Is fatigue a sign of hypercortisolism or hypocortisolism?

Fatigue is a Common Symptom in Both Hypercortisolism and Hypocortisolism

Fatigue is a characteristic symptom that occurs in both hypercortisolism (Cushing's syndrome) and hypocortisolism (Addison's disease), though the underlying mechanisms differ.

Fatigue in Hypercortisolism (Cushing's Syndrome)

Hypercortisolism commonly presents with fatigue as a key symptom. According to the NCCN guidelines:

• Fatigue in hypercortisolism often appears alongside other symptoms such as weight gain, central obesity, easy bruising, and proximal muscle weakness 1
• It may be accompanied by depression and sleep disturbances 1
• The fatigue can be profound and significantly impact quality of life

Physical examination findings that may accompany fatigue in hypercortisolism include:

• Central obesity
• Supraclavicular fat accumulation
• Dorsocervical fat pad ("buffalo hump")
• Facial plethora
• Thinned skin
• Purple and wide (>1 cm) striae
• Proximal muscle weakness 1

Fatigue in Hypocortisolism (Addison's Disease)

Hypocortisolism also presents with significant fatigue, but with different accompanying symptoms:

• Weight loss (rather than weight gain seen in Cushing's)
• Postural hypotension
• Salt craving
• Hyperpigmentation of skin 1

The fatigue in hypocortisolism can be severe and debilitating, often leading to significant impairment in daily activities. It's one of the earliest and most consistent symptoms of adrenal insufficiency.

Differentiating Between the Two Conditions

To differentiate whether fatigue is due to hyper- or hypocortisolism:

1. Look for accompanying symptoms:

   • Hypercortisolism: weight gain, central obesity, easy bruising, hypertension
   • Hypocortisolism: weight loss, postural hypotension, salt craving, hyperpigmentation

2. Laboratory testing:

   • For hypercortisolism: 1mg dexamethasone suppression test (DST) is preferred 1

     • 50 nmol/L excludes cortisol hypersecretion
     • 51-138 nmol/L suggests possible autonomous cortisol secretion

     • 138 nmol/L indicates cortisol hypersecretion

   • For hypocortisolism: Low-normal or subnormal plasma cortisol plus elevated ACTH 2

Research Insights

Interestingly, research has shown that:

• Administration of cortisol has been found to decrease fatigue and increase feelings of vigor in healthy subjects 3, suggesting a complex relationship between cortisol levels and energy
• Hypocortisolism has been associated with chronic fatigue syndrome, with some studies showing that low cortisol is associated with poorer response to cognitive behavioral therapy for chronic fatigue 4

Clinical Approach

When evaluating fatigue:

1. Consider both hyper- and hypocortisolism in the differential diagnosis
2. Look for characteristic constellation of symptoms (weight gain vs. weight loss, hypertension vs. hypotension)
3. Perform appropriate laboratory testing to confirm diagnosis
4. Remember that fatigue in both conditions can significantly impact quality of life and requires proper management

Pitfalls to Avoid

• Don't assume fatigue is always due to hypocortisolism - both high and low cortisol states can cause fatigue
• Don't overlook other common causes of fatigue (thyroid disorders, anemia, depression, sleep disorders)
• Remember that fatigue is a nonspecific symptom that requires careful evaluation of the entire clinical picture