Steroid

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  • Steroid

    1. 1. Steroid hormones by Henry Wormser, Ph.D.
    2. 2. Hormones (introduction) • hormones are chemical messengers that transport signals from one cell to another • there are 4 major chemical classes of hormones – steroid hormones - i.e. progesterone – peptide hormones - i.e. insulin – amino acid derivatives - epinephrine – prostaglandins and related compounds
    3. 3. Three major functional types of hormones • endocrine • example: steroid hormones • paracrine • example: prostaglandins • autocrine • example: interleukin-2
    4. 4. General characteristics of hormones • hormones are required in very small quantities – example 1 molecule of epinephrine --- 1x1011 molecule of glucose • they are degraded very rapidly, thus are very difficult to study • concentrations vary from 10-6 to 10-12 M • from 1 ton of bull testis --- 270 mg of testosterone • modern analytical techniques and chemical synthesis are very important
    5. 5. Steroid Hormones • Steroid hormone biosynthesis • common precursor is cholesterol • first step is degradation of side chain via desmolase and formation of pregnenolone (C21) • pregnenolone can then follow several pathways: – It can be converted to progesterone which can be converted into gluco and mineralocorticoids, C21 (in the adrenal cortex) – It can also be converted through several steps into testosterone (C19) which in turn can be aromatized into estradiol (C18)
    6. 6. Model of steroid hormone action
    7. 7. Steroid hormone receptor structure SH SH SH SH SH HS SH SH SH SH Zn Zn DNA BINDING SITE HORMONE BINDING SITE COOH "ZINC FINGERS" H3N TRANSCRIPTIONAL ACTIVATION ELEMENT
    8. 8. Steroid hormone classes • glucocorticoids • mineralocorticoids • androgens • estrogens • progestins • vitamin D
    9. 9. ADRENOCORTICALADRENOCORTICAL HORMONESHORMONES
    10. 10. Adrenal cortex Composed of 3 layers (zones) • outer zone (zona glomerulosa) – produces aldosterone (mineralocorticoid) • middle zone (zona fasciculata) – produces cortisol (glucocorticoids) • inner zone (zona reticularis) – produces corticosterone and androgens
    11. 11. Major functions of adrenal steroids • Glucocorticoids – increases gluconeogenesis – increases glycogenesis – increases protein catabolism – decreases antibody response – antiinflammatory response – antineoplastic response • Mineralocorticoids – increase sodium and water retention – promote potassium loss
    12. 12. ACTH (adrenocorticotropic hormone) • Single polypeptide chain: 39AA (M.W. 3500) • produced by basophilic cells of adenohypophysis • AA 1 thru 24; needed for full activity • AA 25 - 33: species differences and immunologic specificity • AA 34 - 39 sequence common to all species • biological half-life is ~ 10 min. • controlled by CRH (corticotropin releasing hormone) from hypothalamus
    13. 13. ACTH products • used mainly for diagnostic purposes • limited therapeutic value in conditions responsive to corticosteroids • products: • Corticotropin Injection (Acthar) • Repository corticotropin injection (H.P. Acthar Gel) • Cosyntropin (Cortrosyn)
    14. 14. Actions of ACTH on adrenal cortex • increase in adrenal weight • decrease in adrenal lipids • decrease in adrenal cholesterol • decrease in adrenal ascorbic acid • increase in protein synthesis (enzymes which hydroxylate steroids) • increase in oxidative phosphorylation • increase in rate of glycolysis
    15. 15. GLUCOCORTICOIDS • synthesized from cholesterol • to pregnenolone --------- progesterone -----------17-α−hydroxyprogesterone ------------------------11-deoxycortisol--------cortisol • requires hydroxylating enzymes • 21-beta hydroxylase • 17-alpha hydroxylase • 11-beta hydroxylase
