Chapter 12 Adrenal Steroid Hormones

Transcription

1 Chapter 12 Adrenal Steroid Hormones Nam Deuk Kim, Ph.D. 1

2 1. The Adrenal Glands Embedded above each kidney in a capsule of fat Composed of two endocrine organs Adrenal cortex Outer portion Secretes steroid hormones Adrenal medulla Inner portion Secretes catecholamines 2

3 1) Anatomy of the Adrenal Glands 3

4 Adrenal cortex Consists of three layers or zones Zona glomerulosa outermost layer Zona fasciculata middle and largest portion Zona reticularis innermost zone Categories of adrenal steroids Mineralocorticoids Mainly aldosterone Influence mineral balance, specifically Na + and K + balance Glucocorticoids Primarily cortisol Major role in glucose metabolism as well as in protein and lipid metabolism Sex hormones Identical or similar to those produced by gonads Most abundant and physiologically important is dehydroepiandosterone (male sex hormone) 4

5 2. Chemistry and Synthesis 5

6 Fig Pathways of adrenal steroid hormone biosynthesis. 6

7 Fig Steroid hormone structure and nomenclature. 7

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10 Fig Model for cholesterol homeostasis in the adrenal. 10

11 Compartmentalization of Steroid Synthesis 11

12 LDL Cholesterol from plasma outer membrane Acetyl CoA biosynthesis Cholesterol Increased by ACTH camp induction + PKA phosphorylation StAR ACAT Steroidogenic acute regulatory protein Fatty acids Cholesterol esters Cholesterol storage vacuole cholesterol esterase activated by ACTH in ZF/ZR (camp) or by angiotensin II in ZG (IP 3 -DAG) Pregnenolone SER MITOCHONDRION matrix inner membrane P-450 scc : ACTH-activated: ZF/ZR Angiotensin II-activated: ZG Figure 2. Initial events common to the biosynthesis of adrenal, and other, steroid hormones 12

13 Zona glomerulosa Cholesterol P-450 scc AII Pregnenolone 3 -OHSD 5,4 Isomerase SER Progesterone 21-OHase SER Mineralocorticoid activity 11-Deoxycorticosterone (DOC) Activated by AII 11 -OHase + 18-OHase + 18-OHDH = Aldosterone synthase Mitos Aldosterone primary human mineralocorticoid Figure 3. Biosynthesis of mineralocorticoids in the zona glomerulosa 13

14 Zona fasciculata (reticularis also) Cholesterol ACTH P-450 scc SER Pregnenolone 17 -OHase 17 -OHpregnenolone X Not preferred 3 -OHSD/ 5,4 Isomerase SER 17 -OHase Progesterone 21-Hydroxylase X X 17 -OHprogesterone SER 11-Deoxycorticosterone (DOC) 11-Deoxycortisol 11 -Hydroxylase X Mitos Figure 3. Biosynthesis of glucocorticoids in the zona fasciculata (reticularis, secondarily) Corticosterone Cortisol primary human glucocorticoid 14

15 Cholesterol Pregnenolone 3 -OHsteroid DH/ 5-4 isomerase Progesterone 17 -OHase P-450scc/C-20,22-lyase 17 -Hydroxyprogesterone MITOCHONDRION Cortisol 11 -OHase 21-OHase 11-Deoxycortisol Cortisol SMOOTH ENDOPLASMIC RETICULUM Figure 4. Subcellular compartmentalization of glucocorticoid biosynthesis in zona fasciculata 15

16 3. Control of Synthesis and Secretion Cortisol Stimulates hepatic gluconeogenesis Inhibits glucose uptake and use by many tissues, but not the brain Stimulates protein degradation in many tissues, especially muscle Facilitates lipolysis Plays key role in adaptation to stress At pharmacological levels, can have anti-inflammatory and immunosuppressive effects Long-term use can result in unwanted side effects Displays a characteristic diurnal rhythm Secretion Regulated by negative-feedback loop involving hypothalamic CRH and pituitary ACTH 16

17 Control of cortisol secretion Pro-opiomelanocortin (POMC) MSH β-endorphin ACTH 17

18 Fig Model for the role of IGFs (especially IGF-II) in the control of adrenal steroidogenesis. 18

19 Aldosterone Principal action site is on distal and collecting tubules of the kidney Secretion is increased by Activation of renin-angiotensin-aldosterone system (RAAS) by factors related to a reduction in Na + and a fall in blood pressure Direct stimulation of adrenal cortex by rise in plasma K + concentration Regulation of aldosterone secretion is largely independent of anterior pituitary control 19

20 Urinary System 21

21 Nephron 22

22 Two types of nephrons Nephron Distinguished by location and length of their structures Juxtamedullary nephrons (20%) Cortical nephrons (80%) 23

23 Renin The juxtaglomerular apparatus. 24

24 RAAS 25

25 Fig Angiotensin biosynthesis. 26

26 Fig Renin angiotensin system and Na + homeostasis. Arrows indicate increases (up arrow) or decreases (down arrow) in the factors indicated. 27

