Clinical studies in humans have demonstrated that aldosterone has a detrimental effect on cardiovascular function, independent of its impact on renal sodium and water reabsorption. Aldosterone exerts a proinflammatory and profibrotic effect on the cardiovascular system, leading to left ventricular hypertrophy and remodeling. This effect of aldosterone is associated with increased morbidity and mortality in individuals with essential hypertension.

Aldosterone's physiological actions and regulation are discussed in Chapter 43 of the textbook. The adrenal gland and the steroidogenic pathways in the zona glomerulosa are depicted in Figure 43.15. Notably, aldosterone synthesis involves a series of reactions catalyzed by CYP11B2. Addison's disease is characterized by primary adrenal insufficiency, where both mineralocorticoids and glucocorticoids are usually deficient. In North America and Europe, the most prevalent cause of Addison's disease is autoimmune destruction of the adrenal cortex. The cortisol deficiency in this condition leads to an increase in ACTH secretion. Elevated levels of ACTH can compete for MC1R in melanocytes, resulting in increased skin pigmentation, particularly in skin creases, scars, and gums.

The loss of mineralocorticoids in Addison's disease causes contraction of extracellular volume, leading to circulatory hypovolemia and a subsequent drop in blood pressure. Furthermore, the deficiency of cortisol decreases the vasopressor response to catecholamines, causing a drop in peripheral vascular resistance and facilitating the development of hypotension. Individuals with Addison's disease are also prone to hypoglycemia during periods of stress or fasting, and excessive water intake can result in water intoxication. Muscle weakness occurs due to the importance of cortisol for muscle function. Cortisol deficiency also leads to anemia, decreased gastrointestinal motility and secretion, as well as reduced iron and vitamin B12 absorption. Decreased appetite, coupled with gastrointestinal dysfunction, predisposes these individuals to weight loss. Mood and behavioral disturbances are common, and individuals with Addison's disease are more susceptible to depression.
Clinicalstudiesinhumanshaverevealedadeleteriouseffectofaldosteroneoncardiovascularfunctionindependentofitseffectsonrenalsodiumandwaterreabsorption.Aldosteronehasaproinflammatory, profibrotic effect onthecardiovascularsystemandcausesleftventricularhypertrophyandremodeling.Thiseffectofaldosteroneisassociatedwithincreasedmorbidityandmortalityinpatientswithessentialhypertension.
Physiological Actions of Aldosterone
The actions and regulation of aldosterone are discussed in
CHAPTER 43 The Adrenal Gland •Fig. 43.15 Steroidogenicpathwaysinthezonaglomerulosa.Thefirstcommonreactioninthepathway,conversionofcholesteroltopregnenolonebyCYP11A1,isnotshown.NotethatthelastthreereactionsarecatalyzedbyCYP11B2.(ModifiedfromWhiteBA,PorterfieldSP.EndocrineandReproductivePhysiol-ogy.4thed.Philadelphia:Mosby;2013.)CH3 CH3 CH3 Pregnenolone C O 3˜-HSD CH3 CH3 CH3 Progesterone C O CYP21B HO CH3 CH3 CH2OH 11-Deoxycorticosterone (DOC) C O CYP11B2 CH3 CH3 CH2OH Corticosterone C O CYP11B2 O HO HO CH3 CH3 CH2OH 18(OH) Corticosterone C O CYP11B2 O HO CH3 CH2OH Aldosterone C O O O CH
Addison’s disease isdefinedbyprimary adrenal insufficiency, withbothmineralocorticoidsandglucocorticoidsusuallybeingdeficient.InNorthAmericaandEurope,themostprevalentcauseofAddison’sdiseaseisautoimmune destruction of the adrenal cortex. Becauseofthecortisoldeficiency,ACTHsecretionincreases.ElevatedlevelsofACTHcancompeteforMC1Rinmelanocytesandcauseanincreaseinskinpigmentation,particularlyinskincreases,scars,andgums(see
Fig.43.14 ).Thelossofmineralocorticoidsresultsincontractionofextracellularvolume,whichproducescirculatoryhypovolemiaandthereforeadropinbloodpressure.Becauselossofcortisoldecreasesthevasopressiveresponsetocatecholamines,peripheralvascularresistancedrops,therebyfacilitatingthedevelopmentofhypotension.IndividualswithAddison’sdiseasearealsopronetohypoglycemiawhenstressedorfasting,andwaterintoxicationcandevelopifexcesswaterisingested.Becausecortisolisimportantformusclefunction,muscleweaknessalsooccursincortisoldeficiency.Lossofcortisolresultsinanemia,decreasedGImotilityandsecretion,andreducedironandvitaminB12absorption.Appetitedecreaseswithcortisoldeficiency,andthisdecreasedappetitecoupledwiththeGIdysfunctionpredisposestheseindividualstoweightloss.Thesepatientsoftenhavedisturbancesinmoodandbehaviorandaremoresusceptibletodepression.