Two primary enzymes are involved in the degradation of catecholamines: monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). The neurotransmitter norepinephrine is degraded by MAO and COMT after uptake into the presynaptic terminal. This mechanism is also involved in the catabolism of circulating adrenal catecholamines. However, the predominant fate of adrenal catecholamines is methylation by COMT in nonneuronal tissues such as the liver and kidney. Urinary vanillylmandelic acid (VMA) and metanephrine are sometimes used clinically to assess the level of catecholamine production in a patient. Much of the urinary VMA and metanephrine is derived from neuronal rather than adrenal catecholamines.
Pheochromocytoma isatumorofchromaffintissuethatproducesexcessivequantitiesofcatecholamines.Thesearecommonlyadrenalmedullarytumors,buttheycanoccurinotherchromaffincellsoftheautonomicnervoussystem.Althoughpheochromocytomasarenotcommontumors,theyarethemostcommoncauseofhyperfunctioningoftheadrenalmedullary.Thecatecholaminemostfrequentlyelevatedinpheochromocytomaisnorepinephrine.Forunknownreasonsthesymptomsofexcessivecatecholaminesecretionareoftensporadicratherthancontinuous.Symptomsincludehypertension,headaches(fromhypertension),sweating,anxiety,palpitations,andchestpain.Inaddition,patientswiththisdisordermayshoworthostatichypotension(despitethetendencyforhypertension).Thisoccursbecausehypersecretionofcatecholaminescandecreasethepostsynapticresponsetonorepinephrineasaresultofdownregulationofthereceptors(see ).Consequentlythebaroreceptorresponsetobloodshiftsthatoccursonstandingisblunted.
The zona fasciculata produces the glucocorticoid hormone cortisol. This zone is an actively steroidogenic tissue composed of straight cords of large cells. These cells have a “foamy” cytoplasm because they are filled with lipid droplets that represent stored cholesterol esters (CEs). These cells make some cholesterol de novo but import a significant amount of cholesterol from the blood in the form of low-density lipoprotein (LDL). LDL particles bind to their receptor (LDLR) and are endocytosed. Within endolysosomes, free cholesterol (FC) is released from CEs by a lysosomal lipase, and the FC is transported out of the endolysosome by Niemann-Pick C (NPC) proteins. Free cholesterol is stored in lipid droplets in the cytoplasm after esterification by acyl CoA-cholesterol acyltransferase (ACAT) (
Fig. 43.7 ). The stored cholesterol is continually turned back into free cholesterol by hormone-sensitive lipase (HSL), a process that is increased in response to adrenocorticotropic hormone (ACTH; see
Regulation of
All steroid hormone synthesis begins in the mitochondria, where the first enzyme, CYP11A1, is attached to the inner mitochondrial membrane. Although several proteins appear to be involved in the transfer of FC into the inner mitochondrial matrix, one protein called steroidogenic acute regulatory protein (StAR protein) is indispensable in this process (see