74. Hormone synthesis in the adrenal cortex. The glucocorticoids: biosynthesis, regulation, effects. Adrenal cortex is vital for life!

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1 74. Hormone synthesis in the adrenal cortex. The glucocorticoids: biosynthesis, regulation, effects. Adrenal cortex is vital for life! 5 g each Zona glomerulosa : Mineralocorticoids ALDOSTERON Zona fasciculata: Glucocorticoids CORTISOL Zona reticularis: Androgens DEHYDROEPIANDROSTERONE-SULFATE 1

2 Biosynthesis of mineralocorticoids plasma LDL synthesis Desmolase Cholesterol 17-OH-ase 17,20-lyase 17-HSDH Pregnenolone 17-OH-pregnenolone Androstanedione 3-HSDH Progesterone 17-OH-progesterone Androstenedione Testosterone 21-OH-ase 11-OH-ase 11-deoxycorticosterone Corticosterone 11-deoxycortisol Cortisol aromatase Estrone Estradiol 18-OH-ase 18-HSDH 18-OH-costicosterone Aldosterone Synthesis: Smooth endoplasmic reticulum Mitochondria DHEAS = Dehydroepiandrosterone sulfate Enzymes: Cytochrome P450 Hydroxysteroid dehydrogenases Transport of adrenocortical hormones Aldosterone Free: 40% Transport proteins: -Albumin 40% -CBG 20% CBG: Corticosteroid-binding globulin (Transcortin) Hormone receptors MR: Mineralocorticoids GR: Glucocorticoids + membrane receptors 2

3 Hormone concentrations: Aldosterone: nmol/l Cortisol: nmol/l Kidney 11-DH: 11 β-hydroxysteroid dehydrogenase inactivation (Cortison) Licorice (glycyrrhizin) inhibits the enzyme Protein synthesis Effects Mechanism of action Kidney (distal tubule) Colon Sweat gland Salivary gland Bronchi H 2 O H 2 O Genomic and non-genomic effects! 3

4 Juxtaglomerular apparatus Regulation of aldosterone secretion ANGIOTENSIN III + plasma K + ACTH plasma Na Na ANGIOTENSIN II ANGIOTENSIN I converting enzyme (lung) + ZONA GLOMERULOSA ALDOSTERONE ANGIOTENSINOGEN renin EFFECT JUXTAGLOMERULAR APPARATUS MACULA DENSA Na + delivery to distal tubule β 1 -RECEPTORS Sympathetic activity Catecholamins RENAL VASCULAR BARORECEPTORS Pressure 4

5 Excess mineralocorticoid secretion: CONN s syndrome Plasma: Na + H 2 O K + H + hypertension escape phenomenon alkalosis, muscle weakness Aldosterone escape! (Effect of ANP) max. +15 % ECV Biosynthesis of glucocorticoids Desmolase Cholesterol 17-OH-ase 17,20-lyase 17-HSDH Pregnenolone 17-OH-pregnenolone Androstanedione 3-HSDH Progesterone 17-OH-progesterone Androstenedione Testosterone 21-OH-ase 11-OH-ase 11-deoxycorticosterone Corticosterone 11-deoxycortisol Cortisol aromatase Estrone Estradiol 18-OH-ase 18-OH-costicosterone 18-HSDH Aldosterone 5

6 Transport of adrenocortical hormones Aldosterone Cortisol Free: 40% 10% Transport proteins: -Albumin 40% 15% -CBG 20% 75% CBG: Corticosteroid-binding globulin (Transcortin) Effects of glucocorticoids physiological/pharmachological effects CORTISOL GLUCOSE AMINO ACIDS FREE FATTY ACIDS GLUCOSE PROTEIN SYNTHESIS PROTEOLYSIS GLUCONEOGENESIS LIPOLYSIS LIPOGENESIS MUSCLE PROTEIN GLUCOSE FAT MUSCLE TISSUE GLUCOSE LIVER FAT TISSUE inhibition of glucose transport Increased blood glucose concentration 6

7 Effects of glucocorticoids Anti-inflammatory effect Anti-allergic effect Immunosuppression Bone: inhibition of osteoblast activity osteoporosis Muscle: proteolysis Connective tissue: inhibition of collagen synthesis Gastric mucosa: secretion of HCl CNS: it modifies the excitability of neurons, emotions During fetal life: acceleration of the surfactant secretion in the lung Permissive action: e.g. for catecholamines (lipolytic effect, pressor response) Therapeutic use of glucocorticoids Paracrine effect of glucocorticoids on catecholamine secretion PNMT: phenylethanolamine n-methyltransferase 7

8 Selye János ( ) Stress General Adaptation Syndrome Stress is a condition experienced when demands exceed the resources the individual is able to mobilize. fear, depression, pain, hypoxia, infection, loss of blood, fever, hypoglycemia Cannon s fight or flight reaction Hypothalamus Sympathetic division of the autonomic nervous system Adrenal medulla CRH/ADH Pituitary ACTH Adrenal cortex Adrenaline Glucocorticoids Gonadotropin Releasing Hormone Regulation of glucocorticoid secretion selective? Exercise Stressors Cytokines Infection - CRH - ADH HYPOTHALAMUS (parvocellular neurons) negative feedback loop - ACTH ADENOHYPOPHYSIS ADRENAL CORTEX CORTISOL EFFECT 8

9 Effect of ACTH on the biosynthesis of cortisol StAR: steroidogenic acute regulatory protein sleep circadian rhythm normal acute stress chronic stress 9

10 Cushing s syndrome Prolonged increases in plasma glucocorticoids CUSHING S SYNDROME (stretch marks) Osteoporosis Gastric ulcer Androgens: Acne Hirsutism 10

11 Biosynthesis of androgens in the adrenal cortex Desmolase Cholesterol 17-OH-ase 17,20-lyase 17-HSDH Pregnenolone 17-OH-pregnenolone Androstanedione 3-HSDH Progesterone 17-OH-progesterone Androstenedione Testosterone 21-OH-ase 11-OH-ase 11-deoxycorticosterone Corticosterone 11-deoxycortisol Cortisol aromatase Estrone Estradiol 18-OH-ase 18-OH-costicosterone 18-HSDH Aldosterone DHEAS = Dehydroepiandrosterone sulfate Transport of adrenocortical hormones Aldosterone Cortisol Dehydroepiandrosterone Free: 40% 10% 7% Transport proteins: -Albumin 40% 15% 90% -CBG 20% 75% -GBG 3% CBG: Corticosteroid-binding globulin (Transcortin) GBG: Gonadal steroid-binding globulin 11

12 Addison s disease Adrenocortical insufficiency Addisonian crisis Stress tolerance level is very low 1. Pre-pro-opiomelanocortin (POMC) Signal peptide N-terminal fragment β-lipotropin γ-lipotropin β-endorphin ACTH - Adrenocorticotropic hormone MSH - Melanocyte-stimulating hormone 12

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