Tertiary adrenal insufficiency is a condition where the body cannot produce enough cortisol, a vital hormone that helps us respond to stress, control blood pressure, regulate blood sugar, and maintain other essential life functions. This form of adrenal insufficiency begins in the hypothalamus, a small area of the brain that controls the body’s hormone production system. Understanding this condition is important because it can develop silently over time, often catching patients and even healthcare providers by surprise.

What is Tertiary Adrenal Insufficiency

Tertiary adrenal insufficiency is the third type of adrenal insufficiency, a disorder that occurs when the adrenal glands don’t make enough of certain hormones that are essential for life. The adrenal glands are small organs located just above the kidneys, and they produce hormones that help your body function properly every single day.^[1]

The production of cortisol, a steroid hormone that acts like a “stress hormone,” is normally controlled by two areas of the brain called the hypothalamus and the pituitary gland. The hypothalamus makes a hormone called corticotropin-releasing hormone (CRH), which tells the pituitary gland to make another hormone called ACTH (adrenocorticotropic hormone). ACTH then signals the adrenal glands to produce cortisol. This communication system is known as the hypothalamic-pituitary-adrenal (HPA) axis.^[2]

In tertiary adrenal insufficiency, the problem starts in the hypothalamus. When the hypothalamus doesn’t make enough CRH, the pituitary gland doesn’t make enough ACTH. As a result, the adrenal glands don’t receive the signal they need to make enough cortisol. Without treatment, the adrenal glands can actually shrink and stop working properly over time.^[3]

What makes tertiary adrenal insufficiency different from other types is where the problem begins. In primary adrenal insufficiency, also called Addison’s disease, the adrenal glands themselves are damaged and cannot produce hormones. In secondary adrenal insufficiency, the pituitary gland cannot produce enough ACTH. But in tertiary adrenal insufficiency, the issue lies one step earlier in the chain, at the level of the hypothalamus.^[4]

Causes

The most common cause of tertiary adrenal insufficiency is exposure to long-term or high-dose glucocorticoid (steroid) therapy. When people are prescribed steroid medication as treatment for conditions such as asthma, skin conditions, arthritis, Crohn’s disease, or multiple sclerosis, they may take these steroids for extended periods. This prolonged use can interfere with the normal control mechanisms between the brain and the adrenal glands.^[1]

When artificial glucocorticoids enter the body through medication, the brain essentially thinks that there are too many steroid hormones already present in the body. In response, the adrenal glands can go to “sleep” and stop producing cortisol as they should. This is the body’s way of trying to maintain balance, but it creates a dangerous situation where the body becomes dependent on the external source of steroids.^[8]

When people suddenly stop taking artificial glucocorticoids after long-term use, their adrenal glands may not return to normal cortisol production. This results in adrenal insufficiency because the body has lost its ability to make this essential hormone on its own. The suppression of the HPA axis is an inevitable effect of chronic exogenous glucocorticoid therapy, and recovery of adrenal function varies greatly among individuals.^[14]

Glucocorticoid exposure through oral administration that poses risk for adrenal insufficiency is expected to exceed certain thresholds. The duration of glucocorticoid therapy typically needs to be three to four weeks or greater to pose risk. The dose also matters: any dose greater than a daily hydrocortisone equivalent of 15 to 25 mg can potentially cause suppression of the HPA axis.^[14]

Less commonly, tertiary adrenal insufficiency can result from removal of or injury to parts of the hypothalamus, though this is much rarer than medication-induced cases.^[5]

Epidemiology

The prevalence of secondary and tertiary adrenal insufficiency combined is estimated to be 150 to 280 cases per million inhabitants. This is somewhat higher than primary adrenal insufficiency, which has a prevalence of 100 to 140 cases per million inhabitants.^[9]

