Tertiary Adrenal Insufficiency

Tertiary adrenal insufficiency is a condition where the brain’s control center for hormone production stops sending the right signals to the adrenal glands, resulting in dangerously low levels of cortisol, a hormone essential for life.

Table of contents

• What is Tertiary Adrenal Insufficiency?
• How the Condition Develops
• Main Causes and Risk Factors
• Signs and Symptoms
• Diagnosis and Testing
• Treatment and Management
• Recovery of Adrenal Function

What is Tertiary Adrenal Insufficiency?

Tertiary adrenal insufficiency is the third type of adrenal insufficiency, a disorder where the body does not produce enough of certain hormones needed for survival. The adrenal glands are small organs located just above the kidneys that make hormones essential for life^[1].

Unlike primary adrenal insufficiency (Addison’s disease), where the adrenal glands themselves are damaged, tertiary adrenal insufficiency starts in the hypothalamus, a small area of the brain near another structure called the pituitary gland. The hypothalamus makes corticotropin-releasing hormone (CRH), which tells the pituitary gland to make ACTH (adrenocorticotropic hormone). ACTH then signals the adrenal glands to produce cortisol^[2].

When the hypothalamus doesn’t make enough CRH, the pituitary gland doesn’t make enough ACTH. As a result, the adrenal glands don’t make enough cortisol^[1]. Cortisol is sometimes called the “stress hormone” because it helps your body respond to stress. It also helps control blood pressure, blood glucose (blood sugar), reduce inflammation, and control metabolism^[2].

How the Condition Develops

The production of cortisol from fully functioning adrenal glands is controlled by a complex system called the hypothalamic-pituitary-adrenal (HPA) axis. This system involves communication between the hypothalamus and pituitary gland in the brain and the adrenal glands^[1].

Cortisol helps the body regulate stress, control metabolism, suppress inflammation, regulate blood pressure and blood sugar, and regulate sleep cycles^[3]. When this control system is disrupted, the brain essentially thinks there are too many steroid hormones in the body. 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^[1].

Without treatment, the adrenal glands can shrink and stop working over time^[3]. This makes tertiary adrenal insufficiency a serious condition that requires ongoing medical attention.

Main Causes and Risk Factors

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 (artificial glucocorticoids) 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 can interfere with the normal control mechanisms between the brain and the adrenal glands^[1].

Prolonged use of steroids leads to suppression of the hypothalamic-pituitary-adrenal axis. The most frequent cause is the sudden discontinuation of chronic glucocorticoid therapy^[6]. When people stop taking artificial glucocorticoids suddenly, their adrenal glands may not return to normal cortisol production, which results in adrenal insufficiency^[1].

According to clinical guidelines, glucocorticoid exposure that poses risk for adrenal insufficiency typically exceeds both of the following thresholds: duration of therapy of 3 to 4 weeks or greater, and a daily dose greater than the hydrocortisone equivalent of 15 to 25 mg (4 to 6 mg prednisone or prednisolone, 3 to 5 mg methylprednisone, or 0.25 to 0.5 mg dexamethasone)^[14].

It is important to understand that even low-dose glucocorticoid use increases risks of cardiovascular disease, severe infections, high blood pressure, diabetes, bone loss, and fractures^[14].

Signs and Symptoms

Children and adults with tertiary adrenal insufficiency may experience a range of symptoms. Common symptoms include fatigue, weakness, and slow recovery from illness^[3].

The most common symptoms of adrenal insufficiency in general are chronic (long-lasting) fatigue, muscle weakness, loss of appetite, weight loss, and abdominal pain^[17]. Other symptoms can include nausea, vomiting, diarrhea, low blood pressure that drops further when standing up (causing dizziness or fainting), irritability and depression, joint pain, and craving salty foods^[17].

Because symptoms of adrenal insufficiency come on slowly over time, they may be overlooked or confused with other illnesses^[17]. An important difference between tertiary and primary adrenal insufficiency is that people with tertiary adrenal insufficiency typically do not develop skin darkening (hyperpigmentation), which is nearly always present in long-standing primary adrenal insufficiency^[9].

