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Hormones

Hormones. Biochemistry. Adrenal cortex. Glucocorticoids Mineralocorticoids Androgens Gluconeogenesis Na + and K + balance. Zona glomerolosa Mineralocorticoids Zona fasciculata with zona reticularis Glucocorticoids and androgens There is an overlap of biologic activity

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Hormones

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  1. Hormones Biochemistry

  2. Adrenal cortex • Glucocorticoids • Mineralocorticoids • Androgens • Gluconeogenesis • Na+ and K+ balance

  3. Zona glomerolosa • Mineralocorticoids • Zona fasciculata with zona reticularis • Glucocorticoids and androgens • There is an overlap of biologic activity • Commonality of the hormone response elements

  4. Glucocorticoids are 21 -carbon steroids • Predominant glucocorticoid • Mineralocorticoids are also 21 –carbon steroids • Primary action • Retention of Na+ and excretion of K+and H+ • 11 -deoxycorticosterone (DOC) • Aldosterone • Most potent Mineralocorticoid

  5. Androgens • Dehydroepiandrosterone • Major androgen or androgen precursor (DHEA) • Androstenedione • Certain cancers • Certain enzyme deficiencies • Extra-adrenal conversion • Peripheral aromatization • Androgens to estrogen • Postmenopausal women

  6. BIOSYNTHESIS OF ADRENAL STEROID HORMONES • From cholesterol • The steroid hormones • NOMENCLATURE • Common • 17-carbon cyclopentanoperhydrophenanthrene structure • Estrane ,18 carbons • Androstane 19 carbons • Pregnane, 21 carbons

  7. ANDROGEN SYNTHESIS

  8. Cortisol release occurs with a periodicity • Plasma Transport • Glucocorticoids • Protein-bound and free forms • Corticosteroid-binding globulin (CBG) • Albumin • Free fraction constitutes about 8% of the total • Mineralocorticoids • No transport protein • Weak association with albumin

  9. Metabolism and Excretion • Glucocorticoids • In plasma • 80% of the 17-hydroxycorticoids • Cortisol and its metabolites • About half • dihydro- and tetrahydro metabolites • Substantial amounts • Conjugation at the C3 position with glucuronide • water soluble

  10. Metabolism and Excretion • Excretion • Biliary • Urine (About 70% ) • Feces (About 20% ) • Skin

  11. Metabolism and Excretion • Mineralocorticoids • Aldosterone is very rapidly cleared • tetrahydroaldosterone 3—glucuronide • Androgens • DHEA (sulfate) ,androstenedione • Excreted as 17- keto compounds • Testosterone • androsterone and etiocholanolone

  12. Regulation of synthesis • Glucocorticoid Hormones • Cortisol , ACTH, CRH • feedback loop • Mineralocorticoid Hormones • Primary regulators • renin-angiotensin system • Baroreceptor and salt effects , postural effects • Potassium • Sodium, ACTH, and neural mechanisms

  13. Regulation of synthesis • Angiotensin II • Stimulate the conversion of • Cholesterol to pregnenolone • Corticosterone to 1 8-hydroxycorticosterone and aldosterone • Mediator • Calcium and of phospholipid metabolites

  14. METABOLIC EFFECTS • Increase glucose production • Gluconeogenesis • Delivery of substrate • Amount (and activity) of key enzymes • Glycogenesis • Activation of glycogen synthetase • Lipid metabolism • Promote lipolysis • in extremities • Lipogenesis • face and trunk

  15. METABOLIC EFFECTS • Protein and RNA metabolism • Anabolic effect at physiologic levels • Effects on host defense mechanisms • Suppress the immune response • Suppress the inflammatory response • Decrease circulating leukocytes • Decrease migration to the tissues • Blunt production of the potent inflammatory molecules • Prostaglandins and leukotrienes

  16. METABOLIC EFFECTS • Normal water and electrolyte balance • Restraining ADH release • Increasing angiotensinogen • Maintenance of normal blood pressure and cardiac output

  17. Mineralocorticoid Hormones • Electrolyte Balance and Ion Transport • Na+ retention • Secretion of K+, H+ and NH4+ • Mineralocorticoid Hormones • Include • Aldosterone (the most potent) • 11-deoxycorticosterone (DOC) • Cortisol or corticosterone

  18. The biologic effect depends on • Ability to bind to the receptor (affinity) • Concentration of free hormone

  19. Glucocorticoid Hormones Regulate Gene Expression • By binding to GRE & by forming HRU • Affect amount of critical proteins • Affect other steps in the “information flow” • Control of the rate of gene transcription • regulate the rate of degradation of specific mRNAs • Growth hormone • Phosphoenolpyruvatecarboxykinase) • Posttranslational processing

  20. Aldosterone action • By protein and RNA synthesis • Ion transport • Target Cells • Kidney • Parotid, and colon and other organs • the effective “free” concentration • Greater than corticosterone or DOC • Presence of 11 β-hydroxy steroid dehydrogenase in target tissue

  21. Aldosterone action • Aldosterone increases • Number of apical membrane Na+ channels • activity of several mitochondrial enzymes • Induction citrate synthase • Intracellular concentration of Na+ • Creates the energy source for removal of this ion through the serosal pump

  22. PATHOPHYSIOLOGY OF THE ADRENAL CORTEX • Glucocorticoid Hormone • Insufficiency • Excess • Primary adrenal insufficiency (Addison’s disease) • Hypoglycemia • Low blood pressure • Decreased glomerular filtration rate • Plasma Na+ levels are low • K+ levels are high