At least one percent of the population uses chronic glucocorticoids as anti-inflammatory or immunosuppressive agents, which means a significant number of people are potentially at risk for developing tertiary adrenal insufficiency. The widespread use of steroid medications for common conditions like asthma, rheumatoid arthritis, and inflammatory bowel disease means that tertiary adrenal insufficiency is an underrecognized problem in healthcare.^[14]

The condition can affect people of any age, from children to older adults. Babies, children, and young people with adrenal insufficiency go through a period of rapid growth and change that requires different doses and dosing schedules than adult patients, as well as frequent adjustment to their medication doses to optimize growth and wellbeing.^[13]

Symptoms

The symptoms of tertiary adrenal insufficiency are often nonspecific and can develop slowly over time, which may lead to delayed diagnosis. Many people experience these symptoms for months or even years before the condition is properly identified. The most common symptoms include chronic fatigue, muscle weakness, loss of appetite, and weight loss.^[2]

Children with secondary or tertiary adrenal insufficiency may experience fatigue, weakness, and slow recovery from illness. Adults often report feeling tired all the time, regardless of how much sleep they get. This is not the kind of tiredness that improves after resting; it is a deep, overwhelming exhaustion that affects daily functioning.^[3]

Other symptoms can include upset stomach (nausea), vomiting, diarrhea, dizziness, and abdominal pain. Some people experience low blood pressure that drops even further when they stand up, causing dizziness or fainting. Irritability and depression are also common, as the lack of cortisol affects mood and mental wellbeing.^[5]

People with tertiary adrenal insufficiency may have irregular or no menstrual periods if they are women, and a loss of interest in sex. They may also experience joint pain and muscle aches. Some people develop cravings for salty foods, though this is less common in tertiary adrenal insufficiency than in primary adrenal insufficiency.^[2]

An important feature that helps differentiate tertiary (and secondary) adrenal insufficiency from primary adrenal insufficiency is the absence of skin darkening. In primary adrenal insufficiency, high levels of ACTH cause hyperpigmentation, a darkening of the skin that is most visible on scars, skin folds, pressure points, lips, and mucous membranes. This does not occur in tertiary or secondary adrenal insufficiency because ACTH levels are low rather than high.^[9]

Severe or lengthy illness or infection can result in vomiting and other symptoms that may quickly progress to a medical emergency called adrenal crisis. During an adrenal crisis, a person may experience low blood pressure, low blood sugar, lethargy, and possible loss of consciousness. This is a life-threatening condition that requires immediate medical treatment.^[3]

Risk Factors

The primary risk factor for tertiary adrenal insufficiency is the use of steroid medications over an extended period. People who have been prescribed glucocorticoids for conditions such as asthma, rheumatoid arthritis, inflammatory bowel disease, skin conditions, or multiple sclerosis are at risk if they have taken these medications for three to four weeks or longer at doses that exceed the body’s normal cortisol production.^[1]

The risk increases with both the dose and duration of steroid therapy. Even low-dose glucocorticoid use, such as prednisone at 2.5 to 7.5 mg per day, can increase risks over time. Higher doses and longer treatment periods create greater risk for HPA axis suppression.^[14]

People who have taken inhaled steroids, such as those used in asthma inhalers, can also develop tertiary adrenal insufficiency, though this was not widely recognized until recently. One patient’s story involved taking Seretide inhalers for over 10 years for respiratory conditions without being aware of the risk of adrenal gland suppression.^[20]

Sudden discontinuation of steroid medication is a major risk factor for developing acute adrenal insufficiency or adrenal crisis. This is why doctors typically reduce steroid doses gradually (called “tapering”) rather than stopping them all at once. However, even with gradual tapering, some people’s adrenal glands do not recover function.^[6]

People who experience increased physical or emotional stress while on reduced steroid doses or after stopping steroids are at higher risk. Stress situations include serious infections, surgery, trauma, or significant emotional upheaval. During these times, the body needs more cortisol than usual, and if the adrenal glands cannot respond, an adrenal crisis can develop.^[17]

