1.THE ADRENALS PART 1- ANATOMY AND PHYSIOLOGY Dr Prashant Bansal

2. Adrenals are central to homeostasis 3. HISTORICAL BACKGROUND Distinguished anatomists such as Galen, da Vinci, and Vesalius omitted the adrenal glands in their descriptions of the retroperitoneum. Bartholomaeus Eustachius was the first to describe them in mid-16th century In mid-19th century Thomas Addison, an English physician, described a series of patients with the condition of adrenal insufficiency that now carries his name Charles Brown-Sequard, through a series of animal experiments demonstrated that bilateral adrenalectomy uniformly resulted in death, suggesting that the adrenals were indispensable to the survival of the host William Osler was the first to report treatment of Addison disease with hormonal replacement in 1896. He administered crude extract from adrenals of pigs to a patient with Addison disease and produced significant weight gain in this one individual In the ensuing half-century adrenalin was discovered, and its production was localized to the adrenal medulla (Oliver and Sharpey-Schafer, 1895). 4. The ability of adrenaline to produce a sustained rise in blood pressure was subsequently determined (Abell and Crawford, 1897). Moreover, the failure of this substance, later termed epinephrine to sustain life following bilateral adrenalectomy underscored the complexity and multifunctionality of the adrenal gland and established Addison disease as an ailment of the adrenal cortex (Scott, 1990; Porterfield et al, 2008). Discovery and isolation of cortisol from the adrenal gland in the 1930s and subsequent work on its use to treat rheumatoid arthritis produced a 1950 Nobel Prize in Physiology and Medicine for Edward Kendall, Philip Hench, and Tadeus Reichstein (Scott, 1990). Aldosterone was ultimately isolated from the bovine adrenal in 1952 (Grundy et al, 1952). The latter part of the 20th century witnessed a rapid transformation in our understanding and treatment of adrenal disorders lead by pioneers such as Jerome Conn, Lawson Wilkins, Grant Liddle, and Earl Sutherland HISTORICAL BACKGROUND 5. Embryology 6. The adrenal gland consists of Superficial Cortex Deeper Medulla Adrenal cortex and medulla are two embryologically and functionally distinct units. The cells of the cortex arise from coelomic epithelium (mesoderm). Cortex - Mesoderm The cells of the medulla are derived from the neural crest (ectoderm). Medulla - Neuroectoderm Embryology 7. Embryology Adrenal cortex Derived from intermediate mesoderm of urogenital ridge Formed during 2nd month by a proliferation of coelomic epithelium. The cells of the cortex arise from the coelomic epithelium, that lies in the angle between the developing gonad and the attachment of the mesentery (Figs 18.3A. B). Cells pass into the underlying mesenchyme between the root of the dorsal mesogastrium and mesonephros. Beginning in the 5th week of gestation, mesenchymal cells located at the urogenital ridge and the root of mesentery proliferate ( form Fetal Adrenal Cortex). The cells are large and acidophil. They surround cells of medulla. The proliferating tissue, which extends from T6 to T12, is soon disorganized dorsomedially by Invasion of neural crest cells and Development of venous sinusoids 8. The venous sinusoids are joined by capillaries, which arise from adjacent mesonephric arteries and penetrate the cortex in a radial manner. During the 6th and 7th weeks of gestation additional mesothelial cells surround fetal cortex they will later form Adult Adrenal Cortex. These cells are smaller. When proliferation of coelomic epithelium stops, cortex is enveloped by a mesenchymal capsule which is derived from the mesonephros. By the end of the 8th week of gestation the mesothelial cells forming the cortex are encapsulated by connective tissue and have separated from peritoneal mesothelium. Embryology 9. Adrenal medulla Derived from Neural Crest Cells (from somites 18-24), located in adjacent sympathetic ganglia. Neural Crest Cells are similar to postganglionic sympathetic neurons. Pre-ganglionic sympathetic neurons terminate in relation to them They migrate into medial aspect of fetal cortex by 9th week of gestation They continue to invade cortex until they achieve a central position surrounding the adrenal vein by 18th week of gestation THIS EMBRYOLOGIC RELATIONSHIP EXPLAINS THE BROWN STIPPLING OF ADRENAL CORTEX. Embryology 10. Adrenals In The Neonate At term Each gland weighs 4 g; avg weight of two glands is 9 g (average in adult is 7- 12 g) At birth Adrenals are relatively very large at birth Constitute 0.2% of entire body weight, compared with 0.01% in adult Fetal adrenal gland is twice the weight of an adult adrenal gland, but has not completed development. Left gland is heavier and larger than right, as in the adult Cortex is thicker than in adult and medulla is small. 