Adrenal Insufficiency Symptoms, Causes, Diagnosis, Treatment
Adrenal Insufficiency: This lecture reviews adrenal insufficiency definition, types, Addison’s disease, symptoms, causes, diagnosis, treatment, and more!
Guest Author
Guest Author: Charlotte Watson
This lecture was written by guest author Charlotte Watson, and the medical illustrations were created and provided by EZmed.
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What is Adrenal Insufficiency?
Adrenal insufficiency is a condition in which the adrenal glands, particularly the adrenal cortex, are deficient in the hormones they produce and release.
The hormones produced by the adrenal cortex include:
Mineralocorticoids (i.e. aldosterone)
Glucocorticoids (i.e. cortisol)
Androgens (i.e. DHEA)
The symptoms of adrenal insufficiency are caused by low levels of cortisol, aldosterone, and DHEA.
The specific hormones involved will depend on the type of adrenal insufficiency present.
There are 3 main types of adrenal insufficiency:
Primary Adrenal Insufficiency (Addison’s Disease)
Problem with the adrenal cortex
Secondary Adrenal Insufficiency
Problem with the anterior pituitary gland or
Cessation of chronic exogenous corticosteroid use
Tertiary Adrenal Insufficiency
Problem with the hypothalamus
The low adrenal output can be primary, due to damage to the adrenal glands themselves, or secondary/tertiary, as a result of low stimulating hormones acting on the adrenal glands.
We will discuss each type in more detail below, along with what hormones are involved and why.
We will also review adrenal gland anatomy and the HPA axis, along with the symptoms, clinical signs, pathophysiology, risk factors, diagnosis, treatment, and complications of adrenal insufficiency.
Adrenal Insufficiency Definition: A condition in which the adrenal cortex is deficient in the hormones it produces and releases
Adrenal Gland - Anatomy
To better understand adrenal insufficiency, let’s briefly review the anatomy and structure of the adrenal glands.
The adrenal glands are retroperitoneal structures located superior to (above) the kidneys.
As a result, the adrenal glands are sometimes referred to as the suprarenal glands.
There are 2 adrenal glands in the body, one located above each kidney.
The right adrenal gland has a pyramidal shape, and the left adrenal gland has a crescent or semi-lunar shape.
The adrenal glands are made up of 2 main parts:
Adrenal Cortex (outer part)
Adrenal Medulla (inner part)
Memory Trick: Cortex = Corners; Medulla = Middle
The adrenal cortex and medulla have different embryological origins, which explains their differing functions (see below).
The cortex is derived from the mesoderm, while the medulla is derived from neural crest cells.
The neural crest cells differentiate into functional chromaffin cells.
The outer adrenal cortex differentiates further into 3 functional layers or zones:
Zona Glomerulosa (outermost layer)
Zona Fasciculata (middle layer)
Zona Reticularis (innermost layer)
Memory Trick: Use the acronym GFR (which is a common kidney blood test) to remember the adrenal cortex layers from superficial to deep
Adrenal Gland Anatomy: The adrenal gland is made of the adrenal cortex and medulla. The layers of the cortex include the zona glomerulosa, zona fasciculata, and zona reticularis.
Adrenal Gland - Function
Let’s briefly review the function of the adrenal glands and the hormones they produce, as this will be important to understand adrenal insufficiency!
Adrenal Cortex
The adrenal cortex produces and secretes steroid hormones synthesized from cholesterol.
The functions and hormones of the adrenal cortex include:
Zona Glomerulosa = Produces mineralocorticoids
Namely: Aldosterone
Helps regulate electrolytes and blood pressure by facilitating sodium/ water reabsorption and potassium excretion in the kidneys
Stimulated by the renin-angiotensin-aldosterone system (RAAS)
Zona Fasciculata = Produces glucocorticoids
Namely: Cortisol
Helps regulate and increase glucose levels, bone metabolism, blood pressure, sympathetic nervous system activity, etc.
Stimulated in response to stress and pituitary ACTH (see below)
Zona Reticularis = Produces gonadocorticoids or adrenal androgens
Namely: DHEA
Precursor for testosterone and estrogen synthesis
Stimulated in response to pituitary ACTH
Memory Trick: Use “Salt, Sugar, Sex” to remember the adrenal cortex hormone functions by zone from superficial to deep.
Adrenal Medulla
The adrenal medulla produces and secretes catecholamines.
