The feature of the zona glomerulosa among the steroidogenic zona glomerulosa is its expression of CYP11B2, which is regulated by different signaling pathways. This enzyme catalyzes the unique last three reactions from DOC to aldosterone: 11-hydroxylation of DOC to form corticosterone, 18-hydroxylation to form 18-hydroxycorticosterone, and 18-oxidation to form aldosterone.

ACTH stimulates the production of both cortisol and adrenal androgens, but only cortisol negatively feeds back on ACTH and CRH. In cases where cortisol production is blocked (i.e., CYP11B1 deficiency), ACTH levels increase along with adrenal androgens.

CYP11B1, expressed only in the zona fasciculata, and CYP11B2, expressed only in the zona glomerulosa, are located on chromosome 8 in humans. They display 95% similarity and are separated from each other by about 50 kilobases. This increases the possibility of uneven crossing over during gametogenesis, leading to the formation of hybrid genes. One case involves the fusion of the promoter region and 5' end of the CYP11B1 gene with the 3' end of the CYP11B2 gene. This arrangement causes aldosterone synthase to be expressed in the zona fasciculata and reticularis under the control of ACTH. As aldosterone is no longer under feedback control by the renin-angiotensin system, aldosterone levels are high and hypertension ensues. This form of primary aldosteronism is called glucocorticoid-remediable aldosteronism and is inherited in an autosomal dominant manner. Polymerase chain reaction technique and measurement of 18-hydroxycortisol and 18-oxicortisol in a 24-hour urine sample can confirm this disease. Treatment involves the administration of glucocorticoid, which suppresses ACTH and the expression of the hybrid gene.

Aldosterone binds to albumin and corticosteroid-binding protein in blood with low affinity, resulting in a biological half-life of about 20 minutes. The liver inactivates almost all aldosterone in one pass, conjugating it to a glucuronide group, and the kidney excretes it.

The primary mechanism of aldosterone action is mediated by binding to the mineralocorticoid receptor (MR), similar to cortisol and other steroid hormones. After dissociation of chaperone proteins, nuclear translocation, dimerization, and binding to the mineralocorticoid response element (MRE), the aldosterone-MR complex regulates the expression of specific genes. Cells expressing MR also express 11β-HSD2, which converts cortisol to the inactive steroid cortisone. Cortisone can be converted back to cortisol by 11β-HSD1, expressed in several glucocorticoid-responsive tissues such as the liver and skin.
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.