11. After birth Fetal cortex begins to atrophy and will be completely resorbed by 12 months of age. Fetal cortex undergoes rapid involution during first two years after birth. The glands involute rapidly Each gland loses 25% of its mass Average weight of both glands is 5 g by end of 2nd wk 4 g by 3 months As the fetal cortex is being resorbed, the zona glomerulosa and fasciculata of the adult cortex continue to develop, but the zona reticularis will not complete differentiation until 3 years of age, reflecting the relative late importance of sex steroid production by this part of cortex Birth weight is not regained until puberty Adrenals In The Neonate 12. U/l adrenal agenesis Rare and often a/w U/l renal agenesis (Incidental) Adrenal gland development occurs normally in the absence of ipsilateral renal unit development, mal-rotation, or mal-ascent. In these cases, the adrenal glands are often discoid in shape and located in their normal position within the retroperitoneum Ectopia Adrenal cortical tissue may be present at various ectopic sites. The entire adrenal may be ectopic and may lie deep to the capsule of the kidney. It may be fused to the liver or the kidney. Adrenal heterotopia Results from incomplete separation of primitive adrenal mesoderm from adjacent organs such as the liver or kidney, Results in partial or complete incorporation of the gland into the adjacent organ. Congenital Anomalies 13. Accessory Adrenal Tissue (Adrenal Rests) Can be composed of cortical/medullary tissues Due to the close proximity of adrenal and genitourinary development, adrenal rests can be found anywhere along the path of gonadal descent within the retroperitoneum. Although adrenal rests can be found in up to 50% of neonates, the tissue typically atrophies and is found in only approximately 1% of adults In cases of congenital adrenal hyperplasia (CAH), adrenal rest within testis may become hyperplastic and present as a testicular mass. THIS IS AN IMPORTANT CONSIDERATION PRIOR TO PERFORMING AN ORCHIECTOMY FOR A TESTICULAR MASS IN PATIENTS WITH CAH. Congenital Anomalies 14. Congenital Adrenal Hyperplasia (overdevelopment of cortex) MC abnormality of adrenal development Occurs in 1:5000-1:15000 births. Autosomal recessive Deficiencies in enzymes required for synthesis of cortisol. In 90% of cases cause is deficiency of enzyme 21-hydroxylase accumulation of 17-hydroxyprogesterone is converted to androgens. levels of androgens increase by several hundred times In female it may cause Pseudohermaphroditism Female embryos and foetuses undergo external genital masculinisation ranging from clitoral hypertrophy to formation of a phallus and scrotum Child may be mistaken for a male Masculinisation of brain has also been suggested Congenital Anomalies 15. In male this leads to Adrenogenital Syndrome Do not cause any changes in external genitalia Very early development of secondary sexual characters Precocious masculinisation and accelerated growth Congenital Anomalies 16. Anatomy 17. Adrenal 18. Anatomy Anatomy was first described in 1563 They are paired retroperitoneal organs composed of a cortex and medulla Contained in its own sub-compartment within Gerotas fascia Gross examination reveals Cortex = spiculated, mustard yellow colour Medulla = central, brown colour Weight ~ 4 - 5 g each Size Length = 4 - 6 cm Width = 2 - 3 cm Right adrenal gland is triangular in shape Left adrenal gland is crescent shaped They may sit either immediately superior to kidney, capping the upper pole, or superio-medially to upper pole, cradled by kidney just above renal vessels. 