Adrenal Medulla = Produces catecholamines
Namely: Epinephrine (adrenaline) and norepinephrine (noradrenaline)
Function in the sympathetic nervous system
Stimulated in response to “fight or flight” situations
Adrenal Gland Function: The adrenal cortex produces and secretes hormones including aldosterone, cortisol, and androgens. The adrenal medulla secretes catecholamines including epinephrine and norepinephrine.
Primary Adrenal Insufficiency
Now that we understand the adrenal glands and their functions/hormones, let’s review adrenal insufficiency.
As previously mentioned, there are 3 main types of adrenal insufficiency:
Primary adrenal insufficiency (Addison’s disease)
Secondary adrenal insufficiency
Tertiary adrenal insufficiency
Let’s start with primary adrenal insufficiency.
What is Primary Adrenal Insufficiency?
Primary Adrenal Insufficiency (PAI) occurs when there is an intrinsic problem with the adrenal glands, resulting in deficient production and release of the adrenal cortex hormones discussed above.
Primary adrenal insufficiency is also known as Addison’s disease.
With primary adrenal insufficiency, there is damage or dysfunction to the adrenal cortex itself.
This mainly results in cortisol and aldosterone deficiency, however, adrenal androgen levels may also be reduced.
In other words, all 3 adrenal cortex hormones can become deficient in primary adrenal insufficiency (cortisol, aldosterone, and DHEA).
This is different from secondary adrenal insufficiency, where aldosterone is less affected (see below).
Primary Adrenal Insufficiency (Addison’s Disease): Causes & pathophysiology include autoimmune disease, infection, etc. This leads to adrenal cortex damage and deficient cortisol, aldosterone, and DHEA levels.
Causes and Pathophysiology
As previously mentioned, primary adrenal insufficiency occurs when there is damage or dysfunction to the adrenal cortex, resulting in deficient levels of cortisol, aldosterone, and DHEA.
The adrenal glands can also atrophy (shrink) as a result of the tissue damage.
Causes of primary adrenal insufficiency include:
Autoimmune disease - autoantibodies attack and destroy the adrenal cortex
Autoimmune Adrenalitis (most common cause of PAI)
Autoimmune destruction of the adrenal cortex only
Autoimmune Polyglandular Syndrome
Autoimmune destruction of multiple tissues (in addition to the adrenal cortex)
Can cause comorbid type 1 diabetes mellitus (pancreas), hypoparathyroidism (parathyroid), pernicious anemia, etc.
Antiphospholipid Syndrome
Infection - infection damages the adrenal cortex
TB, HIV, CMV, etc.
HIGH-YIELD: Waterhouse-Friderichsen syndrome is a condition caused by a severe infection, such as N. meningitidis (meningococcemia), which leads to bilateral adrenal gland hemorrhage, and therefore Addison's disease
Metastatic disease - cancerous tumors spread to the adrenal cortex and damage it (resulting in decreased hormonal output)
Drug-induced - some medications can induce adrenal insufficiency
Ketoconazole (inhibits adrenal steroid hormone synthesis)
Immune checkpoint inhibitors - nivolumab, pembrolizumab
Risk Factors
The risk factors for developing PAI or Addison's disease include:
Autoimmune diseases, such as type 1 diabetes mellitus, hypoparathyroidism, hypopituitarism, pernicious anemia, Graves’ disease, etc.
Female
Infection, such as tuberculosis
Long term corticosteroid use (see below)
Family history of Addison's disease
Symptoms & Signs
Reminder: Primary adrenal insufficiency can lead to low levels of cortisol, aldosterone, and adrenal androgens.
Therefore, the symptoms will be secondary to the reduced hormone levels.
Symptoms due to low cortisol levels:
Hypotension
Shock (adrenal crisis)
Hypoglycemia
Fatigue
Vomiting
Decreased appetite
Abdominal pain
Symptoms due to low aldosterone levels:
Hyponatremia
Hyperkalemia
Metabolic acidosis
Dehydration
Symptoms due to low DHEA levels (primarily females):
Irregular menstrual periods
Decreased pubic and axillary hair
Decreased libido
Symptoms due to high ACTH levels (see HPA axis below):
Hyperpigmentation
Primary Adrenal Insufficiency (Addison’s Disease) Symptoms: Signs and symptoms include hyperpigmentation of the skin, hypotension, etc.
The HPA Axis
Secondary adrenal insufficiency is caused by a decrease in the hormones that would normally stimulate the adrenal glands to release their hormones.
