Adrenal insufficiency (AI) is the deficiency in adrenal production of glucocorticoids, adrenal androgens, and mineralocorticoids.
Forms of adrenal insufficiency
- Primary (Addison’s disease): dysfunction or destruction of the adrenal cortex
- Secondary: conditions that cause deficiency in pituitary adrenocorticotropic hormone (ACTH) secretion
- Tertiary: conditions that cause deficiency in the hypothalamic secretion of corticotropin-releasing hormone (CRH)
- Annual incidence: 4–6 cases per million people
- Secondary AI is more common than primary adrenal disorders.
- Autoimmune AI affects women more often than men.
- Most patients are diagnosed in the 6th decade of life.
Etiology of primary adrenal insufficiency
- Autoimmune polyendocrine syndrome type I (APECED (autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy) syndrome):
- Addison’s disease
- Chronic mucocutaneous candidiasis
- Primary gonadal failure
- Hypoplasia of the dental enamel
- Nail dystrophy
- Autoimmune polyendocrine syndrome type II:
- Addison’s disease
- Primary hypothyroidism
- Primary hypogonadism
- Diabetes mellitus type 1
- Pernicious anemia
- Celiac disease
- Fungal infections (coccidioidomycosis, histoplasmosis)
- Intra-adrenal hemorrhage (Waterhouse–Friderichsen syndrome) after meningococcal septicemia
- Congenital adrenal hyperplasia
- ACTH resistance syndromes (familial glucocorticoid resistance)
- Bilateral adrenalectomy
- Drug-induced (e.g., mitotane, ketoconazole, etomidate, suramin, aminoglutethimide)
Etiology of secondary and tertiary adrenal insufficiency
Consequence of dysfunction of the hypothalamus and pituitary gland:
- Pituitary tumors and surgery
- Granulomatous disease (tuberculosis, sarcoid, eosinophilic granuloma)
- Postpartum pituitary infarction (Sheehan’s syndrome)
- Isolated ACTH deficiency:
- Lymphocytic hypophysitis (selective corticotroph absence)
- POMC gene mutations
- TPIT gene mutations
- Familial cortisol-binding globulin deficiency
- Prolonged high-dose glucocorticoid use
- Effect of Cushing’s syndrome treatment:
- Chronic elevation of glucocorticoids (e.g., from tumor effects) has suppressed the hypothalamus–pituitary–adrenal axis.
- The patient still has low cortisol levels (due to chronic suppression) up to a year after surgery and requires glucocorticoid therapy.
- Hypothalamic–pituitary–adrenal (HPA) axis:
- Hypothalamus secretes CRH → release of ACTH from the anterior pituitary gland
- ACTH release:
- Like CRH, release is pulsatile, following the circadian rhythm.
- ↑ in the early morning hours (before awakening), with peak levels in the morning (approximately 8:30 a.m.) and ↓ in the evening
- Adrenal gland (cortex):
- ACTH mainly stimulates the zona fasciculata (cortisol) and zona reticularis (androgens).
- The zona glomerulosa (aldosterone) is primarily regulated by the renin–angiotensin system and potassium levels.
- Metabolic effects:
- ↓ Glucose uptake by cells and ↑ gluconeogenesis
- ↑ Lipolysis → release of fatty acids into the circulation
- ↓ Protein storage → myopathy, bone resorption
- ↑ Smooth muscle (vasculature) sensitivity to catecholamines and angiotensin II (producing ↑ blood pressure)
- Antiinflammatory actions:
- Apoptosis of T cells
- ↓ Antibody production
- ↓ Neutrophil migration
- Metabolic effects:
- DHEA and DHEA sulfate (DHEA-S) are the androgens secreted in great quantities.
- Weak androgenic activity
- Precursor can be peripherally converted to more potent androgens (e.g., testosterone) and estrogens (e.g., estradiol).
- In males, the testes are the main source of androgens.
- Regulation of renal sodium and water reabsorption
- Regulation of potassium excretion
- Manifestations emerge when > 90% of the adrenal cortex (zona glomerulosa, fasciculata, and reticularis) is destroyed.
- Hypocortisolism, hypoaldosteronism, and hypoandrogenism (men still produce androgens in testes)
- Compensatory ↑ ACTH:
- Leads to hyperpigmentation
- Both ACTH and ɑ-melanin-stimulating hormone are derived from pro-opiomelanocortin (POMC) → melanocytes stimulated
- ↓ ACTH → hypocortisolism and hypoandrogenism
- Aldosterone production preserved (as primary regulation is through the renin–angiotensin system)
- No hyperpigmentation, as ACTH is not increased
- ↓ CRH → ↓ ACTH → hypocortisolism and hypoandrogenism
- Aldosterone production preserved
Primary adrenal insufficiency
- Glucocorticoid + mineralocorticoid + androgen deficiency
- ↓ Glucocorticoids:
- Weight loss/anorexia
- Myalgia/joint pain
- Abdominal pain/diarrhea
- Hyponatremia (due to ↑ antidiuretic hormone)
- ↓ Mineralocorticoids:
- Salt craving
- Hyperkalemia, hyponatremia
- ↓ Androgens:
- ↓ Axillary and pubic hair
- Loss of libido
- Amenorrhea in women
- Hyperpigmentation from ↑ ACTH
Secondary and tertiary adrenal insufficiency
- Glucocorticoid + androgen deficiency
- Mineralocorticoid production preserved
- No hyperpigmentation
Adrenal crisis is the acute decompensation of adrenal function that can be triggered by another disease, surgery, stress, or increased glucocorticoid inactivation (hyperthyroidism).