19. Anatomy Relations Located within Gerota fascia at level of 11th and 12th ribs Gerotas fascia connects them to upper pole of kidney Located cephalad to upper pole of kidneys and anterior to crus of diaphragm The right adrenal gland tends to lie more cephalad than the left adrenal gland Right adrenal is bounded Anteriorly = Liver Posterior = Diaphragm Superior = Diaphragm Inferio-laterally = Right Kidney Medially = IVC Medial aspect of the gland is often retrocaval Right adrenal vein enters IVC in a posterolateral position 20. Left adrenal gland is bounded Anteriorly = Stomach, Pancreas (Body), Splenic Vessels Posteriorly = Diaphragm Superiorly = Spleen Inferiorly = Kidney Medially = Aorta Left adrenal is more elongated than right and will lie in a more superomedial position to the kidney. This tends to place the gland closer to the left renal hilum, and these structures must be accounted for during dissection. Close juxtaposition of these organs to adrenal explains why lesions of adjacent organs, such as leiomyomas of greater curvature of stomach, may be confused for an adrenal mass. 21. Left AdrenalRight Adrenal 22. Blood supply Arterial Supply Receives blood @ 7cc/gm/min 3 arterial sources of flow: (IPS-ARMI) Branches from Inferior Phrenic Artery Superior Adrenal A. Direct visceral branches from Aorta Middle Adrenal A. Branches from I/L Renal Artery Inferior Adrenal A. The main adrenal arteries branch to form a subcapsular plexus From subcapsular plexus Some branches continue directly to medulla Others form sinusoids to cortex 23. Venous Drainage: Medullary veins coalesce to form adrenal vein Adrenal vein is surrounded by medullary tissue within the gland. Single main vein on each side Most important surgical structure Right adrenal vein Short Drains directly into post IVC Left adrenal vein Long as compared to right adrenal vein Joined by Inferior Phrenic vein prior to draining into Left Renal Vein The overlapping of both arterial and venous anatomy makes partial adrenalectomy possible with little risk of subsequent adrenal infarction 24. Blood Supply 25. Nerve Supply Sympathetic Medulla Preganglionic sympathetic fibers from sympathetic trunk directly to chromaffin cells Cortex Postganglionic fibers from splanchnic ganglia Parasympathetic to adrenal cortex and medulla Not well defined Branches from Vagus nerve may be present 26. Lymphatics Right Para-caval Lymph Nodes Left Para-aortic Lymph Nodes ?lateral aortic 27. Histology 28. Is divided into 3 zones in the adult gland: Zona Glomerulosa Zona Fasciculata Zona Reticularis Is divided onto 4 zones in the fetal gland: The three zones of the permanent adult cortex constitutes only 20% of the fetal glands size. The remaining zone (fetal cortex) comprises up to 80% of glands size during fetal life. Histology 29. Histology Each adrenal gland is enclosed within a fibrous capsule Directly beneath the capsule is the cortex, which comprises three zones: Zona Glomerulosa (Outermost Layer) Small polyhedral cells with scant eosinophilic cytoplasm and dark round nuclei. Zona Fasciculata Broad layer of large pale cells arranged in vertical columns beneath glomerulosa Zona Reticularis (Innermost layer) Round dark staining cells 30. Adrenal Histology Capsule Glomerulosa Fasiculata Reticularis Medulla 31. Layers of Adrenal Gland 32. Adrenal Physiology 33. Adrenal Cortex Endocrine Medulla Neurocrine 34. Adrenal Glands Divided into two parts; each with separate functions Adrenal Cortex Adrenal Medulla 35. Adrenal Physiology - Cortex 36. Adrenal Cortex: Steroid Hormone Production The cortex is divided into three regions: Zona Glomerulosa Zona Fasciculata Zona Reticularis Hormones produced by the adrenal cortex are referred to as corticosteroids. These comprise Mineralocorticoids (Aldosterone) Glucocorticoids (Cortisol) Sex hormones (Androgens) Synthesized from cholesterolsteroid ring 37. Adrenal Cortex Zona Glomerulosa: Mineralocorticoids Zona Fasciculata: Glucocorticoids Zona Reticularis: Androgens Medulla 38. Outermost Innermost 39. Hormones of the Adrenal Cortex All adrenal cortex hormones are steroid Not stored, synthesized as needed O HO O C = O HO OH CH2OH testosterone cortisol 40. Common precursor = Cholesterol Low-density lipoprotein (LDL) serves as primary source of cholesterol to adrenals