Endocrine System

Homeostasis, i.e., the metabolic equilibrium in the body is actively maintained by several complex biological mechanisms.Thetwomainsystemsthatareinvolvedare TheAutonomicNervousSystemthatactsquickly. TheEndocrineSystemthatactsslowlyforalongtime.

BiochemicalClassificationofHormones...
Polypeptides Polypeptides
Insulin glucagon somatotropin FSH LH vasopressin Aldosterone corticosterone Progesterone Oxytocin thyrotropin ACTH

Steroids Steroids Estrogen testosterone cortisol

Amino acid derivatives Amino acid derivatives

Epinephrine norepinephrine dopamine Thyroxine, T3 and T4 Melatonin Serotonin

Hormonesactthisway...
Allhormonesinteractwithtargetcellsbyfirstbindingtospecificreceptors locatedeitherontheplasmamembraneorasacytosolicprotein.

Control of Endocrine Function

PositiveFeedback(Oxytocin) NegativeFeedback(mostCommon)

Adrenocortical Steroids

The Adrenal Glands

ApairofEndocrineglandsjustabovethekidneys. In common with the pituitary, adrenals are two

glandswithdistinctanatomyandalsophysiology.

Adrenalmedulla(AdrenalineandNorAdrenaline) Adrenalcortex(Mineralocorticoids,Glucocorticoidsand

Reproductivehormones)

Both parts of the adrenals work together to regulate

metabolismandcopewithstress.

The marked portion is the adrenal cortex and the inner portion is adrenal medulla.

SteroidalhormonesareproducedbyAdrenalCortex
ZonaGlomerulosa: Mineralocorticoids

ZonaFasciculata:Glucocorticoids ZonaReticularis:Androgens AllthesehormonesaresynthesizedfromCholesterol. ThestepsuptothispointoccurinmanySteroidproducing tissues(Liver,Intestines,Reproductiveorgans,etc). TheCholesterolistransportedintotheadrenalgland.

Mineralocorticoids:Aldosterone
As the name indicates, this hormone is involved in maintanence of electrolyte balance in the body. i.e., ofSodiumandPotassiumlevels...
Aldosteroneactsonthekidneystoprovideactivereabsorption ofsodiumandanassociatedpassivereabsorptionofwater,aswellas theactivesecretionofpotassium.Thisinturnresultsinanincrease ofbloodpressureandbloodvolume. ThelevelsofAldosteroneareregulatedby ReninAngeotensinSystem, LocalPotassiumandSodiumLevels,and ACTH

Apart from the above action, this also has slow genomic actions thataremediatedthroughNuclearReceptors.

The formed receptorligand complex translocates itself into the cellnucleus,whereitbindstomanyHormoneResponseElements (HREs) in the promoter region of the target genes in the DNA andthereforeregulatetranscription.

Aldosteroneandcortisol(aglucosteroid)havesimilaraffinityfor the mineralocorticoid receptor; however, glucocorticoids circulate at roughly 100 times the level of mineralocorticoids. An enzyme (11beta hydroxysteroid dehydrogenase type II) exists in mineralocorticoid target tissues to prevent over stimulation by glucocorticoids.

Glucocorticoids:Cortisol
As the name indicates, these are involved mainly in Carbohydratemetabolismandalsohasmanyothereffects. Glucocorticoidsareessentialformaintanenceoflife. Theactionsareoftwotypes: Genomicactions Transactivation;Transrepression(preventthetranscription ofproinflammatorygenes); NonGenomicactions Cortisol has a number of rapid actions that are independentoftheregulationsofgenetranscription.

Metabolism: It has reverse actions as insulin. It inhibits Glucose uptake by extrahepaticcellsandpromotesGluconeogenesis&glycogenolysis. It stimulates Lipolysis to free fatty acids. It has catabolic and anaboliceffectsonproteins,enzymesandNucleicacids. ImmuneSystem: It shows antiinflammatory and antiallergic activities owing to their suppressive effects on the inflammatory mediators. But, it supressesbothwantedandunwantedimmunereactionsinthebody as the lymphocytes (T and B cells), monocytes, eosinophils and basophilsdecrease. WaterandelectrolyteBalance: ThishasmildMineralocorticoideffect.

PermissiveEffects:
Glucocorticoidsareessentialformanynormalfunctionsindirectly. The response of vascular and bronchial smooth muscles to catecholaminesisdiminishedintheabsenceofcortisol.Similarly,the lipolysisoffatcellstocatecholamines,ACTH,andgrowthhormoneare attenuatedwintheabsenceofglucocorticoids..

Otheractions:
IncreaseinHClproduction,thusincreasingPepsinogenactivity. PositiveIonotropiceffectonheart. Reducecollagenformation,leadingtothinskin. AntagonisingeffectonVitD,thusdecreasing'Ca'absorption. Glucocorticoids have multiple effects on fetal development includingtheirroleinpromotingmaturationofthelungs.

MechanismofAction...
Cortisolbindsto Nuclearreceptors, whichinclude steroid,sterol (vitaminD),thyroid, retinoicacid,and orphanreceptors. Thereceptorsare primarilyincomplex withHeatshock proteins(Hsp), whichbreaksasthe steroidbindsto them.

