內(nèi)分泌生殖系統(tǒng)教學(xué)課件：04 腎上腺皮質(zhì)1

1、 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 fasciculat

2、a Part 2 Hormones produced by the adrenal cortex Belong to steroid hormones Basic structure: Steroid nucleus C3 = 0 (酮基酮基) C4-5 (雙鍵雙鍵) C20 =0 (羰基羰基) are necessary for adrenocortical hormones AB C O OH 20 c o 21 CH2OH R 3 4 5 17 11 18 D Basic Structure of Adrenocortical Hormones Hormones of adrenal c

3、ortex Case: 4-year-old girl Report from her mother Height and weight lower than expected 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/

4、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 biosynthe

5、sis Raw material: cholesterol Release: from lipid droplets StAR protein phosphorylation Cholesterol ester hydrolase Source De novo synthesis From LDL Stimulated by ACTH 乙酰乙酰CoA 乙酰乙酰乙酰乙酰CoA HMG-CoA MVA 鯊烯鯊烯 膽固醇膽固醇 synthesis of cholesterol CHOOCH2C OH CH3 CH2C O SCoA (HMG-CoA) 2NADPH + H+ HSCoA + 2NAD

6、P+ HMG -CoA 還原酶 CHOOCH2C OH CH3 CH2CH2OH 甲羥戊酸（MVA) 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: 55n

7、g/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 expr

8、ession 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()

9、 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) Funct

10、ional 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

11、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 1. Effects on metabolism 2. Permissive action 3. Anti

12、-inflammatory effects 4. Immunosuppressive and anti-allergic effects 5. Anti-toxic effects 6. Anti-shock effects 7. Effects on blood and hematopoietic system 8. Other effects 1. Effects on metabolism (1) Effects on carbohydrate metabolism: BS a. increase glyconeogenesis b. increase glycogenolysis c.

13、 decrease the oxidation and utilization of glucose Net result: hyperglycemia 1. Effects on metabolism (2) Effects on protein metabolism a. stimulates protein catabolism b. inhibit protein synthesis Net result: negative nitrogen balance 1. Effects on metabolism (3) Effects on lipid metabolism: a. sti

14、mulate 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. antagonizing Vitamin D Definition: GCS facilitates other hormonal effects other than direct effects

15、. eg. Increase the vasoconstriction of CA, increase the hyperglycemic effect of glycagon 2. Permissive action 3. Anti-inflammatory effects Characteristics: rapid, strong , nonspecific , both the early phase and late phase Mechanism of anti-inflammatory action Reducing the vascular response of inflam

16、mation a. Affecting AA metabolism PGs , LTs (inducing lipocortin-1, inhibiting COX) b. Inhibiting iNOS expression NO c. Inducing ACE BK d. Increasing the vasoconstriction of CA L-Arginine iNOS NO GCS - BK ACE Degradation production + Mechanism of anti-inflammatory action Mechanism of anti-inflammato

17、ry action .Reducing the cell response to inflammation a. Inhibiting some pro-inflammatory cytokines expression (eg.IL-1, 2, 5, 6, 8,TNF-) b. Inducing some anti-inflammatorycytokines expression (eg.IL-10,IL-12, IB1). c. Inhibiting adhesion molecule expression (eg.ICAM-1, E-selectin). d. Inducing infl

18、ammatory cells apoptosis : inducing caspase and endonuclease Mechanism of anti-inflammatory action . Postponing the inflammatory sequela Mechanism: inhibiting hyperplasy of blood capillary and fibroblast, preventing adhesion and scar formation Molecular mechanism of anti-inflammatory Clinical Scienc

19、e (1998) 94, (557572) (Printed in Great Britain) Anti- inflammatory actions of glucocorticoids: molecular mechanisms 2. Immunosuppressive effects and anti-allergic effects Mechanisms 1) Inhibiting phagocytosis and management of macrophages on antigen 2) Promoting the redistribution of lymphocyte in

20、human blood, decreasing the number of lymphocytes in circulation 3) Inhibiting IL-1 mediated immunoreactions 4) Stabilizing mast cell membrane 3. Antitoxic effects Mechanism: enhancing body tolerance to bacterial endotoxin Antipyretic mechanism: 1)membrane stabilization： endogenous pyrogens release

21、2)decreasing the sensitivity of body temperature regulating center to endogenous pyrogens. 4. Anti-shock effects: especially infectious-toxic shock Mechanisms: 1) anti-inflammatory and anti-toxic effects 2)directly relaxing the spasmodic vessels and enhancing the contractility of myocardium 3) reduc