27 Fig Kallikrein role in renin activation and bradykinin production. 28

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29 Dual control of aldosterone secretion of K + and Na +. 30

30 Excretion of urine of varying concentration depending on the body s needs. 31

31 Fig Summary scheme of the role of aldosterone in renal renin production. 32

32 An atrial natriuretic peptide (ANP) or atrial natriuretic factor (ANF) inhibits renal tubular Na + reabsorption Inhibits Na + reabsorption Secreted by atria in response to being stretched by Na + retention, expansion of ECF volume, and increase in arterial pressure Release promotes natriuretic, diuretic, and hypotensive effects to help correct the original stimulus that brought about release of ANP (or ANF). 33

33 Fig Primary structure of atrial natriuretic factor (ANF). 34

34 An atrial natriuretic peptide (ANP) or atrial natriuretic factor (ANF) inhibits renal tubular reabsorption 35

35 Fig Biological roles of ANF. 36

36 Fig The role of atrial natriuretic factor (ANF) in blood volume homeostasis. 37

37 4. Circulation and Metabolism Transport proteins: reversibly bound to Cortisol: - transcortin or corticosteroid-binding globulin (CBG) - α2 globulin - about 6%: unbound - t½ : about 80 min Aldosterone: - more than 50% of circulating aldosterone: unbound - t½ : about 30 min 38

38 Fig One pathway of cortisol metabolism and glucuronide formation (in the liver). 39

39 5. Physiological Roles Fig Major effects of excess cortisol in intermediary metabolism. Cortisol Stimulates hepatic gluconeogenesis Inhibits glucose uptake and use by many tissues, but not the brain Stimulates protein degradation in many tissues, especially muscle Facilitates lipolysis Plays key role in adaptation to stress At pharmacological levels, can have anti-inflammatory and immunosuppressive effects Long-term use can result in unwanted side effects 40

40 Aldosterone Fig Physiological effects of aldosterone on renal distal tubular Na + resorption and K + and H + excretion. In response to aldosterone, sodium is actively transported across the tubular serosal membrane into the peritubular space. Potassium and hydrogen ions are passively shunted across the mucosal membrane in exchange for sodium. 41

41 6. Mechanisms of Action Aldosterone s actions are mediated by intracellular mineralocorticoid receptors. Fig Hypothetical mechanisms of aldosterone action on the kidney. 42

42 Angiotensin II actions are mediated by cognate G-protein-coupled receptors, AT1 and AT2. Fig AII receptor-cellular response coupling. PLC, phospholipase C; DAG, diacylglycerol; IP 3, inositol triphosphate; G protein, guanosine triphosphate-binding protein; PKC, protein kinase C; AA, arachidonic acid; PC, phosphatidylcholine; LysPC, lysophosphatidylcholine; LO, lipoxygenase; CO, cyclooxygenase; HETE, hydroxyeicostatetraenoic acid; TXA 2, thromboxane A 2 ; PGs, prostaglandins (e.g., prostaglandin E 2 ); channel, calcium channel; PIP 2, phosphatidylinositol diphosphate; LTs, leukotrienes.

43 GC bound to CBG Free GC diffusion into cell GC receptor GC-receptor complex CYTOPLASM metabolic response Nucleus GRE Induced gene transcription mrna translation mrna protein Model of glucocorticoid (GC) action. GC is transported in plasma bound to corticosteroid binding protein (CBG). 44

44 Physiological roles of adrenal androgens have yet to be clarified. Secretes both male and female sex hormones in both sexes Dehydroepiandrosterone (DHEA) Only adrenal sex hormone that has any biological importance Overpowered by testicular testosterone in males Physiologically significant in females where it governs Growth of pubic and axillary hair Enhancement of pubertal growth spurt Development and maintenance of female sex drive 45

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46 Fig Summary scheme of the etiology of hypocortisolism and hypercortisolism. 47

47 Disorders of Adrenocortical Function Adrenocortical insufficiency Primary adrenocortical insufficiency Addison s disease Autoimmune disease Aldosterone deficiency» Hyperkalemia and hyponatremia Cortisol deficiency» Poor response to stress» Hypoglycemia» Lack of permissive action for many metabolic activities Secondary adrenocortical insufficiency Occurs because of pituitary or hypothalamic abnormality Only cortisol is deficient 48

48 급성부신부전증 Primary Acute Adrenocortical Insufficiency Corticosteroid 를장기간투여하여부신피질이위축된환자에게서급작한 corticosteroid 투여중지 부신기능이약한환자에게서감염또는수술등의스트레스 부신의출혈성파괴 (adrenal apoplexy: Waterhouse- Friderichsen syndrome) 임상증상 : 저혈압, 쇼크, 사망 49

49 Primary Acute Adrenal Cortical Insufficiency (Waterhouse-Friderichsen Syndrome) Meningococci from blood, spinal fluid and/or throat Circulatory collapse, marked hypotension Extensive purpura, shock, prostration, cyanosis Hemorrhagic destruction of adrenal gland Characteristic fever chart 50