Steroid hormone receptors are absent on cellular membranes of target tissues. Instead, steroids diffuse passively into cell bind to their respective receptors intracellularly direct binding of hormone receptor complex to target DNA Gene transcription is modulated. Ratios and types of enzymes in each zone of the adrenal cortex vary, resulting in different hormonal products for each region Mineralocorticoids (ZG) = 100 to 150 mcg/d Glucocorticoids (ZF) = 10 to 20 mg/d Androgens (ZR) = >20 mg/d 41. Zona Glomerulosa (ZG) Outermost region of adrenal cortex - just below the adrenal capsule Secretes Mineralocorticoids. The naturally synthesized Mineralocorticoid of most importance is Aldosterone. Aldosterone = 10 human Mineralocorticoid Only zone of adrenal gland that contains enzyme Aldosterone synthase (CYP11B2). As a result sole source of Aldosterone Mineralocorticoids are aptly termed as they are involved in regulation of electrolytes in ECF. 42. Zona Fasciculata (ZF) Middle zone between the glomerulosa and reticularis Site of Glucocorticoid production due to expression of 17-hydroxylase, 21 hydroxylase, and 11-hydroxylase enzymes Primary secretion is Glucocorticoids. Glucocorticoids, as the term implies, are involved the increasing of blood glucose levels. However they have additional effects in protein and fat metabolism. Cortisol = 10 Glucocorticoid in humans Its secretion is under tight control of ACTH. Production of cortisol by adrenal follows a strict circadian schedule. Majority of cortisol is secreted in the early morning Glucocorticoids are essential to life and modulate complex physiologic pathways that include metabolism, immunity, maintenance of intravascular volume, regulation of blood pressure, and complex modulation of CNS with significant effects on mood, sleep, and potentially memory Cortisol and ACTH are a part of a classic hormonal negative feedback system that features hypothalamus, pituitary gland and adrenal. Some androgen synthesis also occurs in zona fasciculata 43. Zona Reticularis (ZR) Innermost zone of adrenal cortex between fasciculata and medulla Primary secretion is androgens. Presence of 17-hydroxylase and 17,20-lyase production of Dehydroepiandrosterone (DHEA), sulphated DHEA (DHEA-S) and Androstenedione Adrenal Androgens exhibit ~ same effects as male sex hormone (testosterone). Adrenal Androgen secretion appears to be under control of ACTH, and, like cortisol, exhibits circadian patterns DHEA, DHEA-S, and Androstenedione comprise the greatest portion of steroid hormone that is produced by the adrenals (>20 mg/day), but appear to be the least important for adult physiologic homeostasis However, pharmacologic manipulation of adrenal androgen production remains a viable and increasingly targeted strategy for advanced prostate cancer NB.: Overlap in secretions of Androgens and Glucocorticoids exist b/w ZF and ZR 44. Steroid Biosynthesis ACTH Cholesterol Progesterone Pregnenolone Corticosterone DOC 18-OH-Corticosterone Aldosterone StAR, 20,22-desmolase 3HSD 21-hydroxylase 11-hydroxylase 18-hydroxylase 18-oxidase 17-OH-Pregnenolone 17-OH-Progesterone DHEA Androstenedione 17-hydroxylase 17-hydroxylase 3HSD Testosterone Estrone Estradiol aromatase aromatase 17HSD 17HSD 3HSD 17,20-lyase 17,20-lyase 11-deoxycortisol Cortisol 21-hydroxylase 11-hydroxylase 45. Adrenal Cortex: Steroid Hormone Production 46. Adrenal Physiology - Medulla 47. Adrenal Medulla Adrenal medulla comprises less than 10% of total adrenal mass. Embryologically derived from pheochromoblasts (Neuroectoderm) Differentiate into modified neuronal cells More gland than nerve Chromaffin cells Functions of Adrenal Medulla It is an integral part of autonomic nervous system (extension of Sympathetic NS) Acts like sympathetic ganglion (Acts as a peripheral amplifier) Activated by same stimuli as the sympathetic nervous system (examples exercise, cold, stress, hemorrhage, etc.) Chromaffin cells of medulla are innervated by preganglionic sympathetic fibers of T11 to L2, making them analogous to cells of the sympathetic ganglia. 