Why does adrenocorticotropic hormone (ACTH) deficiency cause skin hyperpigmentation?

ACTH Deficiency Does NOT Cause Skin Hyperpigmentation—It's the Opposite

ACTH deficiency causes pale skin (loss of pigmentation), not hyperpigmentation. Hyperpigmentation occurs with ACTH excess, not deficiency. This is a critical distinction in diagnosing adrenal disorders.

The Mechanism: Why ACTH Excess Causes Hyperpigmentation

• ACTH and melanocyte-stimulating hormone (MSH) share a common precursor molecule (pro-opiomelanocortin), so elevated ACTH levels directly stimulate melanogenesis in skin melanocytes 1, 2
• ACTH stimulates tyrosinase activity—the rate-limiting enzyme in melanin production—and increases melanin content in melanocytes at physiological plasma concentrations 1
• In primary adrenal insufficiency (Addison's disease), the adrenal glands fail to produce cortisol, causing compensatory elevation of ACTH from the pituitary, which then drives skin hyperpigmentation 3, 4

Clinical Distinction: Primary vs. Secondary Adrenal Insufficiency

Primary Adrenal Insufficiency (High ACTH)

• Hyperpigmentation is the hallmark cutaneous finding, appearing as diffuse darkening of sun-exposed areas, palmar creases, mucous membranes, and areas of friction 4
• ACTH levels are markedly elevated (often >2000 pg/mL) because the pituitary attempts to stimulate the failing adrenal glands 3, 4
• The combination of low cortisol with high ACTH distinguishes primary from secondary adrenal insufficiency 3

Secondary Adrenal Insufficiency (Low ACTH = ACTH Deficiency)

• Normal skin color or pallor is observed because ACTH levels are low or inappropriately normal 3
• The absence of hyperpigmentation is a key clinical clue distinguishing secondary from primary adrenal insufficiency 3
• ACTH deficiency results from pituitary or hypothalamic dysfunction, not adrenal gland failure 3

Rare Exception: "White Addison's Disease"

• Approximately 10% of primary adrenal insufficiency cases may lack hyperpigmentation despite elevated ACTH levels 5, 6
• This occurs due to accelerated melanosome degradation in secondary lysosomes that overwhelms the increased melanogenic stimulation 5
• The absence of hyperpigmentation can dangerously delay diagnosis, as it removes a cardinal clinical sign 5, 6
• Specific genetic causes (such as SGPL1 gene mutations causing isolated glucocorticoid deficiency) may present without hyperpigmentation 6

Diagnostic Implications

• If you see hyperpigmentation with adrenal insufficiency, think primary (high ACTH); if you see normal skin color, think secondary (low ACTH) 3
• Morning cortisol <250 nmol/L with elevated ACTH confirms primary adrenal insufficiency, while low cortisol with low/normal ACTH suggests secondary adrenal insufficiency 3, 7
• The cosyntropin stimulation test with peak cortisol <500 nmol/L confirms adrenal insufficiency regardless of etiology 3, 7

Common Pitfall to Avoid

• Never assume absence of hyperpigmentation rules out primary adrenal insufficiency—while uncommon, "white Addison's disease" exists and can lead to delayed diagnosis with potentially fatal consequences 5, 6