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It also hasmineralocorticoid-like effects on the kidney at high concentrations.■■Deposition of centripetal (truncal) fat, and therefore,centripetal obesity.Renal sodium retention and potassium loss. Cortisolbinds to mineralocorticoid receptors in addition to glucocorticoid receptors. It is ordinarily converted by thekidney to cortisone, limiting its effects on the renaltubules, but in cortisol excess, mineralocorticoid activityis observed.■■■■Other Effects of GlucocorticoidsOther important actions of glucocorticoids include antiinflammatory, immunosuppressive, and vascular effects.These include:■Inhibition of the production of arachidonic acid metabolites (e.g., prostaglandin, thromboxane, and leukotrienes) and platelet-activating factor.Reduction in T-lymphocytes and their productionof interleukins, interferon, and tumor necrosisfactor.Decreased fibroblast production and their deposition ofconnective tissue.An initial increase in antibody production, but eventually decreased production.Increased responsiveness of vascular smooth muscle tonorepinephrine.
Cortisol is important in maintainingnormal vascular responses to adrenergic stimulationand, thus, normal blood pressure regulation.334Endocrine Physiologyminor role in men, in whom testosterone produced by thetestes is the major androgen. However, in both sexes, adrenalandrogen production rises in mid childhood, and thus thehormones may contribute to early pubertal changes in boysas well as girls (Chapter 31). Adrenarche is the maturation ofthe adrenal cortex, which occurs between 6 and 10 years ofage and results in the three distinct zones of the cortex, andsubsequently, production of adrenal androgens.
Adrenalandrogen levels reach a peak at about 20 years of age anddecline through adulthood.ACTIONS OF ADRENAL ANDROGENSACTH stimulates the zona reticularis of the adrenal cortex tosynthesize and release androgens, although additional factorsare likely involved. The adrenal androgens, dehydroepiandrosterone (DHEA) and androstenedione, have notable effects infemales, because the adrenal gland is normally the only significant source of androgens in women. Effects of adrenalandrogens in females include development of pubic hair,hypertrophy of sebaceous glands (acne), stimulation of libido,and possibly, inhibition of osteoporosis. They have only awith steroids is avoided when possible, due to a wide array ofpotentially serious side effects, including immunosuppression,muscle wasting, osteoporosis, hyperglycemia, neural excitabilityand associated psychiatric effects, and, ultimately, adrenal insufficiency (due to negative feedback on the HPA axis).
When ananti-inflammatory steroid is used systemically, the patient is gradually weaned from the drug, to prevent sudden withdrawal beforeendogenous cortisol production can resume.CLINICAL CORRELATEGlucocorticoids as Anti-inflammatory andImmunosuppressive DrugsBased on their anti-inflammatory and immunosuppressiveproperties, cortisol and various synthetic glucocorticoids (forexample, dexamethasone) are used therapeutically to suppressserious inflammation and allergic reactions, autoimmuneresponses, and transplant rejection. However, systemic treatmentPotentiation of-adrenergicreceptorsPossibleantagonismof cholinergic(vagal) actionsSuprarenalcortexSympatheticnervesDuring acute episode somepatients may have relativesuprarenal insufficiency.Relaxation ofbronchospasmDecreasedmucussecretionVagus nervesCorticosteroidsPlasma clearanceIn chronic steroid administration,if dosage is withdrawn orsuboptimal, severe asthmaticexacerbations may occur.Possible inhibition of histamineformation/storageLysosome stabilizationAnti-inflammatory effectInhibition of antibody formationSteroid-resistant patients mayrequire higher and continuous dosage.Corticosteroid Actions in Bronchial Asthma Anti-inflammatory effects are the basis for use ofinhaled corticosteroids as preventive medication in patients who suffer frequent or severe asthma attacks.Adrenal Hormones■CLINICAL CORRELATECushing’s Syndrome■Cushing’s syndrome is an endocrine disease caused by highlevels of blood cortisol.
Its etiology may be due to a pituitary orectopic ACTH-secreting tumor, hyperplasia or tumor of theadrenal gland, or use of glucocorticoid drugs. The symptoms andsigns of Cushing’s syndrome, which might be predicted based onthe effects of adrenal steroids, include:■■■■centripetal obesity, accompanied by muscle wasting in theextremities“moon face” (a rounding of the face)thinning and bruising of the skinskin hyperpigmentation (if ACTH is elevated; see earlier in thechapter)■hypertensionhyperglycemia and insulin resistanceosteoporosisThe dexamethasone suppression test may be useful in diagnosingthe cause of hypercortisolism.