    16. 16. CH3 CH3 H3C CH3 CH3 HO HH H CH3 CH3 H3C HO O CH3 CH3 H3C O O 3-β-hydroxysteroid dehydrogenase cholesterol pregnenolone progesterone P450scc common pathway
    17. 17. CH3 CH3 H3C O O progesterone CH3 CH3 O OHOCH2 desoxycorticosterone CH3 CH3 HOCH2 O O HO corticosterone 18-hydroxycorticosterone P45021 CH2 CH3 O CH2OHO HO HO CHO CH3 HOCH2 O O HO aldosterone P450aldo P450aldo P450aldo mineralocorticoid pathway
    18. 18. CH3 CH3 H3C O O CH3 CH3 H3C O O OH CH3 CH3 HOCH2 O O OH progesterone 17-α-hydroxyprogesterone 11-deoxycortisol CH3 CH3 HOCH2 O O HO OH cortisol P45021 P45011β P45017α PREGNENOLONE 17-α-HYDROXYPREGNENOLONE P45017α glucocorticoid pathway
    19. 19. CH3 CH3 H3C HO O pregnenolone CH3 CH3 H3C HO O ΟΗ 17-α-hydroxypregnenolone dehydroepiandrosterone CH3 CH3 HO Ο androstenedione CH3 CH3 O O P45017α P45017α 3β-HSD HYDROXYPROGESTERONE P45017α androgenic pathway
    20. 20. GLUCOCORTICOIDS • anti-inflammatory effect – effect on protein synthesis • inhibit protein-translation of inducible COX -II (which also inhibits PG and thromboxanes) • promote synthesis of lipocortins which inhibit phospholipase A2 (this inhibits production of arachidonic acid and hence prostaglandins and leukotrienes) – physiologic effects
    21. 21. GLUCOCORTICOIDS • antiinflammatory effects – physiologic effects • negative effect on lymphocytes, monocytes and macrophages • inhibit the release of IL-1, IL-2 and IL-6 and TNF-alpha • reduced migration of inflammatory cells to site of injury • decreased lymphocyte production • impairment of delayed-type hypersensitivity
    22. 22. GLUCOCORTICOIDS • permissive effects (glucocorticoids required for certain actions) – tissue effects • inhibit fibroblasts (connective tissue loss) • negative calcium balance (osteoporosis) • negative nitrogen balance (catabolism) • CNS: euphoria, behavioral changes, psychosis • GI: increase stomach acid and pepsin production • cardiovascular effects (inc. BP, heart rate) • uptake of fat by fat cells • gluconeogenesis • insulin release and glycogen deposition
    23. 23. Indications for systemic glucocorticoids • ophthalmic diseases • allergic conjunctivitis • keratitis • allergic corneal marginal ulcers • herpes zoster ophthalmicus • iritis and iridocyclitis • optic neuritis • retrobulbar neuritis
    24. 24. O CH3 CH3 CH2OH OH O HO H H H HYDROCORTISONE O CH3 CH3 CH2OH OH O HO H H H PREDNISOLONE GLUCOCORTICOIDS hydrocortisone is the most active natural glucocorticoid prednisolone is a delta-1 derivative with greater potency (made synthetically)
    25. 25. O CH3 CH3 CH2OH OH O HO F H H CH3 DEXAMETHASONE (DECADRON) O CH3 CH3 CH2OH OH O HO H H H OH TRIAMCINOLONE GLUCOCORTICOIDS these are synthetic glucocorticoid with more potent glucocorticoid activity
    26. 26. O CH3 CH3 CH2OCOCH2CH3 OCOCH2CH3 O HO Cl H H CH3 BECLOMETHASONE DIPROPIONATE (BECLOVENT, VANCERIL) O CH3 CH3 CH2OCOC(CH3)3 OH O HO Cl H H F CH3 CLOCORTOLONE PIVALATE (CLODERM) GLUCORTICOIDS
    27. 27. O CH3 CH3 CH2OH O O HO H H H O C CH3 CH3 DESONIDE (DESOWEN) O CH3 CH3 CH2OH O O HO F H H O C CH3 CH3 F FLUOCINOLONE ACETONIDE (SYNALAR) GLUCOCORTICOIDS used in dermatological preparations
    28. 28. O CH3 CH3 CH2OH O O HO F H H O AMCINONIDE (CYCLOCORT) O CH3 CH3 CH2OH O O HO F H H O C CH3 CH3 FLUNISOLIDE (NASALIDE) GLUCOCORTICOIDS
    29. 29. O CH3 CH3 CH2OCOCH3 CH3 O HO H H H OH F PARAMETHASONE ACETATE (HALDRONE) O CH3 CH3 CH2Cl OH O HO F H H CH3 CLOBETASOL (TEMOVATE) GLUCOCORTICOIDS
    30. 30. O CH3 CH3 CH2OCOCH3 O O HO H H H O C CH3 CH3 F FLUOCINONIDE (LIDEX) O CH3 CH3 CH2Cl O O HO Cl H H O O CH3 MOMETASONE FUROATE (ELOCON) GLUCOCORTICOIDS used in dermatological preparations
    31. 31. O CH3 CH3 H O HO F H OH F CH3 OH DIFLORASONE (PSORCON) O CH3 CH3 H O HO H H O Et O O OEt O PREDNICARBATE (DERMATOP)
    32. 32. O CH3 CH3 H O HO Cl H CH3 OH F CLOCORTOLONE (CLODERM) O CH3 CH3 H O HO H H CH3 CH3 CH3 RIMEXOLONE (VEXOL)
