Fig. 43.15 ). A completely unique last three reactions from DOC to aldosterone within the feature of the zona glomerulosa among the steroidogenic zona glomerulosa. These reactions are 11-hydroxylation of glands is its expression of CYP11B2, which is regulated DOC to form corticosterone, 18-hydroxylation to form by different signaling pathways. Furthermore the enzyme 18-hydroxycorticosterone, and 18-oxidation to form aldocoded by CYP11B2, aldosterone synthase, catalyzes the sterone (see
Figs. 43.8 43.15).
•Fig. 43.14 The“loophole”inthehypothalamic-pituitary-adrenalaxis.ACTHstimulatesproductionofbothcortisolandadrenalandrogens,butonlycortisolnegativelyfeedsbackonACTHandCRH.Thusifcortisolproductionisblocked(i.e.,CYP11B1deficiency),ACTHlevelsincreasealongwithadrenalandrogens.(ModifiedfromWhiteBA,PorterfieldSP.Endocrine and Reproductive Physiology. 4thed.Philadelphia:Mosby;2013.)
CYP11B1(expressedonlyinthezonafasciculata)andCYP11B2(expressedonlyinthezonaglomerulosa)arelocatedonchromosome8inhumans,display95%similarity,andareseparatedfromeachotherbyonlyabout50kilobases.Thisincreasesthepossibilityofunevencrossingoverduringgametogenesis,withtheformationofhybridgenes.Inonecasethepromoterregionand5′ endoftheCYP11B1 geneisfusedtothe3′ endoftheCYP11B2 gene.ThisarrangementleadstoaldosteronesynthasebeingexpressedinthezonaefasciculataandreticularisunderthecontrolofACTH.Becausealdosteroneisnolongerunderfeedbackcontrolbytherenin-angiotensinsystem(see ),aldosteronelevelsarehighandhypertensionensues.Thisformofprimaryaldosteronismiscalledglucocorticoid-remediable aldosteronism, anditisinheritedinanautosomaldominantmanner.Thisdiseasecanbeconfirmedbythepolymerasechainreactiontechniqueandbymeasurementof18-hydroxycortisoland18-oxicortisolina24-hoururinesample.Thediseaseistreatedbytheadministration of glucocorticoid, whichsuppressesACTHandthusexpressionofthehybridgene.
Transport and Metabolism of Aldosterone
Aldosterone binds to albumin and corticosteroid-binding protein in blood with low affinity and therefore has a biological half-life of about 20 minutes. Almost all aldosterone is inactivated by the liver in one pass, conjugated to a glucuronide group, and excreted by the kidney.
Mechanism of Aldosterone Action
Aldosterone acts much like cortisol (and other steroid hormones) in that its primary mechanism of action is mediated by binding to a specific intracellular receptor (i.e., mineralocorticoid receptor [MR]). After dissociation of chaperone proteins, nuclear translocation, dimerization, and binding to the mineralocorticoid response element (MRE), the aldosterone-MR complex regulates expression of specific genes (see ). As discussed earlier, cortisol binds to the MR with significant affinity. However, as also discussed, cells that express MR also express 11β-HSD2, which converts cortisol to the inactive steroid cortisone (
Fig. 43.16 ). Cortisone can be converted back to cortisol by 11β-HSD1, which is expressed in several glucocorticoidresponsive tissues, including the liver and skin.