  23. PATHOPHYSIOLOGY OF THE ADRENAL CORTEX • blood lymphocyte and eosinophil counts are increased • Pigmentation of skin • Exaggerated ACTH • Secondary adrenal insufficiency • Deficiency of ACTH • Tumor, infarction, or infection • Like above ,without hyperpigmentation

  24. PATHOPHYSIOLOGY OF THE ADRENAL CORTEX • Glucocorticoid excess • Cushing’s syndrome • Pharmacologic use steroids • ACTH—secreting pituitary adenoma • adrenal adenomas • ectopic production of ACTH • Signs & symptoms • hyperglycemia or glucose intolerance • severe protein catabolic effects • thinning of the skin, muscle wasting • negative nitrogen balance • Osteoporosis

  25. PATHOPHYSIOLOGY OF THE ADRENAL CORTEX • Truncal obesity • hypernatremia, hypokalemia, alkalosis, edema, and hypertension

  26. PATHOPHYSIOLOGY OF THE ADRENAL CORTEX • Disorders of Mineralocorticoid Excess • Primary aldosteronism (Conn’s syndrome) • Manifestations • hypertension, hypokalemia, hypernatremia, and alkalosis • renin and angiotensin II levels are suppressed • Secondryaldosteronism • Renal artery stenosis • Decrease perfusion pressure • hyperplasia and hyperfunction of the juxtaglomerular cells • elevated levels of renin and angiotensin II

  27. PATHOPHYSIOLOGY OF THE ADRENAL CORTEX • Congenital Adrenal Hyperplasia • Enzyme Deficiency • deficiency of end products • accumulation of intermediates • exaggerated production of steroids from alternative pathways • Common Features • develop in utero • deficient cortisol production • ACTH overproduction • adrenal hyperplasia • Overproduction of adrenal androgens • adrenogenital syndrome (alternative designation)

  28. PATHOPHYSIOLOGY OF THE ADRENAL CORTEX • Causes • 21-hydroxylase deficiency • account for more than 90% of cases • 11β-hydroxylase deficiency • Most of the rest • Other deficiencies • 3β-hydroxysteroid dehydrogenase • 17α-hydroxylase • cholesterol desmolase • 1 8- hydroxylase, and 1 8-dehydrogenase • affect only aldosterone biosynthesis • do not cause adrenal hyperplasia

  29. Hormones of the gonads • The Testes cell types • Leydig cells (also called interstitial cells) • Produce testosterone in response to LH • Sertoli cells • Provide the environment • Seminiferous tubules • Produce Spermatozoa

  30. Synthesis of Gonadal Steroids • Critical Steps • Cholesterol Side-Chain Cleavage Enzyme • 3β-Hydroxysteroid Dehydrogenase • Precursor • Cholesterol • Rate—limiting step • Delivery of cholesterol to the mitochondria • by the transport protein (STAR)

  31. Regulation of synthesis • Through a feed back loop • Involves the pituitary and the hypothalamus

  32. Dihydrotestosterone (DHT) • Secretion from the testes • 50—100 µg of DHT per day • Peripheral Conversion • Most DHT • 17β-estradiol (E2) • By testes • Peripheral aromatization • From • Testosterone • Androstenedione

  33. The role of E2 • FSH regulation • Testosterone Binds to a Specific Plasma Protein • Albumin • Sex hormone- binding globulin (SHBG) • Testosterone-estrogen-binding globulin (TEBG) • Production • increased by • Estrogens, certain types of liver disease,hyperthyroidism

  34. Decreased by • Androgens, hypothyroidism • Free (biologically active) form • 1-3% • The primary function of SHBG • to restrict the free concentration • Increase of SHBG • aging, cirrhosis, and hyperthyroidism • Increased free E2: testosteronc ratio • Estrogenization • Gynecomastia

  35. The major steroid secreted by the adult testes • Testosterone • Released as it is produced • Testosterone is metabolized by two pathways • Oxidation at the 17-position • Produces 17-ketosteroids • Reduction of the A ring • Double bond • The 3-ketone • Produces DHT (target tissues) • Most significant metabolic product

  36. Active form of the hormone in • Prostate, external genitalia, and some areas of the skin • Plasma content of DHT • One-tenth that of testosterone • 400 µg of DHT is produced daily • 5 mg of testosterone produced daily

  37. Testosterone is a prohormone • Converted into • Dihydrotestosterone • Estradiol • in the brain • determine the sexual behavior • 17-ketosteroid metabolites • Androsterone • Etiocholanolone • Conjugated with glucuronide and sulfate

  38. Testosterone is Converted into • Dihydrotestosterone • Estradiol • 17-ketosteroid metabolites

  39. Regulation of Testicular Steroidogenesis • Steroidogenesis Is Stimulated by LH • Leydig cells • Membrane receptors • Adenylyl cyclase • cAMP • Cholesterol transport by STAR • Side chain cleavage by P450 scc • Testosterone • Feedback control • Inhibition of GnRH release

  40. Regulation of Testicular Steroidogenesis • FSH • Sertoli cells • Synthesis of androgen-binding protein (ABP) • Provides high concentration of testosterone to support spermatogenesis • FSH and androgens • Sertoli cells • Produce inhibin • Negative feedback • Regulate FSH secretion

  41. Androgens function • Major Androgens • Testosterone and DHT • Target cells for DHT • 5α-reductase activity • Prostate external genitalia, and genital skin • Targets for testosterone • Wolffian structures, spermatogonia, muscles, bone, kidney, and brain

  42. Mechanism of action • Testosterone or DHT ? • Affinity difference (for receptor) • ability of a target tissue to form DHT from testosterone • Nuclear localization • Binding of the receptor-steroid complex to chromatin • Androgen response element • activates specific genes • Increased accumulation of total cellular RNA, including mRNA, tRNA, and rRNA • Effects

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