    33. 33. O CH3 CH3 S H O HO F H CH3 O CH2-F F C O Et FLUTICASONE PROPIONATE (CUTIVATE) HO O CH3 CH3 HH H O O Et O O Pr n O HYDROCORTISONE PROBUTATE (PANDEL)
    34. 34. O CH3 CH3 CH2OH O O HO H H H O C CH3 CH3 F FLURANDRENOLIDE (CORDRAN) O CH3 CH3 CH2OH H O HO H H CH3 DESOXIMETASONE (TOPICORT) GLUCOCORTICOIDS used in dermatological products
    35. 35. O CH3 CH3 CH2Cl O O HO F H H O C CH3 CH3 HALCINONIDE (HALOG) O CH3 CH3 CH2OCOC2H5 OCOC2H5 O HO H H H CH3 Cl ALCLOMETASONE DIPROPIONATE (ACLOVATE) GLUCOCORTICOIDS
    36. 36. O CH3 CH3 CH2F F O HO F H H O CH3 COC2H5 FLUTICASONE (FLONASE) O CH3 CH3 CH2OH O O HO H H H O C CH2CH2CH3 H BUDESONIDE (RHINOCORT) GLUCORTICOIDS used in inhalation products for asthma and allergies
    37. 37. O CH3 CH3 O O O H H H Cl OEt O HO LOPREDNOL ETABONATE (LOTEMAX, ALREX) this
    38. 38. Typical glucocorticoid inhalers
    39. 39. Products for enteric inflammations
    40. 40. Indications for systemic glucocorticoids • endocrine disorders • primary or secondary adrenocortical insufficiency • congenital adrenal hyperplasia • nonsuppurative thyroiditis • hypercalcemia associated with cancer • shock unresponsive to conventional therapy
    41. 41. Indications for systemic glucocorticoids • rheumatic disorders • rheumatoid arthritis • ankylosing spondylitis • acute and subacute arthritis • acute nonspecific tenosynovitis • collagen diseases • systemic lupus erythematosus • acute rheumatic carditis • systemic dermatomyositis
    42. 42. Indications for systemic glucocorticoids • allergic states • seasonal or perennial allergic rhinitis • bronchial asthma • contact dermatitis • atopic dermatitis • serum sickness • drug hypersensitivity reactions
    43. 43. Indications for systemic glucocorticoids • Dermatological diseases • pemphigus • bullous dermatitis herpetiformis • severe erythema multiforme (Stevens-Johnson) • exfoliative dermatitis • mycosis fungoides • severe psoriasis
    44. 44. Indications for systemic glucocorticoids • respiratory diseases • symptomatic sarcoidosis • berylliosis • disseminated pulmonary tuberculosis • pulmonary emphysema • aspiration pneumonitis • diffuse interstitial pulmonary fibrosis
    45. 45. Indications for systemic glucocorticoids • neoplastic diseases • leukemias and lymphomas in adults • acute leukemia of childhood • hematological disorders • idiopathic and secondary thrombocytopenia in adults • acquired (autoimmune) hemolytic anemia
    46. 46. Indications for systemic glucocorticoids • miscellaneous • ulcerative colitis (via rectal enemas) • trichinosis • dental inflammatory reactions • tuberculous meningitis
    47. 47. Indications for systemic mineralocorticoids • replacement therapy for primary and secondary insufficiency in Addison’s disease • treatment of salt-losing adrenogenital syndrome • most common agents: aldosterone, desoxycorticosterone and fludrocortisone (Fluorinef) (most commonly used)
    48. 48. Adrenocortical insufficiency • Acute adrenocortical insufficiency – adrenal crisis (Waterhouse-Friderichsen syndrome) • weakness, dehydration • abdominal pain, high fever • vomiting and diarrhea • low blood pressure and eosinophilia • increased skin pigmentation • low sodium, high potassium serum levels
    49. 49. Adrenocortical insufficiency • Chronic adrenocortical insufficiency – Addison’s disease • weakness and anorexia • nausea, vomiting and diarrhea • hypotension • sparce axillary hair • increased skin pigmentation of creases, nipples and pressure areas (due to ACTH production) • eosinophilia and lymphocytosis