48. Medulla secretes Epinephrine (80%) Norepinephrine (19%) Dopamine (1%) These substances, collectively known as catecholamines, are produced from the amino acid tyrosine and modulate the systemic stress response. Hormones are secreted and stored in medulla and released in response to appropriate stimuli Effects of these catecholamines are mediated through their binding to Adrenoreceptors located on target organs. The nature of these effects depend on the adrenoreceptor subtypes located and stimulated on a particular end organ Enzyme phenylethanolamine-Nmethyl transferase (PNMT), which catalyzes the conversion of norepinephrine to epinephrine, is relatively unique to the adrenal medulla (the brain and organ of Zuckerkandl also express this enzyme). 49. The function of this enzyme is potentiated by the presence of Glucocorticoids, thereby creating one of the few physiologic links between the adrenal cortex and the medulla. Localization of PNMT to the adrenal medulla explains why the gland is the primary source of systemic epinephrine, despite the presence of similar chromaffin cells elsewhere in the sympathetic nervous system Similar to the physiology that controls norepinephrine release at synaptic nerve terminals, the storage and release of adrenal catecholamines involves intracellular vesicles. Liberation of these vesicles through exocytosis results in release of adrenal catecholamines into the blood stream Majority of adr catecholamine metabolism occurs at site of production 50. Important for clinical purposes : 3 metabolites Metanephrine Normetanephrine Vanillyl Mandelic Acid 2 enzymes Catechol-O-Methyl Transferase (COMT) Mono Amine Oxidase (MAO) Methylation of Epinephrine by COMT = Metanephrine Methylation of Norepinephrine by COMT = Normetanephrine 51. COMT: Large amounts present in the liver and kidneys Majority of adrenal catecholamine metabolites are methylated by COMT within the cells of the adrenal medulla > 90% of Metanephrine and ~ 20% of normetanephrine in blood stream are derived from the adrenal medulla. Therefore a measurable rise in the level of these metabolites is very useful when diagnosing potential pheochromocytoma. In the urine, the majority of these metabolites are excreted in a sulfonated form. MAO: MAO and other enzymes subsequently convert catecholamine metabolites to VMA VMA is the primary catecholamine metabolic end product VMA is largely formed by liver Nonadrenal catecholamines from sympathetic nervous system are also similarly converted to VMA 52. Detailed Physiology Hormones of Cortex 53. Aldosterone Exclusively synthesized in ZG Essential for life Functions of Aldosterone Regulates electrolyte metabolism by stimulating epithelial cells of distal nephron to reabsorb Na+ and Cl, while secreting H+ and K+ Promotes Sodium retention and Potassium elimination by kidney Expands ECF volume Aldosterone exerts the 90% of the Mineralocorticoid activity. Cortisol also have Mineralocorticoid activity, but only 1/400th that of Aldosterone Aldosterone increases renal tubular (principal cells) reabsorption of sodium & secretion of potassium Although Aldosterone levels have a profound effects on total body Na+, concentration of the ion does not change, whereas reabsorption of sodium is accompanied by reuptake of free water. Therefore Aldosterone primarily affects total body volume and not sodium concentration 54. Aldosterone Functions contd.. Excess Aldosterone ECF volume & arterial pressure, but has only a small effect on plasma sodium concentration Excess Aldosterone causes hypokalemia & muscle weakness, & too little Aldosterone causes hyperkalemia & cardiac toxicity Excess Aldosterone increases tubular (intercalated cells) hydrogen ion secretion, with resultant mild alkalosis Electrolyte balance in epithelial cells of the submaxillary salivary glands and the large intestine are also under Mineralocorticoid control (? physiologic importance) Aldosterone stimulates sodium & potassium transport in sweat glands, salivary glands, & intestinal epithelial cells 55. a steroid hormone essential for life (acute) responsible for regulating Na+ reabsorption in the distal tubule and the cortical collecting duct target cells are called principal (P) cell stimulates synthesis of more Na/K-ATPase pumps Renal and circulatory effects covered (ECF volume regulation, sodium and potassium ECF concentrations) Promotes reabsorption of sodium from the ducts of sweat and salivary glands during excessive sweat/saliva loss. Enhances absorption of sodium from the intestine esp. colon. absence leads to diarrhea. 