Glucocorticoid Deficiency

Overview

Glucocorticoid deficiency, also known as adrenal insufficiency or hypocortisolism, is a condition in which the adrenal glands fail to produce adequate amounts of cortisol, a vital glucocorticoid hormone. Cortisol plays crucial roles in metabolism, immune response, stress management, blood pressure regulation, and many other essential body functions. Without sufficient cortisol, the body cannot properly respond to stress, maintain blood sugar levels, or regulate inflammation.

The condition can be primary (Addison's disease), resulting from damage to the adrenal glands themselves, or secondary, caused by inadequate stimulation from the pituitary gland's adrenocorticotropic hormone (ACTH). A tertiary form exists due to hypothalamic dysfunction affecting corticotropin-releasing hormone (CRH) production. Additionally, iatrogenic adrenal insufficiency can occur when long-term glucocorticoid therapy is suddenly discontinued.

Glucocorticoid deficiency affects people of all ages but is most commonly diagnosed between ages 30-50. The condition is relatively rare, with primary adrenal insufficiency affecting approximately 100-140 per million people. However, secondary adrenal insufficiency is more common, particularly due to the widespread use of corticosteroid medications. Early recognition and proper treatment are essential, as untreated glucocorticoid deficiency can lead to life-threatening adrenal crisis, especially during times of physical stress such as illness, injury, or surgery.

Symptoms

The symptoms of glucocorticoid deficiency typically develop gradually over months to years, making early diagnosis challenging. However, in some cases, symptoms can appear suddenly, particularly during times of stress. The presentation varies depending on whether the deficiency is primary, secondary, or tertiary, and the severity of hormone deficiency.

Primary Symptoms

Gastrointestinal Symptoms

Additional Symptoms

Growth and Development (Children)

Adrenal Crisis Symptoms

• Severe weakness and confusion
• Severe abdominal, back, or leg pain
• Severe vomiting and diarrhea leading to dehydration
• Very low blood pressure and shock
• Loss of consciousness
• High fever or low body temperature
• Seizures in severe cases

Causes

Glucocorticoid deficiency results from various conditions affecting the adrenal glands, pituitary gland, or hypothalamus. Understanding the underlying cause is crucial for appropriate treatment and management.

Primary Adrenal Insufficiency (Addison's Disease)

• Autoimmune adrenalitis (70-90% of cases):
  • Immune system attacks adrenal cortex
  • Often associated with other autoimmune conditions
  • May be part of autoimmune polyendocrine syndromes
• Infections:
  • Tuberculosis (most common in developing countries)
  • Fungal infections (histoplasmosis, coccidioidomycosis)
  • HIV/AIDS-related infections
  • Cytomegalovirus in immunocompromised patients
• Adrenal hemorrhage or infarction:
  • Waterhouse-Friderichsen syndrome (meningococcal septicemia)
  • Anticoagulation therapy complications
  • Antiphospholipid syndrome
  • Trauma
• Genetic causes:
  • Congenital adrenal hyperplasia
  • Adrenoleukodystrophy
  • Familial glucocorticoid deficiency
• Other causes:
  • Metastatic cancer to adrenal glands
  • Surgical removal of adrenal glands
  • Medications (ketoconazole, etomidate)

Secondary Adrenal Insufficiency

• Pituitary disorders:
  • Pituitary tumors or their treatment
  • Pituitary surgery or radiation
  • Sheehan's syndrome (postpartum pituitary necrosis)
  • Traumatic brain injury
  • Lymphocytic hypophysitis
• Sudden withdrawal of corticosteroids:
  • Most common cause of secondary insufficiency
  • After prolonged glucocorticoid therapy
  • Includes oral, injected, or high-potency topical steroids

Tertiary Adrenal Insufficiency

• Hypothalamic dysfunction
• Prolonged suppression from exogenous glucocorticoids
• Head trauma affecting hypothalamus
• Hypothalamic tumors or infiltrative diseases

Risk Factors

Several factors increase the likelihood of developing glucocorticoid deficiency:

Medical Risk Factors

• Autoimmune diseases:
  • Type 1 diabetes
  • Autoimmune thyroid disease
  • Vitiligo
  • Pernicious anemia
  • Celiac disease
• Long-term corticosteroid use:
  • Treatment for inflammatory conditions
  • Immunosuppression for transplants
  • Cancer treatment protocols
• Pituitary or brain disorders:
  • History of pituitary tumors
  • Brain radiation therapy
  • Traumatic brain injury

