medicine Journal, 2014, 8, (Suppl 1: M6) 93-100 Conor P Woods, Nicola Argese, Matthew Chapman, et al (2015) Adrenal suppression in patients taking inhaled glucocorticoids is highly prevalent and management can be guided by morning cortisol. European Journal of Endocrinology (2015) 173, 633–642 DOI: 10.1530/EJE-15-0608 Whether you're newly diagnosed or have lived with the condition for years - please join our community and support our cause! You'll receive the latest expert advice, guidance and ADSHG news, whilst being part of our inspiring and supportive community. Become a member today! Join the ADSHG Connect on social media! Follow us on X/Twitter, Bluesky, Facebook, Instagram, LinkedIn, Threads, TikTok and YouTube. Manage Cookie Preferences