In order to better understand secondary and tertiary adrenal insufficiency, let’s briefly review the HPA axis.
The release of cortisol and adrenal androgens involves a pathway from the hypothalamus, through the anterior pituitary gland, to the adrenal gland.
This pathway is known as the hypothalamic-pituitary-adrenal (HPA) axis.
Note: Aldosterone is regulated by a separate pathway called the renin-angiotensin-aldosterone-system (RAAS) and is much less affected by the HPA axis.
Normal HPA axis steps:
Hypothalamus produces and secretes corticotropin-releasing hormone (CRH)
CRH travels to the anterior pituitary gland via the hypophyseal portal system
CRH binds to receptors on the anterior pituitary gland, stimulating the synthesis and release of adrenocorticotropic hormone (ACTH)
ACTH is released into the bloodstream, where it travels to the adrenal glands
ACTH stimulates the adrenal cortex to synthesize and release cortisol and adrenal androgens
Cortisol and adrenal androgens enter the bloodstream to carry out their various functions
Negative Feedback Loop:
Circulating cortisol in the bloodstream negatively feedbacks on the hypothalamus and the anterior pituitary gland
This suppresses further release of CRH and ACTH, respectively
This prevents cortisol levels from increasing further, and prevents excessive cortisol levels in the body
The HPA axis is stimulated in response to circadian rhythms and stressors.
The negative feedback loop helps regulate and prevent the continued rise of cortisol.
Cortisol is naturally released in the morning for humans, in line with our circadian rhythm.
Throughout the day, there is a smaller pulsatile secretion of cortisol every 90 minutes.
HPA Axis Pathway: The hypothalamic-pituitary-adrenal axis diagram and steps including the hormones involved. Note: Aldosterone is also released by the adrenal glands, but is primarily stimulated by the RAAS and not ACTH.
Secondary Adrenal Insufficiency
Now that we understand the HPA axis and the hormones involved, secondary adrenal insufficiency is easy to master.
What is Secondary Adrenal Insufficiency?
Secondary adrenal insufficiency (SAI) occurs when the adrenal cortex is not stimulated to produce sufficient hormones, most notably cortisol.
This occurs secondary to a deficit in ACTH being released by the anterior pituitary gland (see HPA axis above).
Simply put, in secondary adrenal insufficiency the adrenal cortex is normal but there is a problem with the pituitary gland.
This differs from primary adrenal insufficiency, in which the pituitary gland was normal but there was a problem with the adrenal cortex.
Furthermore, secondary adrenal insufficiency mainly affects cortisol and DHEA levels as they are ACTH dependent.
Remember aldosterone is stimulated by the RAAS, and therefore is not affected as much by secondary adrenal insufficiency (as the adrenal cortex is still intact).
Again this differs from primary adrenal insufficiency, in which aldosterone levels were also deficient (as the adrenal cortex was damaged).
Secondary Adrenal Insufficiency: Causes and pathophysiology include stopping chronic corticosteroids, pituitary disease, etc. This leads to deficient ACTH, cortisol, and DHEA levels.
Causes and Pathophysiology
As previously mentioned, secondary adrenal insufficiency is caused by low ACTH levels acting on the adrenal cortex, resulting in deficient levels of cortisol and DHEA.
Low levels of ACTH can cause the adrenal glands to atrophy over time.
Causes of secondary adrenal insufficiency include:
Exogenous corticosteroid use (chronic, long-term use) - most common
Corticosteroids act like cortisol
Similar to cortisol, corticosteroids suppress CRH and ACTH production (negative feedback - see HPA axis above)
Decreased ACTH decreases stimulation of the adrenal cortex, leading to decreased endogenous cortisol production
Decreased ACTH can also lead to adrenal atrophy over time
Atrophied adrenal glands are unable to produce endogenous cortisol
If corticosteroids are stopped, adrenal insufficiency/crisis can occur due to residual HPA axis suppression, along with adrenal atrophy and the inability to produce endogenous cortisol
Pituitary disease - Pathology affecting the pituitary gland, resulting in low ACTH production
Pituitary tumor (benign or malignant)
Tumors above the pituitary gland causing its compression (craniopharyngiomas)
Metastatic disease to the pituitary gland
Infection (tuberculosis)
Autoimmune inflammation of the pituitary (lymphocytic hypophysitis)
Pituitary trauma (head trauma)
Risk Factors
Risk factors for secondary adrenal insufficiency are related to the above causes:
Infection (tuberculosis)
Recent head trauma
Exogenous corticosteroid use
Autoimmune disease
Symptoms & Signs
The symptoms of secondary adrenal insufficiency will be the same as primary adrenal insufficiency with the exception of:
No hyperpigmentation
In primary adrenal insufficiency, hyperpigmentation is due to high ACTH levels. The low cortisol levels cause less negative feedback on the pituitary gland. This stimulates the anterior pituitary gland to produce more ACTH and melanocyte-stimulating hormone (a byproduct), both of which can stimulate melanocortin-1 receptors in the skin and cause hyperpigmentation in excess.