Pathophysiology

Understanding how tertiary adrenal insufficiency develops requires knowledge of the normal HPA axis function. In healthy individuals, the hypothalamus releases CRH in response to various signals, including stress, low blood sugar, and the body’s natural daily rhythm. CRH travels a short distance to the pituitary gland and signals it to release ACTH into the bloodstream. ACTH then travels to the adrenal glands and stimulates them to produce and release cortisol.^[3]

Cortisol has many crucial functions in the body. It helps regulate stress responses, controls blood pressure, regulates blood glucose levels, suppresses inflammation, controls metabolism, and helps regulate the sleep cycle. Cortisol also affects how the immune system works and helps the body respond to illness and injury.^[3]

When someone takes glucocorticoid medications over a prolonged period, these artificial steroids circulate in the blood and reach the hypothalamus. The hypothalamus has receptors that detect cortisol levels in the blood. When it senses high levels of glucocorticoids (whether natural or artificial), it reduces or stops producing CRH. This is a normal feedback mechanism designed to prevent too much cortisol in the body.^[1]

With less CRH being produced, the pituitary gland receives fewer signals to make ACTH, so ACTH production decreases. With less ACTH stimulation, the adrenal glands produce less cortisol. Over time, without regular ACTH stimulation, the adrenal glands can actually shrink in size and lose their ability to produce adequate amounts of cortisol, even when they should be able to.^[10]

The suppression of the HPA axis is essentially the brain’s interpretation that the body has sufficient steroid hormones because of the medication. The system goes into a dormant state. When the external source of steroids is removed, the hypothalamus, pituitary, and adrenal glands need time to reactivate and begin functioning normally again. Unfortunately, this reactivation does not always happen, or it may take months to years to occur.^[8]

An important distinction in tertiary adrenal insufficiency is that mineralocorticoid function is typically preserved. Mineralocorticoids, particularly aldosterone, help maintain the balance of sodium and potassium in the body and regulate blood pressure. Aldosterone production is controlled by a different system called the renin-angiotensin-aldosterone system, which is independent of hypothalamic or pituitary signals. This is why people with tertiary adrenal insufficiency generally do not experience the severe salt wasting and dehydration that can occur in primary adrenal insufficiency.^[4]

During times of physical or emotional stress, the body normally increases cortisol production significantly. In tertiary adrenal insufficiency, the HPA axis cannot respond appropriately to these demands. If cortisol levels fall too low during a period of stress, an adrenal crisis can develop, characterized by severe hypotension (low blood pressure), hypoglycemia (low blood sugar), and potentially life-threatening shock.^[9]

Prevention

The key to preventing tertiary adrenal insufficiency is awareness and careful management of glucocorticoid therapy. Healthcare providers who prescribe steroid medications should inform patients about the potential for HPA axis suppression and the importance of not stopping medications suddenly. Patients should understand that long-term steroid use requires gradual dose reduction under medical supervision.^[14]

When steroid medications are necessary, healthcare providers should use the lowest effective dose for the shortest duration possible. This helps minimize the risk of HPA axis suppression while still treating the underlying condition effectively. Regular monitoring and reassessment of the need for continued steroid therapy is important.^[14]

For people who have been on long-term steroid therapy and need to discontinue treatment, a gradual tapering schedule is essential. The tapering process allows the HPA axis time to potentially recover function. The rate of tapering varies depending on the dose, duration of therapy, and individual patient factors. Some patients may need to be tested for adrenal function during or after tapering to ensure their bodies are producing adequate cortisol.^[6]

Education about recognizing the symptoms of adrenal insufficiency is important for patients who are tapering off steroids or who have recently stopped taking them. They should know to seek medical attention if they experience severe fatigue, weakness, nausea, vomiting, or other concerning symptoms, especially during times of illness or stress.^[19]

Patients who have been on long-term steroids should inform all their healthcare providers about this history, even years after stopping the medication. During times of stress, illness, or before surgery, they may need temporary steroid supplementation to prevent adrenal crisis, as adrenal function may not have fully recovered.^[12]