内分泌生殖系统教学课件：05 肾上腺皮质2.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,The Adrenal Glands Part,:,The Adrenal Cortex,Part 1 Introduction,More important than adrenal medulla,Adrenal and their hormones,AD,NE,mineralocorticoid,glucocorticoids,sex hormones,Adrenal,cortex,a Tissue section of adrenal cortex,Capsule,Cortex,Medulla,Parenchyma,Electron micrograph,Zona glomerulosa,Zona fasciculata,Part 2 Hormones produced by the adrenal cortex,Belong to steroid hormones,Basic structure:,Steroid nucleus,C3=0(,酮基,),C4-5,(,双键,),C20=0(,羰基,),are,necessary,for adrenocortical hormones,A,B,C,O,OH,20,c,o,21,CH,2,OH,R,3,4,5,17,11,18,D,Basic Structure of Adrenocortical Hormones,Hormones of adrenal cortex,Case:4-year-old girl,Report from her mother,Height and weight lower than expected,Thirsty,polyuria,Ambiguous genitalia,Public hair developed from 3,BP:70/30mmHg(),Blood test,Serum sodium:127mmol/L(),Serum potassium:5.4mmol/L(),Serum cortisol:128nmol/L(),Serum ACTH:55ng/L(),Plasma renin activity:1242Pmol/L/h(),Serum 17-hydroxyprogesterone:76nmol/L(),Steroid biosynthesis,From cholesterol,Hydroxylation reactions:CYP 450 family,Rate-limiting enzyme:,CYP11A1,Steroid biosynthesis,CYP11A1,CYP21,StAR:,(steroidogenic acute regulatory)protein,StAR deficiency:,lipid adrenal hyperplasia,Steroid biosynthesis,Raw material:cholesterol,Release:,f,rom lipid droplets,StAR protein phosphorylation,Cholesterol ester hydrolase,Source,De novo synthesis,From LDL,Stimulated by ACTH,乙酰,CoA,乙酰乙酰,CoA,HMG-CoA,MVA,鲨烯,HMG-CoA,还原酶,胆固醇,Do novo,synthesis of cholesterol,Defects of steroid biosynthesis,Congenital adrenal hyperplasia,21-hydroxylase encoded by CYP21 deficiency,Case:Establishing the diagnosis,Blood test,Serum sodium:127mmol/L(),Serum potassium:5.4mmol/L(),Serum cortisol:128nmol/L(),Serum ACTH:55ng/L(),Plasma renin activity:1242Pmol/L/h(),Serum 17-hydroxyprogesterone:76nmol/L(),Part 3 Regulation of steroid production,Cortisol:HPA(hypothalamic-pituitary-adrenal cortex)axis,ACTH:,diurnal variation,The actions of ACTH,1.Increase adrenal blood flow,2.Increase steroidogenic enzyme expression,3.Activate StAR protein,4.Activate cholesterol ester hydrolase,4.Increase the size of adrenal gland,Molecular mechanism,of ACTH:,G-protein coupled receptor,Case:,Explanation of plasma ACTH result,Blood test,Serum sodium:127mmol/L(),Serum potassium:5.4mmol/L(),Serum cortisol:128nmol/L(),Serum ACTH:55ng/L(),Plasma renin activity:1242Pmol/L/h(),Serum 17-hydroxyprogesterone:76nmol/L(),Aldosterone:the renin-angiotensin system,Part 4 Actions of adrenal steroids,Glucocorticoids,Mineralocorticoids,Adrenal androgens,Actions of glucocorticoids(GCS),(glucose+cortex+steroid),Functional structure of the glucocorticoid receptor.The glucocorticoid receptor protein has 3 domains:the amino terminus,the DNA binding domain(DBD),and the carboxyl terminus for hormone binding.Two zinc fingers are located in the central region.There are also phosphorylation sites and regions of hormone-independent activation function(AF1)and hormone-dependent activation function(AF2)related to transcription.,Molecular mechanism of,GCS,Glucocorticoid receptor,Molecular mechanism of,GCS,Glucocorticoid receptor Signaling,Actions