Adrenal Insufficiency, Addison Disease, And Laboratory Tests

Addison disease and Adrenal insufficiency are hormonal or endocrine disorders arising from the body’s inability to produce enough aldosterone and adrenal hormones. These conditions typically occur when there is a system malfunction, making it impossible for the body to maintain a close and timely adrenal balance.  

To maintain hormonal balance, the body uses a signaling and feedback system. Signals are sent and received by a combination of the hypothalamus found in the brain, the pituitary gland also located in the brain, and the adrenal glands, found on top of each kidney. This system regulates the production of the adrenal hormone. See the diagram illustrating Cortisol production. 

The adrenal glands have multiple layers, which include: 

  • 1. An outer layer that produces aldosterone. This is a salt-balancing hormone that influences blood pressure. 
  • 2. The middle layer that produces cortisol, a hormone that affects blood pressure, blood sugar, and the inflammatory response.  
  • 3. The inner layer that produces androgens, which are hormones that influence the emergence of acne and the growth of sexual hair. 

There is also the adrenal cortex, which produces and releases the cortisol. The hypothalamus and the pituitary gland regulate the production of this hormone. When blood cortisol drops, the hypothalamus releases the CRH (corticotropin-releasing hormone). This hormone directs the pituitary glands to produce the adrenocorticotropic hormone (ACTH), which in turn stimulates the adrenal glands to release cortisol into the bloodstream. For the body to produce the right amount of cortisol, the hypothalamus, pituitary gland, and the adrenal glands must function correctly. 

Low cortisol and or aldosterone make people dehydrated and weak. Moreover, you are unable to maintain adequate blood pressure, and you are unable to respond to physical stress appropriately. This is because cortisol affects the metabolism of carbohydrates, fats, and proteins. This hormone also affects the blood glucose levels, functions as an anti-inflammatory agent, and enables the body to react to stresses such as trauma and infection appropriately. 

Aldosterone, on the other hand, is produced by the adrenal cortex. Its primary function is to manage potassium and salt balance in the blood. 

Adrenal insufficiency occurs in two ways, via pituitary gland dysfunction and adrenal dysfunction. As such, there are two types of adrenal insufficiencies, including: 

  • Primary Adrenal Insufficiency (Also Known as Addison Disease) 

This is caused by damaged or underactive adrenal glands, which affect aldosterone and cortisol levels in the blood. 

Addison disease is quite rare. Statistics show that it affects 1 person for every 100,000 in the U.S. However, it affects people across the demographic spectrum and all genders in equal measure. Symptoms of the disease typically arise after most of the adrenal cortex (80% to 90%) has been damaged or destroyed. 

In the United States, the most common cause (approximate 75 percent) of adrenal insufficiency among adults is an autoimmune condition. The autoimmune condition may occur alongside other autoimmune processes that affect glands such as the thyroid glands. Other causes of Addison disease include diseases such as tuberculosis, the spread of cancer into the adrenal glands, chronic infections such as fungal infections, and adrenal glands bleeding (hemorrhage). In very rare cases, it is caused by a genetic abnormality that affects the adrenal glands.  

In children, 70% of Addison cases are caused by a congenital disease called congenital adrenal hyperplasia (CAH). The rest of the 30% of the cases are caused by an autoimmune disease, adrenoleukodystrophy (an inherited condition), and some even less common causes. 

  • Secondary Adrenal Insufficiency 

Secondary adrenal insufficiency is caused a decrease in the production of adrenocorticotropic hormone (ACTH), a pituitary hormone. ACTH is a messenger hormone, and its main function is to tell the adrenal cortex to produce cortisol. Insufficiency in ACTH arising from a pituitary tumor, pituitary damage, or other causes leads to lower or no cortisol production.  

Secondary adrenal insufficiency can also arise from abrupt discontinuation of corticosteroid therapy. For instance, a patient may be prescribed prednisone to relieve rheumatoid arthritis or when a patient is prescribed large doses of inhaled steroids to treat asthma. Such treatments suppress, or at the very least, alter natural cortisol production. It takes the body several days or even weeks to resume normal cortisol production. 

Signs and Symptoms 

Adrenal insufficiency presents vague and nonspecific signs and symptoms. However, the signs will first appear during periods of physical stress, such as trauma or infection. After that, they will increase in intensity over several months. Some of the signs and symptoms include the following: 

  • Unexplained weight loss 
  • Fatigue and or extreme weakness 
  • Decreased body hair 
  • Diarrhea or constipation 
  • Muscle weakness and aches  
  • Dizziness and fainting 
  • Abdominal pain 
  • Changes in heart rate and or blood pressure  
  • Nausea and vomiting 
  • Salt craving (caused by Addison disease) 
  • Hypoglycemia (Low blood sugar) 
  • Dehydration (caused by Addison disease) Hyperpigmentation (caused by Addison disease, and is characterized by the formation of dark patches on the skin, especially on the face, back of the hands, in skin folds, and on the neck) 

As you can appreciate, the sign and symptoms that adrenal insufficiency present are gradual and nonspecific, making it difficult to diagnose the condition early enough. In most cases, the diagnosis is made after the condition worsens into a severe condition called adrenal crisis or Addisonian crisis. The onset of adrenal crisis is typically triggered by increased physical stress such as surgery, infection, illness, or trauma. If left untreated, this condition can be fatal. Adrenal crisis presents the following sign and symptoms: 

  • Kidney failure 
  • Abdominal pain 
  • Shock 
  • Difficulty breathing 
  • Low blood pressure 
  • Severe diarrhea and vomiting, causing dehydration 
  • Loss of consciousness 
  • Severe pain affecting the legs, the lower back, and or abdomen 


A medical practitioner may use signs and symptoms such as hyperpigmentation, salt cravings, and low blood pressure to zero in on adrenal insufficiency as the primary health issue, especially when the symptoms appear and worsen during periods of physical stress. Laboratory tests, however, can determine whether adrenal insufficiency is indeed present. The test can further distinguish between primary and secondary insufficiencies, which helps determine the leading cause of the condition. 

