Adrenal Glands. Huiping Wang ( 王会平 ), PhD. Rm C541, Block C, Research Building, School of Medicine Tel:

Transcription

1 Adrenal Glands Huiping Wang ( 王会平 ), PhD Department of Physiology Rm C541, Block C, Research Building, School of Medicine Tel:

2 Outline The Adrenal Glands The adrenal cortex The Adrenal Medulla The Adrenocortical hormones Synthesis of Catecholamines Glucocorticoids Physiologic Actions of E and NE» Synthesis Regulation» Transport» Functions» Mechanism of action» Regulation of cortisol secretion Mineralocorticoids id» Functions» Regulation of aldosterone secretion

3 Adrenal gland is essential for life. Adrenal insufficiency can be life- threatening.

4 The Adrenal Glands Adrenal cortex: 80% to 90% Adrenal medulla:10% d to 20%

5 The Adrenal Cortex 15% 75%

6 The Adrenal Cortex Three distinct layers Zona glomerulosa: 15% Aldosterone Zona fasciculata: 75% Cortisol, corticosterone Zona reticularis Androgens, estrogens and glucocorticoids GFR corresponds with Salt (Na + ), Sugar (glucocorticoid), and Sex (androgen)

7 The Adrenocortical hormones Corticosteroids: 3 groups Glucocorticoids Cortisol Corticosterone Mineralocorticoids Aldosterone Sex hormones Androgens(dehydroepiandrosterone, DHEA and androstenedione), estrogens

8 The Adrenocortical hormones Synthesis Adrenal cortical steroid synthetic pathways P450scc (+) ACTH, AgII

9 Diurnal rhythm high in the morning low in late afternoon and night Can be altered by consistent revision of the timing and duration of the sleep /wake schedule S ti f CRH i h th i d l til Secretion of CRH is rhythmic and pulsatile In response to CRH, the secretion of ACTH is pulsatile which ultimately results in the pulsatile secretion of cortisol

10 Transport of Adrenocorticosteroids 75% of cortisol are bound to corticosteroidbinding globulins (CBG) or transcortin 15% of cortisol are bound to albumin 10% free

11 Glucocorticoids id Activity Cortisol: very potent, 95% of all glucocorticoid activity Corticosterone(~4% of total glucocorticoid activity) Others Hydrocortisone, Cortisone (synthetic, as potent t as cortisol) Dexamethasone (synthetic, 30 times as potent as cortisol) Absolutely essential for life. (maintaining homeostasis)

12 Actions of Cortisol Maintain homeostasis Influence: Organic metabolism (promote energy mobilization via gluconeogenesis) Vascular tone (permissive action) Immune response Renal function (to a limited extent)

13 Actions of Cortisol Effects on carbohydrate metabolism Blood glucose concentration Gluconeogenesis(from amino acids) Glycogenolytic effect Glucose uptake & utlilization ti (anti-insulin i effect ) Assist in maintaining the fasting blood G level to insure a continuous G supply for the brain Excessive hyperglycaemia adrenal diabetes

14 Actions of Cortisol Effects on protein metabolism protein breakdown (except liver, cardiac muscle) for gluconeogenesis High levels of cortisol cause skeletal muscle mass, bone mass and cutaneous tissue somatic growth and GH secretion

15 Actions of Cortisol Effects on fat metabolism Lipolysis and fatty acid mobilisation (from adipose tissue) Oxidation of fatty acids Permissive action Lipolytic actions of GH, T3, CA and Glucagon

16 Actions of Cortisol Obesityy caused by y excess cortisol Excess deposition of fat in the trunk and head Buffalo-like torso Rounded moon face Centripetal fat distribution distrib tion

17 Actions of Cortisol Hemopoietic Effect RBC, neutrophils, monocytes and platelets Lymphocytes, eosinophils, and basophils

18 Actions of Cortisol Effects on Vascular System Permissive action Upregulate 1-Rs on vascular SMCs. optimize vascular responses to catecholamines Basal levels of cortisol is necessary to maintain i normal BP. (Excessive hypertension) (Deficient hypotension)

19 Actions of Cortisol Effects on the CNS Excitability of CNS Alters mood and behavior Excessive Insomnia, euphoria, irritability, and psychotic depression Deficient Mental fatigue, depression, inability to concentrate or perform mathematical calculations

20 Actions of Cortisol Effects on digestive system A trophic effect on the GI mucosa GI acid and enzyme production

21 Actions of Cortisol Anti-inflammatory effect (a pharmacologic effect) depress the immune response by stabilizing lysosomal membrane capillary permeability ( PGs) production of inflammatory cytokines (-) function of certain immune cells (-) histamine release from mast cells widely used in the treatment of allergy, asthma, arthritis, other auoimmune diseases and graft rejection.

22 Actions of Cortisol Important role in the body s adaptive stress responses Acute physical stressor (trauma, infection, intense coldness and heat, surgical operation, illness, burns, fever, hypotension, exercise, hypoglycemia) y or psychological stressor mainly activates the hypothalamic-pituitary-adrenal cortex axis.