In secondary adrenal insufficiency, ACTH levels are low
Fewer electrolyte imbalances
In secondary adrenal insufficiency, aldosterone is less affected
Aldosterone is stimulated by the RAAS, which is independent of ACTH and the HPA axis
Aldosterone was affected in primary adrenal insufficiency because there was damage to the adrenal cortex itself. This causes electrolyte imbalances, such as hyponatremia and hyperkalemia
In secondary adrenal insufficiency, the adrenal cortex is normal and ACTH levels are low, which have no effect on aldosterone
Secondary adrenal insufficiency can lead to low levels of cortisol and adrenal androgens, due to the low ACTH.
Reminder: Cortisol and adrenal androgens are ACTH dependent, whereas aldosterone is RAAS dependent (which is independent of the HPA axis and not affected by secondary adrenal insufficiency)
Therefore, symptoms will be due to low levels of cortisol and adrenal androgens.
Symptoms due to low cortisol levels:
Hypotension
Shock (adrenal crisis)
Hypoglycemia
Fatigue
Vomiting
Decreased appetite
Abdominal pain
Symptoms due to low DHEA levels (primarily females):
Irregular menstrual periods
Decreased pubic and axillary hair
Decreased libido
Secondary Adrenal Insufficiency Symptoms: Signs and symptoms include hypotension, hypoglycemia, etc. Unlike primary, secondary adrenal insufficiency has no hyperpigmentation or aldosterone effects.
Tertiary Adrenal Insufficiency
Tertiary adrenal insufficiency occurs when the hypothalamus produces low levels of CRH, resulting in decreased ACTH production by the anterior pituitary gland, and decreased stimulation of the adrenal cortex as a result.
Simply put, tertiary adrenal insufficiency is caused by a problem with the hypothalamus.
This differs from secondary adrenal insufficiency, in which the problem was with the pituitary gland, and primary adrenal insufficiency, in which the problem was with the adrenal cortex.
Causes of tertiary adrenal insufficiency include:
Hypothalamic disease - condition affecting the hypothalamus, resulting in low CRH production
Hypothalamus tumor
Hypothalamus trauma (head trauma)
Symptoms of tertiary adrenal insufficiency will be similar to secondary adrenal insufficiency.
This is because the low CRH levels will lead to low ACTH levels, which will have the same downstream effects as secondary adrenal insufficiency.
Tertiary Adrenal Insufficiency: Causes and pathophysiology include hypothalamic disease. This causes low CRH, resulting in low ACTH, and deficient cortisol and DHEA levels as a result.
Diagnosis and Tests
The following steps can be taken to diagnose adrenal insufficiency.
Step 1: Morning Cortisol Level
If a patient is suspected of having adrenal insufficiency, the first line investigation should be a morning cortisol level.
If cortisol is low, then this may suggest adrenal insufficiency.
If cortisol levels are high, then adrenal insufficiency is less likely.
Step 2: ACTH Stimulation Test
To confirm adrenal insufficiency, an ACTH stimulation test can be performed.
The patient receives a dose of synthetic ACTH (cosyntropin), and the plasma cortisol levels are then measured at various intervals to observe a rise in the cortisol levels.
Cortisol levels should normally increase with ACTH.
If cortisol levels remain low, then this suggests adrenal insufficiency (any type).
