A number of issues with the endocrine system can lead to low cortisol or adrenal insufficiency. Find out when low cortisol levels is cause for concern.

Cortisol is a steroid hormone produced by your body’s two small adrenal glands. These glands are located just above your kidneys and are part of your body’s endocrine system — the network of organs that produces hormones.

Although the adrenal glands make several different steroids, cortisol is by far the most important, says James W. Findling, MD, clinical professor of medicine and surgery at the Medical College of Wisconsin in Menomonee Falls and a spokesperson for the Endocrine Society 1. “Every organ in the body is dependent on cortisol,” he says.

Cortisol is commonly known as the “stress hormone” because it fluctuates in response to different kinds of stress. But it has a number of other important roles as well. It plays a part in metabolism by supporting glucose production in the liver, counters inflammation and helps regulate both your blood pressure and your heart rate, according to the Society for Endocrinology 1.

Cortisol is also intimately involved with your internal clock. “When you wake up in the morning, assuming you have a normal sleep-wake cycle, your cortisol levels are high because you have to get up and get going,” says Dr. Findling. “Later in the day, cortisol levels are very, very low because you’re ready to sleep.”

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The adrenal glands work in close concert with the pituitary gland and the hypothalamus region of the brain, according to the Society for Endocrinology 1. When cortisol levels in the blood are low, the hypothalamus tells the pituitary to tell the adrenal glands to release more cortisol.

This process happens naturally during the course of any given day, but sometimes low cortisol levels — aka adrenal insufficiency — happens for reasons other than normal day-to-day stress or activity.

The causes of adrenal insufficiency are divided into three categories, depending upon where in the body they occur: primary (in which the adrenal glands are affected), secondary (when the pituitary gland is the culprit), or tertiary (when the problem originates in the hypothalamus), according to Cedars-Sinai Medical Center 45.

Primary Causes of Adrenal Insufficiency

When the problem that's causing low blood cortisol develops in the adrenal gland itself, it's called primary adrenal insufficiency, or Addison’s disease 245. “[This] is when the primary adrenal glands have become malfunctioning or destroyed,” says Dr. Findling.

According to the National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK), 80 to 90 percent of Addison's cases are autoimmune-related: The immune system mistakenly produces substances called autoantibodies, which attack the adrenal gland 245. What triggers the generation of these destructive antibodies is not yet clear, says Dr. Findling.

Primary adrenal insufficiency is relatively rare: According to a 2016 paper published in the Journal of Clinical Endocrinology and Metabolism, it affects only about 100 to 140 out of every million Americans 34.

People with Addison’s disease have to take a replacement hormone for the rest of their lives, but aside from that, their lives can be relatively normal and active 2. However, many people with Addison’s have other autoimmune conditions as well, such as autoimmune thyroid disease and/or type 1 diabetes 2.

Secondary Causes of Adrenal Insufficiency

Secondary adrenal insufficiency is when the cause of low blood cortisol is located in the pituitary, a tiny gland at the base of your brain. It's the most common of the three causal categories of adrenal insufficiency, says Dr. Findling 4.

Normally, the pituitary makes adrenocorticotropic hormone (ACTH), which is what directs the adrenal glands to produce cortisol. If the pituitary can’t make and send ACTH, the adrenals never get the message to produce cortisol.

Taking steroid medications is one of the most common causes of secondary adrenal insufficiency, Dr. Findling says. "Prednisone, for example, suppresses ACTH and lowers cortisol production. That’s one of the reasons [doctors] don’t abruptly discontinue steroids, but taper them gradually and judiciously." This way, the pituitary has time to begin to make ACTH again, he explains.

However, secondary adrenal insufficiency can occur for other pituitary-related reasons as well, including tumors, inflammation or injury to or removal of the gland, according to the NIDDK 4.

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Tertiary Causes of Adrenal Insufficiency

Tertiary adrenal deficiency is when the cause of low blood cortisol originates in the brain's hypothalamus. One of the jobs of the hypothalamus is to send messages — in the form of corticotropin-releasing hormone, aka CRH — to the pituitary, which then alerts the adrenal glands via ACTH. If CRH isn't released properly, ACTH won't be, either, according to the NIDDK.

Taking opioids or narcotics is the most common cause of tertiary adrenal insufficiency, says Dr. Findling. The good news is that the effect is usually very short-lived: Cortisol levels return to normal soon after the opioids are discontinued.

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When To Be Concerned

Day-to-day fluctuations in blood cortisol levels are normal, but persistently low levels are not. Adrenal insufficiency is often associated with low levels of other adrenal hormones, which play many important roles in the body. If you experience a loss of muscle strength, a sense of fatigue that gradually worsens or poor appetite accompanied by weight loss, you might have low blood-cortisol levels, according to the NIDDK.