What can cause low cortisol levels?

Cortisol is a steroid hormone that has many important roles in the body, including of course its most well-known role as part of the stress response. Receptors that cortisol can bind to are found in almost all tissues in the body, which means that cortisol is able to affect nearly every organ system (1).

What are the functions of cortisol?

  • Controls the inflammatory response in an immune response
  • Cortisol surge helps provide energy during stressful situations
  • Role in the metabolism of fats, protein, and carbohydrates
  • Helps control blood pressure and salt and water balance
  • Involved in memory formation
  • Enhances the activity of epinephrine (adrenalin)
  • Supports developing fetus during pregnancy

How are cortisol levels controlled?
Cortisol is synthesized from cholesterol in the adrenal glands, with secretion controlled by the HPA axis. The HPA axis is a combination of glands that includes the hypothalamus, the pituitary gland, and the adrenal gland. This HPA axis follows a circadian rhythm, which means that cortisol levels are generally higher in the morning and lower at night (1).

When the hypothalamus detects low cortisol, low blood sugar, or times of stress, it releases corticotropin-releasing hormone (CRH), which signals for the pituitary to release adrenocorticotropic hormone (ACTH). ACTH then acts on the adrenal gland to trigger the synthesis and secretion of cortisol. Elevated cortisol levels inhibit the release of CRH and ACTH, providing a negative feedback loop to control cortisol levels (1).

What can cause low cortisol levels?
Low cortisol can be caused by different abnormalities in the HPA axis.

Primary adrenal insufficiency (Addison disease) is when there is an issue with the adrenal gland that inhibits cortisol production and release. This is most commonly caused by an autoimmune reaction (where the body’s own cells target and destroy cells in the adrenal gland), but can also be due to cancer, an infection (e.g., tuberculosis, AIDS, syphilis), an inherited disorder, drug use, or some other disease (2). Damage to the adrenal gland cells also affects the production of mineralocorticoids (e.g., aldosterone that control blood pressure) and sex hormones (e.g., testosterone and estrogen that are produced in low levels in the adrenal gland) (3).

Secondary adrenal insufficiency occurs when the pituitary gland does not produce enough ACTH; hence there is reduced stimulation of the adrenal gland and less cortisol produced. This is commonly caused by chronic exogenous glucocorticoid use but can also be due to pituitary disease, pituitary tumors or trauma, other infections (e.g., meningitis), or genetic disorders (1,2).

Tertiary adrenal insufficiency is an abnormality one step further back when the hypothalamus does not release enough CRH, therefore less stimulation of the pituitary gland, and subsequently less stimulation of the adrenal gland and less cortisol produced. It is most commonly caused by chronic exogenous glucocorticoid use, and can also be due to hypothalamic tumors, infections, and trauma (2).

What are the symptoms of low cortisol?
Generally, the symptoms of low cortisol are quite similar regardless of the cause (2). Symptoms can include:

  • Weakness
  • Fatigue
  • Weight loss and anorexia
  • Abdominal pain
  • Low blood pressure
  • Salt craving
  • Nausea
  • Vomiting
  • Diarrhea (may alternate with constipation)
  • Diminished sex drive
  • Menstruation may stop in women
  • Less pubic hair
  • Low blood sugar

Primary adrenal insufficiency is also characterized by hyperpigmentation of the skin. This is due to increased production and secretion of ACTH from the pituitary gland, as there is not enough cortisol present for the negative feedback loop to be working effectively. This hyperpigmentation does not occur in secondary and tertiary adrenal insufficiency as ACTH production is not increased (2).

The onset of adrenal insufficiency is often gradual, particularly for primary adrenal insufficiency, when more than 90% of the adrenocortical tissue is lost before symptoms occur. Often an illness or some other stress is what triggers an adrenal crisis, typically characterized by shock, and then other symptoms also become apparent (2).

How is adrenal insufficiency diagnosed?
There are three parts to an adrenal insufficiency diagnosis:

  • Demonstrating low cortisol levels: Serum cortisol levels < 3 µg/dL (80 nmol/L) at 8 am are strongly suggestive of adrenal insufficiency, while <10 µg/dL (275 nmol/L) make the diagnosis likely. Low salivary cortisol can also be used for a diagnosis (2). We offer a test of serum cortisol levels from a self-collected finger-prick blood sample. Our cortisol test is available here.
  • Determining whether the cortisol deficiency is due to primary, secondary, or tertiary adrenal insufficiency: This involves various different analyses, including measuring ACTH and CRH levels, and insulin tolerance tests (2).
  • Determining the cause: Again, various different analyses may be required here, including autoantibody screens and CT and MRI imaging (2).

1. Thau L, et al. Physiology, Cortisol. StatPearls [Internet].
2. Nicolaides NC, et al. Adrenal Insufficiency. Endotext [Internet].
3. Grossman AB. (Reviewed Oct 2020). Addison Disease. Merck Manual Consumer Version.

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