- Hypovolemic shock (from reduced volume and mineralocorticoid deficiency)
- Can mimic acute abdomen (abdominal tenderness, nausea, vomiting, fever)
- Decreased responsiveness progressing to coma
Initial tests for hypocortisolism
- Morning serum cortisol:
- Normal: 10–20 µg/dL
- ≥ 18 µg/dL is a reassuring level and predicts a normal cosyntropin test.
- Low cortisol (≤ 3 µg/dL): strongly suggests AI
- ACTH levels:
- Obtain baseline level simultaneously with morning cortisol:
- ↑ ACTH: suggests primary AI
- ↓ Or normal ACTH: suggests secondary/tertiary AI
- Obtain baseline level simultaneously with morning cortisol:
- Standard high-dose ACTH-stimulation test:
- Obtain baseline cortisol and ACTH.
- 250 µg of IV or IM ACTH (1-24)/cosyntropin administered, with measurement of serum cortisol concentrations at 30 and 60 minutes
- Low cortisol (< 18–20 µg/dL) after 30 and 60 minutes indicates AI.
- Primary AI: confirmed if with ↑ basal ACTH
- Secondary AI: confirmed if with ↓ or low normal basal ACTH
- Basal renin, aldosterone, and electrolyte levels help in interpretation, especially in primary AI.
|Primary AI||Secondary or tertiary AI|
|ACTH||↑||↓ or normal|
|ACTH-stimulation test||No increase in cortisol||Increase in cortisol*|
ACTH: adrenocorticotropic hormone
*In prolonged secondary/tertiary adrenal insufficiency, chronically decreased ACTH leads to adrenal atrophy (low cortisol). This results in no or little increase in cortisol.
Additional tests for hypothalamic–pituitary–adrenal function
Performed when initial tests are indeterminate
- Metyrapone test:
- Metyrapone blocks conversion of 11-deoxycortisol to cortisol.
- Oral metyrapone given, followed by obtaining 11-deoxycortisol and cortisol after 24 hours
- Primary AI: ↑ ACTH but no increase in 11-deoxycortisol and cortisol
- Secondary/tertiary AI: low ACTH, no increase in 11-deoxycortisol and cortisol
- Insulin-induced hypoglycemia test:
- Insulin causes ↓ glucose, which in turn, triggers cortisol secretion in normal circumstances.
- Inject insulin.
- Glucose, ACTH, and cortisol are measured in intervals.
- Primary AI: ↑ ACTH without increase in cortisol despite hypoglycemia
- Secondary AI: Inadequate ↑ in cortisol and ACTH at the onset of hypoglycemia
- Contraindicated in cardiovascular disease and seizures
- Corticotropin-releasing hormone test differentiates secondary from tertiary adrenal insufficiency.
- Secondary AI: no ACTH response
- Tertiary AI: ↑ ACTH response
- Does not make a difference in therapy
Diagnosing the etiology
In suspected primary AI:
- Review medications (rule out drug-induced AI).
- Adrenocortical antibodies or antibodies against 21-hydroxylase:
- Autoimmune adrenalitis
- Autoimmune polyendocrine syndrome (proceed with other tests for hypoparathyroidism, diabetes, thyroid disease)
- Plasma very-long-chain fatty acids (VLCFAs):
- In male patients with isolated Addison’s disease and negative autoantibodies
- Elevated in adrenoleukodystrophy (genetic testing required)
- In children in whom AI presents in infancy or childhood:
- Serum 17-hydroxyprogesterone (17-OHP)
- Routine newborn screening
- CT of the adrenal glands:
- Tuberculous adrenalitis: spotty calcifications late in the disease
- May detect malignancy such as lymphoma and adrenal metastases
- Adrenal infiltration (sarcoidosis, amyloidosis, hemochromatosis)
- Adrenal hemorrhage
In suspected secondary/tertiary AI:
- Workup of hypopituitarism (e.g., thyroid-stimulating hormone (TSH))
- MRI of the hypothalamus and pituitary gland
Chronic adrenal insufficiency
- Glucocorticoid replacement:
- Oral hydrocortisone (in 2 to 3 divided doses to mimic diurnal rhythm)
- Situations of stress require escalated doses (e.g., surgery, infection).