23 Actions of Cortisol Increased cortisol is important to resist stress Maintain BP Provide extra fuel sources in the blood Temporarily shut down nonessential functions Ensure the brain and muscles get the lion s share of glucose Chronic, excessive or inappropriate stress lead to Bone density, worsen the symptoms of diabetes Immune function cancer, resistance to infection Reproductive fertility Development of hypertension and atherosclerosis

24 Mechanism of cortisol action Genomic effect: Intracellular Rs mediate delayed response Nongenomic effect: Membrane Rs mediate rapid response

25 Metabolic fate of cortisol Chemical transformation and inactivation occurs in the liver. Cortisol can be reversibly oxidized dto cortisone in the liver. Excreted in urine conjugated to glucuronic acid Cortisone is biologically inert, but can be g y, reconverted to cortisol.

26 If glucocorticoids are administered at a high enough dosage for long peroids, what is the side effect of such treatment?

27 Regulation of cortisol secretion Hypothalamus-pituitary- adrenal cortex axis Stress CRH ACTH cortsiol ACTH (adrenocorticotropin): Polypeptide Cortisol secretion Hypertrophy and proliferation of the adrenocortical cells Secretion: with MSH (from precursor-pomc)

28 Regulation of cortisol secretion Hypothalamus-pituitary- adrenal axis Negative feed-back long -loop by free cortisol short-loop by ACTH on CRH secretion Stress overrides negative feed-back i.e. cortisol secretion is stimulated even though cortisol level is high, but magnitude is diminished What are the disadvantages of long-term, high dose treatment with glucocorticoids?

29 Mineralocorticoids i id The mineralocorticoids get their name from their effect on mineral metabolism. The most important of them is the steroid aldosterone. Accounts for about 90% of all mineralocorticoid activity About 60% are bound to plasma proteins Half life is about 20 min

30 Functions of aldosterone 3 major and related effects Na + reabsorption and water K + excretion BP (blood volume) Excess hypokalemia, alkalosis, hypertension Deficient hyperkalemia, acidosis, hypotension

31 Regulation of aldosterone secretion (In order of importance) 1. Increased K 2. Increased activity of Renin-angiotensin system (RAS). 3. ACTH

32 The Adrenal Medulla Preganglionic neurons innnervate the adrenal directly. Adrenal medulla and sympathetic nervous system make up an anatomical and physiological unit referred to as the sympathoadrenal system. Release of Hs at the adrenal medulla is initiated by CNS control. is triggered by sympathetic stimulation in response to physical or mental stress.

33 The Adrenal Medulla Epinephrine (E): 80% Norepinephrine (NE): 20% Adrenomedullin

34 The Adrenal Medulla Synthesis of Catecholamines (DA, NE, E)

35 Physiologic Actions of E and NE Cardiovascular effects Mtbli Metabolic effects Glucose production Cl Calorigeniceffect i Emergency reaction fight-or-flight response (activation of sympathoadrenal system) Stress response (activation of sympathoadrenal system)

36 Adrenergic Receptors and Mechanism of Action The physiologic effects of E and NE are initiated by their binding to adrenergic receptors on the surface of target t cells. Receptor Effectively Binds Effect of Ligand Binding Alpha 1 Adrenaline, Noradrenaline Increased free calcium Alpha 2 Beta 1 Adrenaline, Noradrenaline Adrenaline, Noradrenaline Decreased cyclic AMP Increased cyclic AMP Beta 2 Adrenaline Increased cyclic AMP Complex physiologic responses result from adrenal medullary stimulation because there are multiple receptor types which are differentially expressed in different tissues and cells Receptors adrenaline (equally on alpha & beta) - noradrenaline (mainly on alpha, beta receptor Beta 1 only)

37 The Adrenal Medulla Regulation Sympathetic nervous system Feedback end-product inhibition ACTH and glucocorticoids

38 Which of the following is/are not stimulated by cortisol during stress? QUIZ a. gluconeogenesis b. protein catabolism c. glucose uptake and oxidation d. triglyceride catabolism e. All of the choices are stimulated by cortisol.

39 Which of the following is/are not stimulated by cortisol during stress? QUIZ a. gluconeogenesis b. protein catabolism c. glucose uptake and oxidation d. triglyceride catabolism e. All of the choices are stimulated by cortisol.

40 The major hormone responsible for mediating the body's response to stress is QUIZ a. thyroid hormones. b. growth hormone. c. testosterone. d. aldosterone. e. cortisol.

41 The major hormone responsible for mediating the body's response to stress is QUIZ a. thyroid hormones. b. growth hormone. c. testosterone. d. aldosterone. e. cortisol.

42 Summary Glucocorticoids Functions Effects on carbohydrate, protein and fat metabolism Resisting stress Effects on blood cells, vascular system, bone formation Effects on nervous system, digestive system Anti-inflammatory effects Regulation of cortisol secretion Hypothalamus-pituitary- adrenal axis

43 Summary Mineralocorticoids Functions Regulation of aldosterone secretion Disorders of the adrenal Hypercortisolism (Cushing s syndrome) Primary hypoadrenalism (Addison s disease) The Adrenal Medulla Physiologic Actions of E and NE Regulation sympathoadrenal system

44 The End.