The enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) protects the mineralocorticoid receptor (MR) from activation by cortisol. It converts cortisol to inactive cortisone. Cortisone can be converted back to cortisol in glucocorticoid target cells by the enzyme 11β-HSD type 1. The mineralocorticoid receptor (MR) is involved in the mineralocorticoid-specific biological response, while the glucocorticoid receptor (GR) is involved in the glucocorticoid-specific biological response. Both receptors undergo dimerization, nuclear transport, binding to specific response elements (MREs or GREs), and recruitment of coactivator proteins and general transcription factors (GTFs). This leads to altered transcription of aldosterone-regulated genes in mineralocorticoid target cells and cortisol-regulated genes in glucocorticoid target cells.

Excessive secretion of adrenocortical hormones is known as Cushing's syndrome. The most common cause of Cushing's syndrome is the pharmacological use of exogenous corticosteroids. The second most prevalent cause is ACTH-secreting tumors. Cushing's disease refers to the form of Cushing's syndrome caused by a functional pituitary adenoma. The fourth most common cause is primary hypercortisolism resulting from a functional adrenal tumor. In cases where the disorder is primary or a result of corticosteroid treatment, ACTH secretion is suppressed and increased skin pigmentation does not occur. However, if hypersecretion of the adrenal is due to an ACTH-secreting nonpituitary tumor, ACTH levels may be high enough to cause increased skin pigmentation.

Increased cortisol secretion leads to weight gain with a characteristic centripetal fat distribution and the formation of a "buffalo hump." The face appears rounded due to fat deposition, and the cheeks may be reddened, partly because of polycythemia. The limbs become thin due to skeletal muscle wasting and muscle weakness, resulting from muscle proteolysis and hypokalemia. Proximal muscle weakness is evident, causing difficulties in climbing stairs or rising from a sitting position. Abdominal fat accumulation, along with atrophy of the abdominal muscles and thinning of the skin, leads to a protruding abdomen. Purple abdominal striae can be seen as a result of damage to the skin caused by prolonged proteolysis, increased intraabdominal fat, and loss of abdominal muscle tone. Capillary fragility occurs due to damage to the connective tissue supporting the capillaries. Patients may also show signs of osteoporosis and poor wound healing. They experience metabolic disturbances, including glucose intolerance, hyperglycemia, and insulin resistance.
•Fig. 43.16 Themineralocorticoidreceptor(MR)isprotectedfromactivationbycortisolbytheenzyme11β-hydroxysteroiddehydrogenasetype2(11β-HSD2),whichconvertscortisoltoinactivecortisone.Cortisonecanbeconvertedbacktocortisolinglucocorticoidtargetcellsbytheenzyme11β-HSDtype1.GRE,glucocorticoidresponseelement;GTF,generaltranscriptionfactors;MRE,mineralocorticoidresponseelement.(ModifiedfromWhiteBA,PorterfieldSP.Endocrine and Reproductive Physiology. 4thed.Philadelphia:Mosby;2013.)Aldosterone Aldosterone 11˜-HSD2 MR-chaperone complex Dissociated chaperones Dissociated chaperonesMR-aldosterone complex Mineralocorticoid-specific biological response Glucocorticoid-specific biological response Mineralocorticoid target cell 11˜-HSD1 Glucocorticoid target cell • Dimerization • Nuclear transport • Binding to MREs • Recruitment of coactivator proteins and GTFs • Altered transcription of aldosterone-regulated genes • Dimerization • Nuclear transport • Binding to GREs • Recruitment of coactivator proteins and GTFs • Altered transcription of cortisol-regulated genes Cortisol Cortisol Cortisol GR-chaperone complex GR-cortisol complex Cortisone Cortisone Cortisone Blood
Adrenocortical hormone excess istermedCushing’s syndrome. Pharmacological useofexogenouscorticosteroidsisnowthemostcommoncauseofCushing’ssyndrome.ThenextmostprevalentcauseisACTH-secreting tumors. TheformofCushing’ssyndromecausedbyafunctionalpituitaryadenomaiscalledCushing’s disease. ThefourthmostcommoncauseofCushing’ssyndromeisprimary hypercortisolism resultingfromafunctionaladrenaltumor.Ifthedisorderisprimaryorifitisaresultofcorticosteroidtreatment,secretionofACTHwillbesuppressedandincreasedskinpigmentationwillnotoccur.However,ifhypersecretionoftheadrenalistheresultofanACTH-secretingnonpituitarytumor,ACTHlevelssometimesbecomehighenoughtoincreaseskinpigmentation.
Increasedcortisolsecretioncausesweightgainwithacharacteristiccentripetalfatdistributionanda“buffalohump.”
Thefaceappearsrounded(fatdeposition),andthecheeksmaybereddened,inpartbecauseofthepolycythemia.Thelimbsarethinowingtoskeletalmusclewasting(fromincreasedproteolysis),andmuscleweaknessisevident(frommuscleproteolysisandhypokalemia).Proximalmuscleweaknessisapparent,sothepatientmayhavedifficultyclimbingstairsorrisingfromasittingposition.Theabdominalfataccumulationcoupledwithatrophyoftheabdominalmusclesandthinningoftheskinproducesalargeprotrudingabdomen.Purpleabdominalstriaeareseenasaresultofdamagetotheskinbytheprolongedproteolysis,increasedintraabdominalfat,andlossofabdominalmuscletone.Capillaryfragilityoccursbecauseofdamagetotheconnectivetissuesupportingthecapillaries.Patientsarelikelytoshowsignsofosteoporosisandpoorwoundhealing.Theyhavemetabolicdisturbancesthatincludeglucoseintolerance,hyperglycemia,andinsulinresistance(see