of GCS:various,1.Effects on metabolism,2.Permissive action,3.Anti-inflammatory effects,4.Immunosuppressive and anti-allergic effects,5.Anti-toxic effects,6.Anti-shock effects,7.Effects on blood system,8.Other effects,1.Effects on metabolism,(1)Effects on glucose metabolism:BS,a.increase,glyconeogenesis,b.increase,glycogenolysis,c.decrease glucose oxidation and utilization,Net result,:,hyperglycemia,1.Effects on metabolism,(2)Effects on protein metabolism,a.stimulate protein catabolism,b.inhibit protein synthesis,Net result:,negative nitrogen balance,1.Effects on metabolism,(3)Effects on lipid metabolism:,a.,stimulate lipolysis,b.cause dramatic,redistribution,of body fat,Result:concentric obesity,1.Effects on metabolism,(4)Effects on salt and water metabolism,a.mineralocorticoids-like activity:weak,b.effect on plasma calcium,cortisol,Definition:,GCS facilitates other hormonal effects other than direct effects.,2.Permissive action,3.Anti-inflammatory effects,Characteristics:,rapid,strong,nonspecific,both the early phase,and late phase,Mechanism of anti-inflammatory action,Reduce the,vascular,response in inflammation,a.Affect AA metabolism,PGs,LTs,(,induce lipocortin-1,inhibite COX,),b.Inhibit,iNOS,expression,NO,c.Induce,ACE,BK,d.Increase the vasoconstriction of CA,L-Arginine,iNOS,NO,GCS,-,BK,ACE,Degradation production,+,Mechanism of anti-inflammatory action,Mechanism of anti-inflammatory action,.Reduce the,cell,response in inflammation,a.Inhibit pro-inflammatory cytokines expression,b.Induce anti-inflammatory cytokines expression,c.Inhibit adhesion molecule expression,d.Induce inflammatory cells apoptosis,Mechanism of anti-inflammatory action,.Postpone the inflammatory sequela,Mechanism:inhibit hyperplasy of blood capillary and,fibroblast,prevent adhesion and scar formation.,Molecular mechanism of anti-inflammatory,Clinical Science(1998)94,(557572)(Printed in Great Britain)Anti-inflammatory actions of glucocorticoids:molecular mechanisms,ACE,cytokins,2.Immunosuppressive effectsand anti-allergic effects,1)Inhibit phagocytosis and management of macrophages on antigen,2)Promote the,redistribution,of lymphocyte in human blood,3)Inhibit IL-1 mediated immunoreactions,4)Stabilize mast cell membrane,3.Antitoxic effects,Mechanism:,enhance body tolerance,to bacterial endotoxin,Antipyretic effects:,1)membrane stabilization,：,EP(endogenous pyrogens)release,2)decrease the sensitivity of body temperature regulating center to EP.,3.Antitoxic effects,4.Anti-shock effects:,especially infectious-toxic shock,1)anti-inflammatory and anti-toxic effects,2),directly,relax the spasmodic vessels and enhancing the contractility of myocardium,3)membrane stabilization,MDF,production and release,(MDF:myocardial-depressant factor),ischemia,hypoxia,shock,acidosis,lysosomal membrane disruption,Proteinase release,plasma proteinMDF,Myocardial depression,vasospasm,vicious cycle,GCS,-,5.Effects on blood system,(1)Stimulate hemopoiesis:,RBC,PLT,Hb,(2)Neutrophils:,number,function,(3)Other blood cells:,(lymphocytes,basophilic,eosinophile granulocytes),6.Other effects,(1)Central nervous system:,excitation,(2)Digestive system:,excitation,(3)Skin and bone,relieve