50 Primary Chronic Adrenal Cortical Insufficiency (Addison Disease) 1. Autoimmune adrenalitis: 60~70% 2. Infections (e.g., tuberculosis) 3. Metastatic neoplasia 4. etc., histoplasmosis, trauma, etc. (5%) Progressive weakness and easy fatigability Gastrointestinal disturbances Hyperpigmentation: hair, skin, nipple, scars, mucous memb. Vitiligo Hyperkalemia Hyponatremia Volume depletion Hypotension Hypoglycemia (rarely) 51

51 Laboratory Findings In Primary Adrenal Cortical Insufficiency (Addison s Disease) -1 52

52 부신기능항진증 1. Hyperaldosteronism ( 원발성알도스테론증 ): aldosterone 2. Cushing syndrome ( 쿠싱증후군 ): cortisol 3. Adrenogenital or virilizing syndrome ( 부신-성증후군 ): androgen 53

53 Disorders of Adrenocortical Function Aldosterone hypersecretion May be caused by Hypersecreting adrenal tumor made up of aldosteronesecreting cells Primary hyperaldosteronism or Conn s syndrome Inappropriately high activity of the renin-angiotensin system Secondary hyperaldosteronism Symptoms Excessive Na + retention and K + depletion High blood pressure 54

54 원발성알도스테론증 (Conn Syndrome) 1. Adenoma ( 부신선종 ): 80% 2. Uncommon cause 3. Rare cause: glucocorticoid suppressible 55

55 Fig Genetic defect in 17 -hydroxylase activity leading to hyperaldosteronism. 56

56 Primary Hyperaldosteronism (Conn Syndrome) Increased aldosterone Extracellular fluid increased Body sodium increased Body potassium decreased Increased fecal potassium loss Polydipsia Hypertension Chvostek s sign positive Trousseau s positive Polyuria Increased urinary aldosterone 57

57 Disorders of Adrenocortical Function Cortisol hypersecretion Cushing s syndrome Causes Overstimulation of adrenal cortex by excessive amounts of CRH and ACTH Adrenal tumors that uncontrollably secrete cortisol independent of ACTH ACTH-secreting tumors located in places other than the pituitary Signs and symptoms Hyperglycemia and glucosuria (adrenal diabetes) Abnormal fat distributions buffalo hump and moon face 58

58 Hypercortisolism(Cushing Syndrome) 뇌하수체성쿠싱증후군 : 70%( 내인성 ) 부신성쿠싱증후군 : 20%( 내인성 ) 이소성쿠싱증후군 : ~10%( 내인성 ) 의원성쿠싱증후군 : 실제로가장흔함 소세포폐암 59

59 Cushing s Syndrome: Clinical Findings Elevated glucocorticoids Excessive gluconeogenesis Hyperglycemia Protein shortage Adrenal diabetes Red cheeks Moon faces: 85% Abnormal fat distributions Fat pads (Buffalo hump): 85-90% Mobilization of amino acids Red striae: 50% Thin skin Bruisability/Ecchymoses Poor wound healing Osteoporosis: 70% High B.P.: 75% Thin arms and legs Pendulous abdomen Compressed (Codfish) vertebrae 60

60 Disorders of Adrenocortical Function Adrenal androgen hypersecretion Adrenogenital syndrome Symptoms Adult females Hirsutism Deepening of voice, more muscular arms and legs Breasts become smaller and menstruation may cease Newborn females Have male-type external genitalia Prepubertal males Precocious pseudopuberty Adult males Has no apparent effect 61

61 Hormonal interrelationship in adrenogenital syndrome 62

62 Adrenogenital syndrome Consequences of C-21 hydroxylase deficiency 63

63 Adult Female Adrenogenital Syndromes( 부신성증후군 ) 17-Ketosteroids 1. Overactivity of adrenal cortex 2. Hyperplasia of adrenal cortex 3. Adnoma of adrenal cortex 4. Carcinoma of adrenal cortex Receding hair line, baldness Acne Facial hirsutism Androgenic flush Small breasts Male escutcheon Clitoral enlargement Heavy muscular arms and legs Generalized hirsutism 64

64 Newborn females 그림

65 The Biological Actions of 17-Ketosteroids: (Dehydroepiandrosterone) (DHEA) Increased muscle mass Bone matrix deposition Calcium deposition Adrenarche Pyrogenic effect Hair line recession Sebaceous gland Hypertrophy (Acne) Facial hair Axillary hair Laryngeal enlargement Pubic hair Precocious Pseudopuberty 66

66 성조숙증급증 : 5 년새 4.4 배 ( ) 성조숙증 (precocious puberty) 성조숙증환자는여자아이의경우만 8 세이전에가슴이발달하고, 남자아이는 9 세이전에고환이커지는증상을보임. 성조숙증으로진료받은나이는지난해를기준으로 5~9 세아동이 71% 를차지했음. 성별로는여자아이가 92.5% 로대부분임. 성조숙증의원인은소아비만과환경호르몬의영향등을꼽음. 난소나중추신경계에종양이생겨호르몬분비에이상이생기는경우도드물게있음. 성조숙증을앓게되면성장판이빨리닫혀키가충분히클수없는문제점이있음. 67