Laboratory Tests 

Cortisol levels vary in the blood throughout the day, peaking in the morning. However, if the adrenal gland is functioning improperly or not being stimulated as usual by ACTH, the cortisol levels will be low throughout the day. Cortisol tests, where the blood samples (which are collected in the morning), are used in combination with other tests such as ACTH stimulation test, and ACTH tests help diagnose adrenal insufficiencies. 

ACTH is a hormone produced in the pituitary glands. Its main function is to signal the adrenal glands to start producing cortisol. The ACTH test is ordered as a basic test to determine if the pituitary is functioning correctly and producing the right amount of ACTH. A patient with adrenal insufficiency, having low ACTH levels indicates that the patient is suffering from secondary adrenal insufficiency. On the other hand, a high level of ATCH demonstrates that the patient has Addison disease (primary adrenal insufficiency). 

  • ACTH Stimulation Test 

According to the Endocrine Society, the ACTH stimulation test is the optional test when testing for primary adrenal insufficiency. The test involves measuring the level of cortisol in the patient’s blood before and after the injection of synthetic ACTH. When the adrenal glands are working as they should, the level of cortisol in the blood should rise in response to the increased ACTH levels. If the adrenal glands are not functioning correctly or they are damaged, the response to the ACTH will be insignificant.  

The ACTH Stimulation test is ordered along with the baseline ACTH test. If results show abnormal results, a prolonged ACTH stimulation test is run for 1 to 3 days, helping differentiate between secondary and primary adrenal insufficiency. 

An aldosterone test is done to help diagnose Addison disease. The test helps determine whether the adrenal gland is producing aldosterone. When the test results indicate that aldosterone levels are low, it is indicative that a patient may be suffering from primary adrenal insufficiency. 

When a patient is suffering from primary adrenal insufficiency, Renin activity is elevated since the lack of aldosterone results in increased renal sodium losses. Consequently, the patient experiences reduced blood sodium levels, which in turn decreases the amount of fluid in the patient’s blood. This lowers blood pressure and blood volume, which in turn activates renin production by the kidney. 

Potassium, sodium, carbon dioxide, and chloride are measures to help detect and evaluate an existing electrolyte imbalance. This test is done to monitor and evaluate the effectiveness of treatment. While electrolytes are affected by many different conditions, Addison disease causes potassium levels to be very high while lowering sodium, carbon dioxide, and chloride levels. 

An adrenal crisis causes glucose levels to plummet. As such, glucose testing is ordered to monitor a patient suffering from an adrenal crisis. 

  • Corticotropin-Releasing Hormone (CRH) Stimulation Test 

This test is not available in the U.S. However, in other countries, the test ordered when the ACTH test results are abnormal to help determine the causes of adrenal insufficiency. CRH is an ACTH production stimulating hormone release by the hypothalamus. In turn, the ACTH hormone is used to stimulate cortisol production in the adrenal glands. This test involves injecting synthetic CRH intravenously and, after that, measuring ACTH and cortisol levels at time intervals, say 30 minutes and 60 minutes. A normal response should yield an ACTH peak and then a cortisol peak. 

Patients with Addison disease produce an ACTH peak, but no cortisol peak. 

Patients suffering from secondary adrenal insufficiency have delayed or absent ACTH responses. In a patient with a damaged pituitary, the CRH does not stimulate ACTH production. A lack of ACTH indicates that the pituitary is the cause of the insufficiency. If results show delayed ACTH response, it suggests the hypothalamus is the main culprit. 

Tests That Identify the Underlying Cause 

  • Insulin-Induced Hypoglycemia Test 

A health practitioner may order this test to determine whether the pituitary disease is what is causing adrenal insufficiency. For the test, cortisol and glucose levels are measured at predetermined intervals after injecting insulin. The insulin stresses the pituitary gland. In a healthy person, the blood cortisol levels increase while the glucose levels fall. On the other hand, individuals with adrenal insufficiency, the glucose levels fall, and cortisol levels remain low and recover slowly.  

This test requires specialist experience in conducting the test. It should be done in specialized facilities where the patient can be monitor closely throughout the test. 

  • 21-hydroxylase autoantibodies test is sometimes ordered to aid the diagnosis process, especially when autoimmune is suspected of causing the disease. The test is useful at identifying autoimmune Addison disease. 
  • 17-hydroxyprogesterone and any other adrenal androgen can also be used to aid in the diagnosis of congenital adrenal hyperplasia (CAH), which is known to cause low cortisol and aldosterone. 

Very long-chain fatty acids (VLCFA) are also assessed among males suffering from adrenal insufficiency whose cause is not known to evaluate adrenoleukodystrophy. Learn more about this in the resources list in our Related Pages section. 

  • TB screening (whether blood or skin test) is also ordered to detect tuberculosis. 

Other hormonal assays and autoimmune markers may be tested to detect conditions that affect multiple endocrine glands – checking for autoimmune polyglandular syndromes.