56. Mechanism of Action of Aldosterone 57. Mechanism of Action of Aldosterone 58. Regulation of Aldosterone secretion: Primarily regulated by Angiotensin II through Renin-angiotensin-aldosterone system (RAAS) Directly by serum potassium levels Primary stimulus for release of Aldosterone is Angiotensin II Other: ACTH, low serum Na, elevated K, JGA via low kidney perfusion Rise in ACTH can also increase Aldosterone (much less potent stimulus). For this reason ZG is the only region of cortex that does not atrophy upon pituitary failure Inhibitory regulators: ANP = main inhibitor, providing an imp link b/w cardiac, adrenal and renal function Somatostatin, dopamine, and others may also play a role Aldosterone 59. Regulation of Aldosterone Release Direct stimulators of release Increased extracellular K+ Decreased osmolarity ACTH Indirect stimulators of release (RAAS) Decreased blood pressure Decreased macula densa blood flow 60. Regulation of Aldosterone Secretion 61. Figure 6.12b 62. Atrial natriuretic peptide Decreased blood pressure stimulates renin secretion 63. RAA Axis Principal factor controlling Angiotensin II levels = Renin Decreased circulating volume stimulates Renin release via: Decreased BP (Symp effects on JGA). Decreased [NaCl] at macula densa (NaCl sensor) Decreased renal perfusion pressure (renal baroreceptor) 64. Renin Aldosterone Adrenal cortex Corticosterone Angiotensinogen (Lungs) renal blood flow &/or Na+ ++ Juxtaglomerular apparatus of kidneys (considered volume receptors) Angiotensin I Converting enzymes Angiotensin II (powerful vasoconstrictor) Angiotensin III (powerful vasoconstrictor) Renin-Angiotensin System: N.B. Aldosterone is the main regulator of Na+ retention. 65. RAA Axis 66. Pathway of RAAS 67. Renin-angiotensin system 68. Renin-Angiotensin-Aldosterone System 69. Na+ Reabsorption Angiotensin II can raise blood pressure by: Vasoconstrictor effects Stimulating Aldosterone secretion 70. nephron low Blood Osmolarity blood osmolarity blood pressure ADH increased water reabsorption increase thirst renin increased water & salt reabsorption high pituitary angiotensinogen angiotensin nephronadrenal gland aldosterone JuxtaGlomerular Apparatus (JGA) Ooooooh! Zymogen! 71. Aldosterone: Role in Diseases Complete failure to secrete Aldosterone leads to death (dehydration, low blood volume). Hyperaldosterone states: Contribute to hypertension associated with increased blood volume. 72. Glucocorticoids - Cortisol 73. Cortisol Glucocorticoids (including cortisone and cortisol) Steroid hormone Plasma bound to corticosteroid binding globulin (CGB) or transcortin Essential for life (long term) The net effects of cortisol are catabolic Prevents against hypoglycemia Produced in the middle layer of the adrenal cortex Promote normal cell metabolism Help resist long-term stressors Released in response to increased blood levels of ACTH 74. Physiological Actions of Cortisol Promotes Gluconeogenesis Promotes breakdown of skeletal muscle protein Enhances fat breakdown (Lipolysis) Suppresses immune system Breakdown of bone matrix (high doses) Anti-inflammatory Effects of Cortisol Reduces phagocytic action of white blood cells Reduces fever Suppresses allergic reactions Wide spread therapeutic use 75. Effect on Blood Cells and Immunity Decrease production of eosinophils and lymphocytes Suppresses lymphoid tissue systemically therefore decrease in T cell and antibody production thereby decreasing immunity Decrease immunity could be fatal in diseases such as tuberculosis Decrease immunity effect of cortisol is useful during transplant operations in reducing organ rejection. Effect of cortisol on protein metabolism Reduction of protein storage in all cells except those of liver protein catabolism & protein synthesis Cortisol increases liver & plasma proteins Mobilizes amino acids from non hepatic cells, thus increase blood amino acid level. amino acid transport to liver cells & transport of amino acids into other cells Physiological Actions of Cortisol 76. Permissive Effects of Cortisol on Development Cortisol is required for normal development Permissive