itching,anti-hyperplasy,osteoporosis,The effects of GCS in stress,1.Stress:,is a bodys response to a stressor induced challenge.,2.Stress hormone is increased:HPA,3.Cortisol is an essential part of the bodys response to stress.,Actions of mineralocorticoids,(mineral+cortex+steroid),lumen,space,ATP,R,ADH,R,Na,+,K,+,H,2,O,Cl,-,ADS,ADS-R,K,+,-Na,+,交换,Tubular cell,Na,+,K,+,Na,+,K,+,ADH-R,Case:Salt wasting,Report from her mother,Height and weight lower than expected,Thirsty,polyuria,Ambiguous genitalia,Public hair developed from 3,BP:70/30mmHg(),Blood test,Serum sodium:127mmol/L(),Serum potassium:5.4mmol/L(),Serum cortisol:128nmol/L(),Serum aldosterone?,Serum ACTH:55ng/L(),Plasma renin activity:1242Pmol/L/h(),Serum 17-hydroxyprogesterone:76nmol/L(),Actions of mineralocorticoids,11-HSD:11,hydroxysteroid dehydrogenase,AME:apparent mineralocorticoid excess,11-HSD,Cortisol,(active),Cortisone,(inactive),11-HSD2,11-HSD1,cortisol,cortisone,Actions of adrenal androgens,Actions of adrenal androgens,1.Virilizing effects,(1)Children:,ambiguous genitalia,(2)Adult:,androgenization,2.Can be converted to estrogens,Part 5 Disorders of adrenal steroids,Congenital adrenal hyperplasia,Glucocorticoid excess,Mineralocorticoid excess,Adrenal insufficiency,Congenital adrenal hyperplasia(CAH),Deficiency of biosynthesis enzyme,Case:congenital adrenal hyperplasia,Treatment:,replacement therapy,Follow-up:,dose adjustment,genetic counseling,Glucocorticoid excess:,Cushing,s syndrome,Causes,1.Exogenous corticosteroid administration,2.Cushing,s disease,3.Adrenal adenoma,4.Ectopic ACTH production,Glucocorticoid excess:,Cushing,s syndrome,Cushing,s syndrome,Investigations of GCS excess,Blood test,(1)Basic test:,serum cortisol and ACTH,a.Exogenous GCS:Cor(-),ACTH(-),b.Cushing,s disease:Cor(,),ACTH(,),c.Adrenal adenoma:Cor(,),ACTH(,),d.Ectopic ACTH production,(2),Dynamic test:DEX suppression test,2.,Image examination:CT and MRI,Mineralocorticoid excess:,Conn,s syndrome,Causes,1.Aldosterone-secreting adrenal adenoma,2.Idiopathic hyperaldosteronism,Symptoms:,hepertensionand hypokalaemia,Treatment:,Operation;,ADS receptor blockers,Seconary,Hypothalamus,pituitary,Primary,:adrenal,cortex,(Chronic:Addisons disease,Acute:adrenal crisis),Adrenal insufficiency,Part 6 Pharmacological use of GCS,Structure-activity Relationship,(differences of glucocorticoids and m,ineralocorticoids,),glucocorticoids,mineralocorticoids,Structure-activity relationship of GCS,(cortisol),Structure-activity relationship of glucocorticoids,Drugs,Metabolism on electrolyte and water,（,rate,）,Metabolism on carbohydrate,（,rate,）,Anti-inflammation,（,rate,）,hydrocortisone,cortisone,prednisone,prednisolone,methylprednisolone,dexamethasone,betamethasone,fludrocortisone,fluocinolone,1.0,0.8,0.6,0.6,0.5,0.1,0.1,125,100,1.0,0.8,3.5,4.0,11,20,11,10,1.0,0.8,3.5,4.0,5.0,30,25,35,12,40,Pharmocological uses of GCS,Absorption,Distribution:,PPBR90%,80%:corticosteroid binding globulin(CBG),CBG:Liver,estrogen,10%:albumin,Metabolism,:,HSD1,cortisone hydrocortisone,prednisone prednisolone,Excretion,:kidney,Pharmacokinetics of GCS,Pharmacological uses of GCS,1.Replacement therapy,2.S,evere infection and inflammation,3.,Autoimmune and