Early in embryogenesis, primitive sympathetic nervous system ganglion cells migrate from neural ectoderm, differentiate into pheochromoblasts, and penetrate the adrenal cortex. These pheochromoblasts develop into the chromaffin cells of the adrenal medulla.

The adrenal medulla is innervated by sympathetic nerves that originate in the splanchnic system. This sympathoadrenal system is controlled by a complex set of central neural connections and is involved in the production, storage, and secretion of catecholamines. The adrenal medulla is exposed to
the relatively high concentration of cortisol found in the venous drainage of the adrenal cortex.

The major catecholamines in humans are dopamine, norepinephrine, and epinephrine, all of which are synthesized in nerve endings. Epinephrine is the major product of the adrenal medulla. In its biosynthesis, tyrosine is hydroxylated to form dopa, which then is converted to dopamine, a neurotransmitter within the central nervous system (CNS). Dopamine also acts as the precursor for synthesis of norepinephrine, the principal neurotransmitter of the sympathetic nervous system. Then norepinephrine is converted to epinephrine in the adrenal medulla, in an enzymatic step controlled by cortisol. Epinephrine exerts its physiologic effects by interaction with alphaand beta-adrenergic receptors. The physiologic effects of epinephrine are widespread and are separated into the alphaand beta-receptor effects (Box 382.1).

Measurements of single catecholamine levels, such as norepinephrine and epinephrine, generally are not helpful because patients who produce excessive amounts of these catecholamines may have periods of low blood levels, and persons with normal production have high levels in response to stress. Persons with symptoms of excess of catecholamines are evaluated best by measuring their catecholamines and their metabolites. The most helpful tests include 24-hour urinary normetanephrine, metanephrine, homovanillic acid, vanillylmandelic acid (VMA), and plasma-free metanephrine. Serial measurements of these compounds in blood and urine after paroxysmal attacks of catecholamine release also may be informative.

Abnormalities of the adrenal medulla are caused by benign or malignant tumors that secrete catecholamines. Adrenal medullary deficiency, which occurs after adrenalectomy or in patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency, is not known to pose a significant health risk.