role in final maturation of many organs Required for synthesis of digestive enzymes, surfactant Required for skeletal growth in children Body Responses to Stress Permissive effect on glucagon Memory, learning and mood Gluconeogenesis Skeletal muscle breakdown Lipolysis, calcium balance Immune depression Circadian rhythms Physiological Actions of Cortisol 77. Cortisol and Chronic Stress Prolonged exposure to high cortisol levels can lead to break down of muscle, excessive epinephrine release, hyperglycemia, weakening of bone, destruction of the immune system, inhibition of reproductive function, and other complications. Physiological Actions of Cortisol 78. Mechanism of Cortisol Action The actions of cortisol are mediated through the Glucocorticoid receptor. Intracellular receptor in steroid receptor superfamily Stimulates transcription of target genes by interaction of bound receptor with GRE in 5 flanking region. Inhibits transcription of some genes by interaction of receptor with AP1 (jun/fos dimer), decreasing AP1-mediated gene expression. GRcortisol AP1 AP1 site transcription 79. Mechanisms of Cortisol Action Hormone Effects on Gene Activity 80. Cortisol release is regulated by ACTH Release follows a daily pattern circadian Negative feedback by cortisol inhibits the secretion of ACTH and CRH Enhanced release can be caused by: Physical trauma Infection Extreme heat and cold Exercise to the point of exhaustion Extreme mental anxiety Regulation Of Cortisol Secretion 81. Cortisol Levels as per Circadian rhythm 82. Regulation Of Cortisol Secretion 83. Regulation Of Cortisol Secretion HYPOTHALAMUS CRH ANTERIOR PITUITARY ACTH ADRENAL CORTEX TARGET ORGANS CORTISOL STRESS DIURNAL RHYTHM + + - - INCREASED BLOOD GLUCOSE BLOOD AA BLOOD FATTY ACIDS 84. Regulation Of Cortisol Secretion 85. Control of Cortisol Secretion: Feedback Loops External stimuli Hypothalamic Anterior Pituitary Adrenal cortex Tissues 86. Cortisol: Role in Diseases and Medication Use as immunosuppressant Hyperimmune reactions (bee stings) Serious side effects Hypercortisolism (Cushing's syndrome) Tumors (pituitary or adrenal) Iatrogenic (physician caused) Hypocortisolism (Addison's disease) 87. Cortisol In Stress 88. The General Adaptation Syndrome 89. The General Adaptation Syndrome 90. The General Adaptation Syndrome 91. Detailed Physiology Medulla 92. Catecholamine Synthesis Tyrosine Dihydroxyphenylalanine Dopamine Norepinephrine Epinephrine tyrosine hydroxylase L-aromatic amino acid decarboxylase dopamine-B-hydroxylase phenylethanolamine-N-methyltransferase 93. Mechanism of Action receptor mediated adrenergic receptors peripheral effects are dependent upon the type and ratio of receptors in target tissues Receptor Norepinephrine +++++ ++ Epinephrine ++++ ++++ Relative effects of epinephrine and norepinephrine on and adrenergic receptors. Guyton 94. Differences between Epinephrine and Norepinephrine Epinephrine >> norepinephrine in terms of cardiac stimulation leading to greater cardiac output ( stimulation). Epinephrine < norepinephrine in terms of constriction of blood vessels leading to increased peripheral resistance increased arterial pressure. Epinephrine >> norepinephrine in terms of increasing metabolism Epi = 5-10 x Norepi. = 100% normal 95. Effects of Epinephrine Gets you ready to fight or run Heightens your senses, tenses your muscles, openings breathing passages, etc. In response to stress Take less than 30 seconds to kick in and last several minutes 96. Effects of Epinephrine metabolism - glycogenolysis in liver and skeletal muscle - mobilization of free fatty acids - increased metabolic rate can lead to hyperglycemia O2 consumption increases 97. Adrenal Medulla: Modified Sympathetic Ganglion Sympathetic stimulation Catecholamine release to blood Epinephrine Norepinephrine Travel to: Multiple targets Distant targets 98. Adrenal Medulla: Modified Sympathetic Ganglion 99. Mechanism: Norepinephrine Release and Recycling 100. Review of Efferent Pathways: Motor and Autonomic 101. Catechalomines: Activity Stimulates the fight or fight reaction Increased plasma glucose levels Increased cardiovascular function Increased metabolic function Decreased gastrointestinal and genitourinary function 102. Activity of Epinephrine