Pharmacokinetics
Glucocorticoid synthesis is regulated by Negative Feedback Mechanism. In the normal adult, 1020mg of cortisol is secreted daily. The rateofsecretionfollowsacircadianrhythm.

Cortisol binds to Corticosteroidbinding globulin (CBG), an Alfa2 globulin synthesized by the liver. It binds about 90% of thehormoneinplasma.Theremainderisfreeorlooselyboundto albuminandisavailabletoexertitseffectontargetcells. CBG rises in pregnancy, with estrogen administration and in hyperthyroidism. It is decreased by hypothyroidism, genetic defectsinsynthesisandproteindeficiencystates.

The halflife of cortisol is about 6090 minutes; it may increase when given in large amounts or when stress, hypothyroidism, or liverdisease.Only1%ofcortisolisexcretedunchangedinurine. About 20% of cortisol is converted to cortisone by 11 hydroxysteroid dehydrogenase in kidneys and other tissues with mineralocorticoid receptors. Most cortisol is metabolized in liver mainly by conjugation with glucuronic acid or sulfates, hydroxyls intheliver.Theyarethenexcretedintheurine.

Aldosterone is secreted at the rate of 100200 mcg/d in normal individuals with a moderate dietary salt intake. The halflife of aldosteroneis1520minutes,anditdoesnotappeartobefirmly boundtoserumproteins. Themetabolismofaldosteroneissimilartothatofcortisol.

AndrogensandEstrogens
These are Reproductive Hormones produced in very minimal quantitiesbyAdrenalCortexbothinmenandwomen. Ofboth,Androgensareproducedinhigheramounts,whichhave a variety of effects ranging from increase in muscle mass, Stimulationofcellproliferation,etc. DeHydroEpiAndrosterone(DHEA)initssulfatedformDHEAS isthemajoradrenalandrogen. Hyper secretion in men goes unnoticed. But in females, it is manifested as increase in growth of body hair, deepening of voice,etc.

Abnormalities associated with Adrenocortical Hormones

Addison'sDisease:
Chronic adrenal insufficiency is a rare, chronic endocrine disorder in which the adrenal glands do not produce sufficient steroidhormones(glucocorticoidsandoftenmineralocorticoids).

Itischaracterisedbysymptomslikeabdominalpain,weakness, fever, weight loss, changes in mood & personality, hyperpigmentation of skin, low BP, hypoglycemia, hyperkalemia,hyponatremiaetc.Rarelythesemayprogressto Addisonian crisis, asevere illness which may include very low bloodpressureandcoma..

Causes
Adrenaldysgenesis Allcausesaregenetic,andgenerallyveryrare. Impairedsteroidogenesis Interruptionsinthedeliveryofcholesterol,mitochondrialDNA mutations,somemedicationandacceleratedbreakdownofhormones bytheliver. Adrenaldestruction(autoimmunediseaseagainsttheenzyme21 hydroxylase,certaininfectionsorvariousrarercauses) Corticosteroidwithdrawal(Useofhighdosesteroidsformorethan aweek) Itisa'primaryadrenalinsufficiency'andnottobeconfusedwith adrenalinsufficiencycausedbydeficiencyofACTHorCRH.

Cushing'sSyndrome:
Cushing's syndrome describes the signs and symptoms associated with prolonged exposure to inappropriately high levelsofthehormonecortisol.

Symptomsincluderapidweightgain,particularlyofthetrunk andfacewithsparingofthelimbs(centralobesity)andaround faceoftenreferredtoasa"moonface". Other symptoms include hyperhidrosis, muscle weakness, persistent hypertension and hyperglycemia, hypokalemia and hypernatremia, peptic ulcers, osteoporosis, immunesupression, highketonebodyproduction,edema,etc.

Causes
ThereareseveralpossiblecausesofCushing'ssyndrome. The most common cause of Cushing's syndrome is exogenous administration of glucocorticoids to treat other diseases (called iatrogenicCushing'ssyndrome). Endogenous Cushing's syndrome may result from pituitary secretion of ACTH (known as Cushing's disease), or by adrenal gland tumors or by tumors outside the normal pituitaryadrenal system(calledectopicorparaneoplasticCushing'sdisease). Pseudocushing'ssyndrome Elevatedlevelsoftotalcortisolcanalsobeduetoestrogenfound in oral contraceptive pills. Estrogen can cause an increase of cortisolbindingglobulinandtherebycausethetotalcortisollevelto beelevated.

Hyperaldosteronism:
The symptoms include fatigue, headache, constipation, hypertension, excessive thirst, muscle spasms, frequent urination, periodic paralysis, leg muscle weakness, Postural hypotension,etc.

Hyperaldosteronismisclassifiedasprimaryorsecondary. Primaryhyperaldosteronismmeansyouhaveaproblemwith youradrenalglanditselflikecancerorbenigntumors. Secondary hyperaldosteronism has some other causation, such as over activity of Renin Angeotensin system, Cushing's syndrome,verylowsodiumdiet,etc.