Genetic Factors

• Family history of adrenal insufficiency
• Genetic syndromes affecting adrenal function
• HLA associations with autoimmune adrenalitis

Environmental and Lifestyle Factors

• Living in areas with endemic tuberculosis
• HIV infection or immunosuppression
• Use of certain medications (azole antifungals, etomidate)
• Severe physical stress without diagnosed insufficiency

Demographic Factors

• Gender: Autoimmune adrenalitis more common in women
• Age: Peak incidence in 30s-50s for primary insufficiency
• Pregnancy: Risk of Sheehan's syndrome with severe hemorrhage

Diagnosis

Diagnosing glucocorticoid deficiency requires a high index of suspicion due to its nonspecific symptoms. A combination of clinical assessment, laboratory tests, and imaging studies helps confirm the diagnosis and determine the underlying cause.

Clinical Assessment

• Medical history:
  • Symptom onset and progression
  • Medication history, especially steroids
  • Family history of endocrine disorders
  • Previous infections or autoimmune diseases
  • History of brain injury or pituitary problems
• Physical examination:
  • Blood pressure (lying and standing)
  • Skin pigmentation patterns
  • Signs of other autoimmune conditions
  • Assessment of muscle strength
  • Evaluation for dehydration

Laboratory Tests

• Morning cortisol:
  • Low morning cortisol (<3 μg/dL) suggests insufficiency
  • Normal (>18 μg/dL) makes insufficiency unlikely
  • Intermediate values require further testing
• ACTH stimulation test (gold standard):
  • Measures cortisol response to synthetic ACTH
  • Peak cortisol <18 μg/dL indicates insufficiency
  • Standard dose (250 μg) or low dose (1 μg)
• Plasma ACTH levels:
  • Elevated in primary insufficiency
  • Low or normal in secondary/tertiary insufficiency
• Additional tests:
  • Electrolytes (hyponatremia, hyperkalemia in primary)
  • Blood glucose (hypoglycemia)
  • Complete blood count (eosinophilia, lymphocytosis)
  • Thyroid function tests
  • 21-hydroxylase antibodies (autoimmune etiology)

Imaging Studies

• Adrenal imaging:
  • CT scan: enlarged adrenals (infection, hemorrhage) or atrophic (autoimmune)
  • MRI for better soft tissue detail
• Pituitary imaging:
  • MRI brain with pituitary protocol
  • Evaluate for tumors, empty sella, infiltrative disease

Special Considerations

• Insulin tolerance test: Gold standard for secondary insufficiency but contraindicated in many patients
• Metyrapone test: Alternative for assessing HPA axis
• CRH stimulation test: Distinguishes secondary from tertiary insufficiency
• Genetic testing: For suspected hereditary causes

Treatment Options

Treatment of glucocorticoid deficiency involves lifelong hormone replacement therapy to replace the missing cortisol. The goal is to mimic normal cortisol production patterns while avoiding over-replacement. Patient education about dose adjustments during stress is crucial for preventing adrenal crisis.

Glucocorticoid Replacement

• Hydrocortisone (preferred):
  • Most physiologic replacement
  • Typical dose: 15-25 mg daily in divided doses
  • Larger dose in morning, smaller in afternoon
  • Some use three times daily dosing
• Alternative glucocorticoids:
  • Prednisone: 3-5 mg daily
  • Dexamethasone: 0.25-0.75 mg daily
  • Longer acting but less physiologic
• Modified-release hydrocortisone:
  • Once-daily formulations available
  • Better mimics circadian rhythm
  • Improved quality of life in some patients

Mineralocorticoid Replacement (Primary Insufficiency Only)

• Fludrocortisone:
  • Typical dose: 0.05-0.2 mg daily
  • Replaces aldosterone
  • Monitor blood pressure and potassium
  • May need dose adjustment in hot weather
• Salt supplementation:
  • Liberal salt intake encouraged
  • Salt tablets in hot weather or with exercise

Stress Dose Management

• Minor illness (fever, flu): Double or triple daily dose
• Major stress (surgery, severe illness):
  • Hydrocortisone 50-100 mg IV/IM every 6-8 hours
  • Taper to maintenance as stress resolves
• Patient education essential:
  • Written sick day rules
  • Emergency injection training
  • Medical alert identification