- Mineralocorticoid replacement:
- Prevention of hyperkalemia, loss of fluids and sodium
- Fludrocortisone daily
- Dose increased in warm weather due to salt loss in perspiration
- Monitor BP, electrolytes, renin
- Adrenal androgen replacement:
- In women, the adrenal gland is the main source of androgens.
- DHEA may improve loss of libido and/or low energy levels in women.
- Underlying causes must be treated (e.g., resection of tumors, antibiotics for infections).
Secondary and tertiary AI:
- Glucocorticoid replacement:
- Similar to primary AI
- ACTH not used for monitoring and titration of glucocorticoid dose
- Mineralocorticoid replacement rarely required
- Replacement of other anterior pituitary hormones if indicated
- Acute AI is a life-threatening emergency!
- Clinical suspicion of adrenal crisis requires immediate therapy even before diagnosis is established.
- Serum cortisol and electrolytes are drawn and treatment is given.
- In some cases, samples of blood are held for possible later testing (ACTH, renin, aldosterone) if initial cortisol suggests AI.
- Aldosterone/mineralocorticoid deficiency leads to:
- Wasting of sodium (↓ Na+)
- Positively charged ions (↑ K+ and H+) are retained → hyperkalemia and non–anion-gap metabolic acidosis
- Initial management:
- IV fluid resuscitation (avoid hypotonic solution, which can worsen hyponatremia)
- Blood drawn (serum cortisol, ACTH, aldosterone, renin, and chemistries)
- IV hydrocortisone (has mineralocorticoid activity): 100-mg bolus, then 50 mg every 6 hours
- Treat hypoglycemia.
- Search for underlying condition and treat accordingly.
- Hypopituitarism: pituitary hormone deficiency, resulting from a disease of the pituitary gland (commonly tumors), but may arise from hypothalamic dysfunction: The anterior lobe produces growth hormone, follicle-stimulating hormone, luteinizing hormone, TSH, ACTH, and prolactin. Loss of antidiuretic hormone and oxytocin occurs in posterior lobe damage. Diagnosis is via hormone levels, provocation tests, and brain imaging. Treatment is hormonal replacement.
- Syndrome of inappropriate antidiuretic hormone (SIADH): disorder of impaired water excretion due to the inability to suppress the secretion of ADH/vasopressin: This disorder can be due to disease, medications, ectopic secretion by cancer, or hereditary causes (nephrogenic SIADH). SIADH also occurs in cortisol deficiency. Loss of cortisol results in absence of negative feedback on ADH secretion, increasing ADH. Low cortisol also triggers increased CRH, an ADH secretagogue. Hyponatremia and hypoosmolality are findings. Management depends on the underlying etiology.
- Congenital adrenal hyperplasia (CAH): inherited autosomal recessive disease characterized by enzyme deficiency that impairs adrenal hormone production, which results in the overproduction of the hormone precursor: 95% of CAH is due to the absence of the enzyme 21-hydroxylase, leading to inability to produce cortisol, and often accompanied by salt wasting. Females exhibit atypical genitalia from virilizing effects (increased androgen from hyperplasia). Neonatal screening is by measurement of 17-OHP (elevated). Management involves glucocorticoid and mineralocorticoid therapy.
- Adrenoleukodystrophy: a rare X-linked genetic disorder caused by a mutation in the ABCD1 gene and associated with buildup of VLCFAs: This buildup causes destruction of the myelin sheath of nerves, adrenal cortex, and testes. Children have learning disabilities, behavior problems, and quadriparesis. Adrenoleukodystrophy can present in adulthood, with young adults having spinal cord and gonadal dysfunction. Adrenal insufficiency is one of the manifestations. Diagnosis is via a VLCFA panel. Treatment options include glucocorticoid therapy, hematopoietic-cell transplantation, and supportive interventions.
- Angelousi A, Margioris A, Tsatsanis C. (2020) ACTH actions on the adrenals. EndoText. Retrieved March 7, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK279118/
- Arlt W (2018). Disorders of the adrenal cortex. Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J (Eds.), Harrison’s Principles of Internal Medicine, 20th ed. McGraw-Hill.
- Carroll TB, Aron DC, Findling JW, Tyrrell J. (2017). Glucocorticoids and adrenal androgens. Gardner DG, Shoback D (Eds.), Greenspan’s Basic & Clinical Endocrinology, 10th ed. McGraw-Hill.
- Nieman L. (2021) Causes of secondary and tertiary adrenal insufficiency in adults. UpToDate. Retrieved March 3, 2021, https://www.uptodate.com/contents/causes-of-primary-adrenal-insufficiency-addisons-disease
- Nieman L. (2020) Causes of primary adrenal insufficiency (Addison’s disease). UpToDate. Retrieved March 3, 2021, from https://www.uptodate.com/contents/causes-of-primary-adrenal-insufficiency-addisons-disease
- Nicolaides N, Chrousos G, Charmandari E. (2017) Adrenal insufficiency. Endotext. Retrieved March 3, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK279083/