allergic diseases,4.Shock,5.Others,(1)blood disorder,(2)topical use3)cancer,1.Replacement therapy:in small dose,Primary/secondary,acute/chronic adrenal cortex hypofunction,Acute:,Water-house Friderichsen syndrome,adrenal crisis,ablation of bilateral adrenal glands,Chronic:,Addison,s disease(primary),hypofunction of hypothalamus or pituitary(secondary),2.Severe infection and inflammation,1)Severe acute,bacterial,infections,Eg:fulminant epidemic meningitis(,暴发性流脑,),toxic bacillary dysentery(,中毒性菌痢,),toxic pneumonia,scarlet fever,acute miliary tuberculosis of lung,septicemia(,败血症,),large-dose,short-term,treatment of GCS may help patients go through dangerous stage.,Attention:,must be used plus,enough effective,antibacterial agents.(why?),2)Some virus infection:,with caution,Eg.,severe infective hepatitis,epidemic parotitis(,流行性腮腺炎,),measles(,麻疹,),Japanese B encephalitis(,乙脑,),SARS,2.Severe infection and inflammation,3)Prevention for inflammatory sequela,1)tuberculous diseases:,Eg.meningitis,pleuritis(,胸膜炎,),pericarditis(,心包炎,),(2)ocular diseases:,iritis(,虹膜炎,),keratitis(,角膜炎,),retinitis(,视网膜炎,),2.Severe infection and inflammation,1)Autoimmune diseases,:,used widely,rheumatic fever,rheumatic or rheumatoid arthritis,rheumatic myocarditis,systemic lupus erythematosus(SLE),autoimmune hemolytic anemia,nephrotic syndrome,3.Autoimmune and allergic diseases,2)Organ transplantation:,combined with immunosupressive agents,3)Allergic diseases:,be given as,supplements,to the primary therapy,3.Autoimmune and allergic diseases,4.Shock,effective to all kinds of shock,1)infectious-toxic shock:,first choice,2)other shocks:,supplements,5,.Other clinical uses,(1)Blood disorders,acute lymphatic leukemia,aplastic anemia(AA),thrombocytopenia,granulocytopenia,(2)Topical uses:local therapy,some skin diseases,some,ocular,diseases,Adverse reactions,Adverse reactions caused by,continuous,and,longtime,use of,large doses,of GCS,Withdrawl reactions:adverse reactions caused by,sudden withdrawl,after a continuous and longtime use.,1.Adverse reactions caused by continuous and longtime use of large doses of GCS,1),Latrogenic(,医源性,)Cushing,s syndrome,2),Induction and aggravation of infection,3),Possible risk of peptic ulcers,4),Cardiovascular complications,：,HBP,AS,5)Other complications,a.osteoporosis,b.psychosis,euphoria,c.growth retardation,d.glaucoma,：,GIG,e.abnormity,满月脸,水牛背,向心性肥胖,皮肤变薄,高血压,(,有时有,),上下肢消瘦,欣快,(,有时出现抑郁或情绪不稳定及其它精神症状,),易于感染,创伤不易愈合,还有：负氮平衡,食欲增加,低血钾,高血压倾向,消化性溃疡,长期应用糖皮质激素后的不良反应,骨质疏松,2.Withdrawal reactions,1)Latrogenic adrenocortical insufficiency,:,long-term suppression of the HPA axis,adrenal crisis,2),Rebound phenomenon,and withdrawal symptoms,Adrenal crisis,Contraindications,Severe psychosis and epilepsy,Active peptic ulcer,Restore period of fracture and wound,Corneal ulcer,Severe hypertension,Diabetes,Pregnancy,Uncontrolled infection,Steroid treatment card,Patients with a long course of oral GCS therapy should carry a steroid card.,Methods of application,1)Substitution therapy with small dose,2)Impact therapy with large dose,3)Long-term therapy with moderate dose,(1)Therapy on every morning,(2)Therapy on every other morning,ACTH:,diurnal variation,Thank you,