Treatment of Adrenal Crisis

• Immediate interventions:
  • Hydrocortisone 100 mg IV bolus
  • Aggressive IV fluid resuscitation (0.9% saline)
  • Dextrose for hypoglycemia
  • Treat precipitating cause
• Ongoing management:
  • Hydrocortisone 50-100 mg IV every 6 hours
  • Monitor electrolytes and glucose
  • Gradual taper to maintenance doses

Monitoring and Follow-up

• Regular clinical assessment for adequacy of replacement
• Avoid routine cortisol measurements on replacement
• Monitor for signs of over-replacement (weight gain, osteoporosis)
• Annual review of doses and stress management
• Bone density monitoring
• Cardiovascular risk assessment

Special Situations

• Pregnancy:
  • Usually requires increased hydrocortisone in third trimester
  • Stress doses during labor and delivery
  • Monitor closely postpartum
• Children:
  • Weight-based dosing
  • Monitor growth and development
  • Transition planning for adolescents

Prevention

While primary glucocorticoid deficiency due to autoimmune or genetic causes cannot be prevented, several strategies can help prevent secondary insufficiency and adrenal crisis in at-risk individuals:

Prevention of Iatrogenic Adrenal Insufficiency

• Careful corticosteroid use:
  • Use lowest effective dose for shortest duration
  • Consider alternate-day therapy when possible
  • Gradual tapering of long-term steroids
  • Document all steroid use in medical records
• Alternative treatments:
  • Explore non-steroidal options first
  • Use topical or inhaled steroids when appropriate
  • Steroid-sparing immunosuppressants

Prevention of Adrenal Crisis

• Patient education:
  • Recognition of crisis symptoms
  • Stress dose guidelines
  • Emergency injection training
  • Importance of medical compliance
• Emergency preparedness:
  • Medical alert bracelet/card
  • Emergency hydrocortisone kit
  • Written emergency plan
  • Family/caregiver education
• Healthcare provider awareness:
  • Clear documentation of diagnosis
  • Pre-procedure steroid protocols
  • Communication between providers

Screening Recommendations

• Screen family members of patients with autoimmune adrenalitis
• Monitor patients with other autoimmune endocrine disorders
• Assess HPA axis before stopping long-term steroids
• Consider testing in unexplained chronic fatigue with risk factors

When to See a Doctor

Early recognition of glucocorticoid deficiency and prompt treatment of adrenal crisis can be life-saving:

Seek Immediate Emergency Care For:

• Severe weakness or fatigue with inability to function
• Persistent vomiting preventing medication intake
• Severe abdominal, back, or leg pain
• Confusion or altered mental status
• Very low blood pressure or dizziness with standing
• High fever or signs of severe infection
• Loss of consciousness
• Signs of shock (cold, clammy skin, rapid pulse)

Schedule Appointment For:

• Unexplained chronic fatigue lasting weeks to months
• Recurrent nausea, especially in morning
• Unintentional weight loss
• New skin pigmentation changes
• Salt cravings with other symptoms
• Muscle weakness affecting daily activities
• History of pituitary problems or long-term steroid use
• Poor growth in children

For Diagnosed Patients - Contact Provider If:

• Any illness with fever
• Vomiting or diarrhea
• Planned surgery or procedures
• Significant injury or trauma
• Pregnancy
• Symptoms suggesting inadequate replacement
• Side effects from medications

Related Conditions

References

1. Bornstein SR, et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. Journal of Clinical Endocrinology & Metabolism. 2016;101(2):364-389.
2. Husebye ES, et al. Adrenal insufficiency. Lancet. 2021;397(10274):613-629.
3. Charmandari E, et al. Adrenal insufficiency. Lancet. 2014;383(9935):2152-2167.
4. Bancos I, et al. Diagnosis and management of adrenal insufficiency. Lancet Diabetes & Endocrinology. 2015;3(3):216-226.
5. Fleseriu M, et al. Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline. Journal of Clinical Endocrinology & Metabolism. 2016;101(11):3888-3921.
6. National Institute of Diabetes and Digestive and Kidney Diseases. Adrenal Insufficiency & Addison's Disease. 2023.