In primary adrenal insufficiency (Addison's disease), the characteristic skin hyperpigmentation occurs because:
- A Elevated ACTH directly stimulates melanocortin-1 (MC1R) receptors on melanocytes, increasing eumelanin production
- B Elevated MSH (derived from the same POMC precursor as ACTH) stimulates melanocytes; the hyperpigmentation mirrors the degree of ACTH excess
- C Loss of cortisol removes negative feedback on the pituitary, massively upregulating pro-opiomelanocortin (POMC) gene transcription; POMC is cleaved to both ACTH and alpha-MSH, both of which stimulate MC1R on melanocytes ✓
- D Elevated CRH from the hypothalamus directly stimulates dermal melanocytes via CRH receptors
Explanation
In Addison's disease, the loss of adrenal cortisol removes negative feedback on both the hypothalamus (CRH) and pituitary corticotrophs, causing massive upregulation of POMC transcription. POMC is cleaved into ACTH, beta-lipotropin, and in the skin-associated cells/intermediate lobe, into alpha-MSH. Both ACTH and alpha-MSH share structural homology and act as agonists at melanocortin-1 receptors (MC1R) on dermal melanocytes, stimulating tyrosinase activity and eumelanin synthesis. The hyperpigmentation is particularly evident in sun-exposed areas, pressure points, buccal mucosa, and skin creases — all areas with baseline melanocyte activity. Option B is partially correct (MSH is involved) but C is more complete by explaining the full POMC mechanism.
Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.
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