A condition where the adrenal glands don’t produce enough cortisol — resulting in fatigue, low blood pressure, and sometimes visible skin darkening.Primary adrenal insufficiency (Addison’s disease) is caused by adrenal gland failure. The pituitary compensates by massively increasing ACTH secretion. Because ACTH weakly activates MC1R on skin melanocytes, chronically elevated ACTH produces the characteristic bronze hyperpigmentation of Addison’s disease. This is the endogenous human pharmacology that originally motivated the development of synthetic MC1R agonists for tanning — researchers asked whether a selective, stable MC1R agonist could replicate the pigmentation effect without also activating the adrenal stress axis.