22、ing the sensitivity of some vasoconstrictive substances on vessels 4) membrane stabilization, MDF production and release (MDF: myocardial-depressant factor) ischemiahypoxia shock acidosis lysosomal membrane disruption Release of proteinase plasma proteinMDF Myocardial depressionvasospasm vicious cyc

23、le GCS - 5. Effects on blood system (1) Stimulating 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 r

24、elieving itching anti-hyperplasy osteoporosis The effects of GCS in stress 1. Stress 2. Stress hormone is increased 3. Cortisol is an essential part of the bodys response to stress. Actions of mineralocorticoids (mineral+ cortex + steroid) Actions of mineralocorticoids 11-HSD: 11hydroxysteroid dehyd

25、rogenase AME: apparent mineralocorticoid excess Actions of adrenal androgens In disease states Virilizing effects Can be converted to estrogens Part 5 Disorders of adrenal steroids Congenital adrenal hyperplasia Glucocorticoid excess Mineralocorticoid excess Adenal insufficiency Congenital adrenal h

26、yperplasia (CAH) Deficiency of biosynthesis enzyme Glucocorticoid excess: Cushings syndrome Causes 1. Exogenous corticosteroid administration 2. Cushings disease 3. Adrenal adenoma 4. Ectopic ACTH production Glucocorticoid excess: Cushings syndrome Investigations of GCS excess 1. Blood test (1) Basi

27、c test: Serum levels of cortisol and ACTH (2) Dynamic test: Dex suppression test 2. Image examination: CT and MRI Mineralocorticoid excess: Conns syndrome Causes 1. Aldosterone-secreting adrenal adenoma 2. Idiopathic hyperaldosteronism Sympotoms: hepertension and hypokalaemia Treatment: ADS receptor

28、 blockers Seconary Hypothalamus pituitary Primary :adrenal cortex Adrenal insufficiency Acute: Water-house Friderichsen syndrome adrenal crisis ablation of bilateral adrenal glands Chronic: Addison s disease (primary) hypofunction of hypothalamus or pituitary (secondary) Adrenal insufficiency Adrena

29、l crisis 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

30、 11 10 1.0 0.8 3.5 4.0 5.0 30 2535 12 40 Pharmocological uses of GCS Absorption Distribution: PPBR90% 80% :corticosteroid binding globulin (CBG) CBG: Liver, estrogen 10%: albumin Metabolism: liver cortisone hydrocortisone prednisone prednisolone Excretion: kidney Pharmacokinetics of GCS Pharmocologi

31、cal uses of GCS 1. Replacement therapy 2. Severe infection and inflammation 3. Autoimmune and allergic diseases 4. Shock 5. Others (1) blood disorder (2) topical use (3) cancer 1. Replacement therapy: in small dose Primary/secondary, acute/chronic adrenal cortex hypofunction Acute: Water-house Fride

32、richsen 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(暴發(fā)性流腦暴發(fā)性流腦), toxic bacillary dysen

33、tery(中毒性菌痢中毒性菌痢), toxic pneumonia, scarlet fever, acute miliary tuberculosis of lung, septicemia(敗血癥敗血癥) 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 Eg. severe

34、 infective hepatitis epidemic parotitis (流行性腮腺炎流行性腮腺炎) measles (麻疹麻疹) Japanese B encephalitis (乙腦乙腦) SARS 2. Severe infection and inflammation 3) Prevention for inflammatory sequela (1) tuberculous diseases: Eg. meningitis, pleuritis(胸膜炎胸膜炎), pericarditis(心包炎心包炎) (2) ocular diseases: iritis(虹膜炎虹膜炎),

35、 keratitis(角膜炎角膜炎),retinitis(視網(wǎng)膜炎視網(wǎng)膜炎) 2.Severe infection and inflammation 1) Autoimmune diseases rheumatic fever, rheumatic or rheumatoid arthritis rheumatic myocarditis systemic lupus erythematosus (SLE), autoimmune hemolytic anemia nephrotic syndrome 3. Autoimmune and allergic diseases 2) Organ t

36、ransplantation: Combined with immunosupressive agents 3)Allergic diseases: bronchial asthma, urticaria(蕁麻疹蕁麻疹), hay fever, anaphylactic rhinitis(過(guò)敏性鼻炎過(guò)敏性鼻炎) be given as supplements to the primary therapy 3.Autoimmune and allergic diseases 4. Shock effective to all kinds of shock 1)infectious-toxic s

37、hock :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 (3) Some cancers 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