    50. 50. Tests for adrenal insufficiency • ACTH test: • give ACTH and measure cortisol (helps to distinguish between primary and secondar adrenal insufficiency) • primary insufficiency: cortisol levels remain low • secondary insufficiency: cortisol levels increase • metyrapone test: • confirmatory test for secondary adrenal insufficiency • metyrapone inhibits 11-beta hydroxylation and thus cortisol synthesis • should result in high ACTH levels (if not, we know the problem is secondary)
    51. 51. Mineralocorticoid pathway cholesterol ----- pregnenolone -----progesterone --------11-deoxycorticosterone ------corticosterone --------aldosterone corticosterone and aldosterone both have mineralocorticoid activity, however are not used therapeutically Aldosterone is the most powerful agent
    52. 52. FLUDROCORTISONE C HF OH O H CH2OH O HO FLUDROCORTISONE (FLORINEF) a potent steroid with both glucocorticoid and mineralocorticoid activity. Used mainly for its mineralocorticoid activity in Addison’s disease dose: 0.1 mg 2- 7 X weekly
    53. 53. Adrenocortical overactivity • Cushing’s syndrome or adrenal hyperfunction • Cushing’s disease or pituitary basophilism – buffalo obesity (moon face and buffalo hump) – easy bruisability (ecchymoses) – purple striae – impotence or amenorrhea – osteoporosis – hypertension, glucosuria – low serum potassium – low eosinophils and lymphopenia
    54. 54. Toxicity of adrenocorticoids • pituitary-adrenal suppression (adrenal insufficiency) • fluid and electrolyte disturbances • hyperglycemia and glucosuria • increased susceptibility to infections • peptic ulceration • myopathy (weakness of muscles of arms and legs) • osteoporosis and vertebral compression fractures • posterior subcapsular cataracts
    55. 55. C C CH3 H2N NH2 CH3 O AMPHENONE B N C C N CH3 CH3O METYRAPONE glucocorticoid antagonists amphenone B block hydroxylation at 11, 17 and 21 position. metyrapone is more selective in blocking beta 11-hydroxylation at low doses. Used more commonly in testing adrenal function.
    56. 56. C CH H ClCl Cl Cl MITOTANE N C2H5 OO H NH2 AMINOGLUTETHIMIDE glucocorticoid antagonists mitotane and aminoglutethimide both interfer with the biosynthesis of glucocorticoids. Aminoglutethimide is also an aromatase inhibitor involved in estrogen biosynthesis
    57. 57. O O N NC O CH2 N Cl Cl N H H3C O KETOCONAZOLE (NIZORAL) O O S C CH3 O O HH H SPIRONOLACTONE (ALDACTONE) spironolactone is a mineralocorticoid antagonist ketoconazole is a non-specific inhibitor of adrenal and gonadal steroid biosynthesis
    58. 58. Mineralocorticoid receptor antagonists • compounds or drugs which interfer with the action of aldosterone • currently 2 such drugs are available in the U.S. : spironolactone (Aldactone) and eplerenone (Inspra) • other drugs: canrenone, potassium carenoate (not available in the U.S.)
    59. 59. SPIRONOLACTONE (Aldactone) • a competitive antagonist of aldosterone • action occurs in the distal portion of tubule • only effective if sufficient sodium reaches the distal tubule and if excess aldosterone is present • has demonstrated tumorigenic action in rodents; not humans • causes occasional hormonal problems, i.e. gynecomastia in males • has gradual onset; activity peaks in 2 - 3 days • 80% is metabolized to canrenone CH3 CH3 O O O SCOCH3
    60. 60. Spironolactone (Aldactone) • useful in patients with gout or diabetes, since it causes no hyperuricemia or impairment of glucose tolerance • do not administer potassium supplement - hyperkalemia • effective in the management of primary and secondary aldosteronism • dosage: 10 mg/day initially for edema; for essential hypertension: 100 - 400 mg • frequently combined with HCTZ ( Aldactazide)
    61. 61. Eplerenone • a selective aldosterone receptor antagonist (acts on the mineralocorticoid receptor) • chemical similarity to aldosterone • used in the management of hypertension
    62. 62. Eplerenone (Inspra) O O O CH3 CH3 O OEt O EPLERENONE (INSPRA)

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