Although secretion of ACTH by thepituitary (and thus, adrenal cortisol production by the adrenalgland) is normally suppressed by administration of dexamethasone (a glucocorticoid drug), pituitary ACTH-secreting tumorshave reduced sensitivity to such inhibition. When hypercortisolism is the result of an adrenal tumor, cortisol production isunaffected by exogenous glucocorticoid (dexamethasone) administration. Once the cause of glucocorticoid excess is identified andappropriately addressed (often by surgery), treatment withreplacement steroids is usually necessary.Hypersecretionof ACTH bypituitary gland(Cushing’s disease)Ectopic ACTHsecretion bynonendocrine tumorAdrenal hyperplasiaExcess levels of cortisoland deoxycorticosterone (DOC)Adenoma of adrenal cortexCarcinoma of adrenal cortexHypertensionExogenous glucocorticoidsClinical featuresRed cheeksFat pads(buffalohump)Moon faceBruiseability,ecchymosesTypical clinical findings in Cushing’s syndrome.These features are often absent in the ectopicACTH syndrome.
Glucocorticoid excess canresult in hypertension associated with spontaneoushypokalemia simulating primary aldosteronism.Thin skinRedstriae HypokalemiaalkalosisOsteoporosisThin armsand legs335PendulousabdomenPoorwoundhealingCauses of Cushing’s Syndrome Cushing’s syndrome may result from a variety of causes, all of whichresult in elevated plasma glucocorticoid level. ACTH, adrenocorticotropic hormone.336Endocrine PhysiologyRenal factorsBlood volumeHyperkalemiaCardiac factorsStimuliBlood lossReninAtrial natureticpeptideAngiotensin IIStimulationInhibitionGlomerulusAldosteroKidney tubuleneAdrenal glandMedullaCortexCirculating bloodSweat glandSalivary glandK+Na+K+Na+IntestineK+Na+Na+Aldosterone causessodium and waterretention.H 2OK+Aldosterone enhancesexcretion of potassiumand hydrogen ion.H+H2OExtracellularfluid and sodiumincreasedAldosterone tendsto increase bloodvolume.H2ONa+K+Aldosterone plays asupportive rolein raising bloodpressure.Figure 28.5 Actions of Aldosterone The steroid hormone aldosterone has the important functionsof regulating extracellular fluid volume and K+ levels.
Synthesis and release of aldosterone is promoted byangiotensin II and hyperkalemia and is inhibited by atrial natriuretic peptide. Its action results in water andNa+ retention and K+ and H+ excretion by the kidney; it has similar effects on the intestine, sweat glands,and salivary glands.REGULATION AND ACTIONS OF ALDOSTERONEThe mineralocorticoid aldosterone is a regulator ofextracellular fluid volume and K+ homeostasis (Fig. 28.5).Its actions are accomplished mainly by effects on the collecting ducts and late distal tubules of the kidney, where itstimulates:■■■Na+ reabsorption, and as a result, water retention andexpansion of extracellular fluid volume; in excess,hypertension results.K+ excretion; excess aldosterone will causehypokalemia.H+ excretion; in excess, aldosterone causes metabolicalkalosis.Adrenal HormonesIn addition to the renal tubules, aldosterone also affects Na+and K+ handling by the intestines, salivary glands, and sweatglands.The primary stimuli for secretion of aldosterone by cells ofthe adrenal zona glomerulosa are (see Fig.
28.5):■■■Hyperkalemia (elevated plasma K+), which directlyacts on the adrenal gland to increase aldosterone secretion; aldosterone reduces plasma K+ through its renalactions.Angiotensin II, which stimulates aldosterone secretion.Reduction of blood volume results in renin release bythe kidney, which cleaves the plasma protein angiotensinogen to angiotensin I, which is subsequently cleavedby angiotensin-converting enzyme (ACE) to form angiotensin II (see Section 5, “Renal Physiology”).
Aldosterone, by promoting Na+ and water retention, increasesblood volume.Atrial natriuretic peptide (ANP), which inhibits aldosterone secretion. ANP is released by cardiac myocyteswhen blood volume is elevated, for example, in congestive heart failure. Inhibition of aldosterone secretionresults in reduction of blood volume.While ACTH is required for synthesis of aldosterone, theabove listed factors play a more important regulatory role inits synthesis and release. Release of aldosterone, like release ofcortisol and adrenal androgens, is greatest in the early morninghours. The physiology of aldosterone is discussed in greaterdetail in Section 5, “Renal Physiology.”THE ADRENAL MEDULLAIn addition to the following discussion, physiological effectsof adrenal catecholamines are discussed throughout thevarious chapters of this book in relation to the physiology ofvarious target systems and in the specific context of the autonomic nervous system as a whole in Chapter 7.The adrenal medulla, the central portion of the adrenal gland,is functionally distinct from the cortex, acting as a postganglionic effector of the sympathetic nervous system.
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