Hypoaldosteronism:
Itusuallyoccursaspartofadrenalinsufficiency. It causes symptoms of dehydration, hyponatremia,lowbloodpressure, hyperkalemia,

The below normal level of aldosterone may be because of Addisons disease, very high sodium diet, congenital adrenal hyperplasiaorhyporeninemichypoaldosteronism.

Adrenocortical Steroids

Drugs acting on

SYNTHETICCORTICOSTEROIDS
Glucocorticoids have become important agents for use in the treatment of many inflammatory, immunologic, hematologic and otherdisorders. Pharmaceutical steroids are usually synthesized from cholic acidobtainedfromcattleorsteroidsapogeninsfoundinplants. Alterationsintheglucocorticoidmoleculeinfluenceitsaffinity for receptors as well as its proteinbinding affinity, side chain stability,rateofeliminationandmetabolicproducts. They are well absorbed when given orally. Drug disposition remainssimilartonaturalsteroidswithlittlechanges. Therearealsoafewpotentsaltretainingsyntheticdrugsthat areusedinaldosteronedisfunctions.

SYNTHESISINHIBITORS&GLUCOCORTICOIDANTAGONISTS Inhibitors of steroid synthesis act at several different steps andoneglucocorticoidantagonistactsatthereceptorlevel.

Aminoglutethimide
It blocks the conversion of cholesterol to pregnenolone and causesareductioninthesynthesisofallhormonallyactivesteroids. In a dosage of 1 g/d it was well tolerated; however, with higher dosages,lethargyandskinrashwasacommoneffect. Itcanbeusedinconjunctionwithmetyraponeorketoconazoleto reducesteroidsecretioninpatientswithCushingssyndromedueto adrenocorticalcancer. Italsoapparentlyincreasestheclearanceofsomesteroids.

Trilostane
Itisa317hydroxysteroiddehydrogenaseinhibitorthatinterfereswith the synthesis of adrenal and gonadal hormones and is similar to aminoglutethimide.Adverseeffectsaremainlygastrointestinal.

Ketoconazole
Ketoconazole, an antifungal agent, is a potent and nonselective inhibitor of adrenal and gonadal steroid synthesis. Its effects on steroid biosynthesisareseenonlyathighdoses. This compound inhibits the cholesterol sidechain cleavage, P450c17, C17,20lyase, 3 hydroxysteroid dehydrogenase, and P450c11 enzymes requiredforsteroidhormonesynthesis. ItisusedforthetreatmentofCushingssyndrome.Itisusedatdoses of2001200mg/d. Thisdrughassomehepatotoxicity.

Abiraterone
Itblocks17hydroxylase(P450c17)and17,20lyase,andreducessynthesis ofcortisolandgonadalsteroids. AcompensatoryincreaseoccursinACTHandaldosteronesynthesis.This canbepreventedbycoadministrationofdexamethasone.

Metyrapone
It is a selective inhibitor of steroid 11hydroxylation, interfering with cortisolandcorticosteronesynthesis. There is a compensatory rise in ACTH release and adrenal 11 deoxycortisolsecretion.Thisresponseisadaptedasadiagnostictest. The drug may produce transient dizziness and GI disturbances. Other adverseeffectsobservedaresaltandwaterretentionandhirsutism. Metyrapone is the only adrenalinhibiting medication that can be administeredtopregnantwomenwithCushingssyndrome.

Mitotane
Itisaninsecticide(DDTclass),hasa mildnonselectivecytotoxicaction ontheadrenalcortex(reductionintumormass). Thisdrugisadministeredorallyindivideddosesupto12gdaily. The toxic effects include diarrhea, nausea, vomiting, depression, somnolence,andskinrashes.

Mifepristone(RU486)
Itisapharmacologicantagonistatthesteroidreceptor. Itcauses (1)stabilizationoftheHspglucocorticoidreceptorcomplexand inhibition of the dissociation of the RU486bound glucocorticoid receptorfromtheHspproteins;and (2) alteration of the interaction of the glucocorticoid receptor with coregulators, favoring the formation of a transcriptionally inactivecomplexinthecellnucleus. The mean halflife is 20 hours.It extensively binds to plasma proteinsandlessthan1%ofthedailydoseisexcretedintheurine. At present, this is only used for inoperable patients with ectopic ACTH secretion or adrenal carcinoma who have failed to respondtootherdrugs.

Spironolactone
It is a mineralocorticoid antagonist and a diuretic.It is used in the treatmentofprimaryaldosteronismatadoseof50100mg/d. Adverse effects include hyperkalemia, cardiac arrhythmia, menstrual abnormalities, gynecomastia, sedation, headache, gastrointestinaldisturbances,andskinrashes. Spironolactoneisalsoanandrogenantagonistandissometimesused inthetreatmentofhirsutisminwomen.

Eplerenone, another aldosterone antagonist, is approved for the

treatmentofhypertension.Ithasnoeffectsonandrogenreceptors. The standard dosage in hypertension is 50100 mg/d. The most commontoxicityishyperkalemiabutthisisusuallymild.

References
RangandDale'sPharmacology BasicandClinicalPharmacologyLange Internet
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