Severe or lengthy illness or infection can result in vomiting, which may quickly progress to a medical emergency called an adrenal crisis. People suffering from adrenal crisis will experience low blood pressure, low blood sugar, extreme tiredness (lethargy), and possible loss of consciousness^[3]. Adrenal crisis is a potentially life-threatening condition that requires immediate medical treatment^[12].

Diagnosis and Testing

Diagnosis involves steps that healthcare professionals take to find out if you have tertiary adrenal insufficiency. Your healthcare professional will talk with you about your medical history and your symptoms^[11].

The recommended initial laboratory workup in the evaluation of adrenal insufficiency is the ACTH stimulation test. This test measures the level of cortisol in the blood before and after an injection of laboratory-made ACTH^[11]. The short corticotropin test administered with a 250 microgram dose is considered the gold standard test to confirm a diagnosis of adrenal insufficiency^[7].

If the stimulation test is not available, a combination of morning cortisol and plasma ACTH testing can be used preliminarily^[7]. Blood tests can measure blood levels of sodium, potassium, cortisol, and ACTH^[11].

An important distinction in patients with tertiary adrenal insufficiency is the presence of preserved mineralocorticoid (aldosterone) function. Those with secondary or tertiary adrenal insufficiency will typically have preserved mineralocorticoid function due to separate feedback systems. Mineralocorticoid levels are regulated by a system called the renin-angiotensin system that is independent of hypothalamic or pituitary signals^[4].

Imaging tests may also be used. An MRI of the pituitary gland can spot damage that may cause secondary or tertiary adrenal insufficiency^[11].

Treatment and Management

In the majority of cases, adrenal insufficiency is a chronic and irreversible condition that requires lifelong hormone replacement therapy. There is no cure available. Treatment requires the replacement or substitution of the hormones that the adrenal glands ceased to produce and should begin as soon as the diagnosis is confirmed^[12].

The preferred treatment of adrenal insufficiency is oral hydrocortisone, which is the most natural option for cortisol replacement available today. The patient’s well-being usually dramatically improves within 24 hours after the first dose is taken^[12].

Treatment typically involves taking corticosteroid medicines by mouth such as hydrocortisone, prednisone, or methylprednisolone to replace cortisol. These medicines are taken on a schedule to help mimic the changes in cortisol levels the body typically goes through over 24 hours^[11].

The daily hydrocortisone dose should be given in two to three doses, with half to two-thirds of the total daily dose in the morning. The goal is to mimic the natural rhythm of the body’s cortisol production as closely as possible^[12]. Since every person with adrenal insufficiency has a different residual function of their adrenal glands and a different metabolism, fixed dosage recommendations are not available. Dosing needs to be adjusted to meet the needs of each individual^[12].

It is important to understand that there is a difference between replacing a hormone that is no longer produced by the body and taking higher doses of cortisone to treat another condition. The feared side effects associated with cortisone treatment, such as bone loss, weight gain, eye problems, or mood changes, are not to be expected when replacing cortisol in adrenal insufficiency at proper replacement doses^[12].

Because people with tertiary adrenal insufficiency typically have preserved mineralocorticoid function, they usually do not need aldosterone replacement therapy, unlike those with primary adrenal insufficiency^[4].

With treatment, most people with tertiary adrenal insufficiency can live happy and normal lives^[3]. It is highly recommended to have an endocrinologist (a specialist in hormone disorders) oversee and manage dosage and necessary adjustments^[12].

Recovery of Adrenal Function

It is important to emphasize that even if a person stops taking artificial glucocorticoids, they may never recover adrenal function, or it may take many years^[1]. The suppression of the hypothalamic-pituitary-adrenal axis is an inevitable effect of chronic external glucocorticoid therapy, and recovery of adrenal function varies greatly among individuals^[14].

The decrease in adrenal function may be masked until stress or illness triggers an adrenal crisis^[4]. For this reason, ongoing medical monitoring and management are essential for people with tertiary adrenal insufficiency.