In primary adrenal insufficiency, the adrenal cortex is damaged and cannot release cortisol regardless of ACTH stimulation
In secondary adrenal insufficiency (particularly chronic cases), the adrenal glands atrophy over time from a lack of ACTH, and they are unable to produce cortisol regardless of ACTH stimulation
Theoretically, an ACTH analogue should stimulate cortisol release by the adrenal glands
You might think that in secondary adrenal insufficiency where there is low ACTH, a synthetic ACTH would cause cortisol release
However, in chronic secondary adrenal insufficiency, there is atrophy of the adrenal glands due to the lack of ACTH stimulation, resulting in the inability to produce cortisol and to respond to ACTH
This means that even when the synthetic ACTH is provided, there is no significant rise in plasma cortisol measured
Note: In acute or subacute secondary adrenal insufficiency, there may be a slight to normal rise in cortisol
In tertiary adrenal insufficiency, low levels of CRH lead to low levels of ACTH, and the same explanation as secondary adrenal insufficiency above
Step 3: Plasma ACTH Level
The first 2 steps suggest whether adrenal insufficiency is present or not, however, they do not determine which type of adrenal insufficiency is present.
The cause of adrenal insufficiency can first be determined by measuring the serum ACTH level.
If ACTH is high and cortisol is low, then primary adrenal insufficiency is likely (see HPA axis above).
If ACTH is low and cortisol is low, then secondary or tertiary adrenal insufficiency is likely.
Step 4: Further Investigations
A plasma aldosterone level can also be measured.
Low aldosterone and high renin levels may suggest primary adrenal insufficiency.
Remember, aldosterone levels are low in primary adrenal insufficiency but normal in secondary/tertiary adrenal insufficiency.
A CRH stimulation test can also be performed to differentiate secondary and tertiary adrenal insufficiency.
If CRH stimulation increases ACTH, then tertiary adrenal insufficiency is likely (as the problem is in the hypothalamus not the pituitary gland).
If ACTH remains low after CRH stimulation, then secondary adrenal insufficiency is likely (as the problem is in the pituitary gland).
Further investigations can then be done to determine the exact cause of each of these, such as autoimmune testing, infectious testing, or imaging for an adrenal tumor, pituitary tumor, etc.
Adrenal Insufficiency Diagnosis: Algorithm and guidelines for diagnosing adrenal insufficiency and Addison’s disease, including morning cortisol level.
Treatment
Treatment involves replacing the affected adrenal cortex hormones.
Acute Adrenal Insufficiency (Adrenal Crisis - see below)
Replace cortisol: IV hydrocortisone
Replace aldosterone: IV fluids
Correct hypoglycemia: IV D50
Correct electrolytes
Hypotension/Shock: IV fluids, hydrocortisone, vasopressors, etc.
Chronic Adrenal Insufficiency (Primary) - Addison’s Disease
Replace cortisol: Glucocorticoids (prednisone, hydrocortisone, etc.)
Replace aldosterone: Fludrocortisone
Replace androgens: DHEA
Chronic Adrenal Insufficiency (Secondary)
Replace cortisol: Glucocorticoids (prednisone, hydrocortisone, etc.)
Replace androgens: DHEA
Reminder: Aldosterone not affected in secondary
Patients should undergo regular monitoring of their hormone levels.
Patients are recommended to wear a steroid bracelet, so that in the case they become acutely unwell, medics can be alerted to their adrenal insufficiency and provide the appropriate treatment sooner.
Patients should also be made aware of the sick day rules associated with steroid replacement.
In times when the body is under stress, such as in infection, patients should increase their usual dose of glucocorticoid.
This will prevent them from experiencing an adrenal crisis.
Adrenal Insufficiency Treatment: Guidelines and medications for treatment of adrenal insufficiency and Addison’s disease.
Adrenal Crisis
The most significant complication arising from adrenal insufficiency is adrenal crisis, a life-threatening state which needs to be treated immediately to reduce mortality risk.
An adrenal crisis occurs when there is increased stress on the body (infection, injury, etc.), and the adrenal glands are unable to release cortisol in response to that stress due to underlying adrenal insufficiency.
Remember cortisol is a hormone normally released during stress, and it has important roles in the regulation of blood pressure, glucose, etc.
The inability to increase cortisol levels during physiological stress (due to underlying adrenal insufficiency) can cause acute adrenal insufficiency or an adrenal crisis, which can be detrimental and life-threatening.
Adrenal Crisis Presentation:
A patient will appear in adrenal crisis if they are suffering from an acute episode of adrenal insufficiency. The symptoms are more extreme than those seen in chronic adrenal insufficiency. They include:
Severe hypotension or shock
Vomiting
Abdominal pain
Fever
Altered mental state
Primary vs Secondary Adrenal Insufficiency
The following table summarizes the main differences between primary and secondary adrenal insufficiency.
Primary (Addison’s) vs Secondary Adrenal Insufficiency: Symptoms, treatment, hormones, and electrolyte differences
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