Control. Mineralocorticoids Glucocorticoids Weak Androgens. Progesterone, Estrogens. Androgens. Scheme

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1 Biosynthesis of Steroid Hormones Lipid hormones with intracellular receptors, ell-specific enzyme sortiment, N storage : acutely synthesized when needed Scheme ontrol Mineralocorticoids Glucocorticoids Weak Androgens Progesterone, Estrogens Androgens

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3 rutches for studying the reaction steps: 1, Structure of cholesterol with the numbering of -atoms 2, Most reactions are hydroxylations catalyzed by cytochrome-p450 isoenzymes, with the overall equation: NADPH + H Substrate-H NADP+ + H 2 + Substrate-H Intracellular localization: ER or Mitochondria 3, the other frequent reaction-type is oxidoreduction catalyzed by dehydrogenases using NAD+/NADH+H+ 4, cell-type cell-specific enzyme sortiment hormone end product? effects - regulation

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5 Just like you studied from Biotransformation

6 Isolated from Adrenal glands, hence the names

7 ytochrome P450 isoenzyme in the synthesis of steroid hormones gene loc. activities YP11A1 mito side-chain cleavage enzyme YP11B1 z. fasciculata and reticularis mito 11-Hase YP11B2 z.glomerulosa mito 11-Hase, 18- Hase/DH or aldo-synthase YP17A1 NT in z. glomerulosa ER 17-Hase +/- 17,20-lyase YP19A1 ER aromatase YP21A2 ER 21-Hase

8 holesterol Pregnenolone P450 scc Side chain cleavage enzyme D NADPH H D H A B 2 A B H cholesterol (27) H + H-H 2 -H 2-22H-cholesterol NADPH 2 H H NADPH H pregnenolone (21) + isocaproaldehyde Pregnenolon + Izokaproaldehid A H 2 H D 20, 22H-cholesterol B

9 holesterol Pregnenolone: Regulation LDL-cholesterol HDL-cholesterol mitochondrium cholesterol cholesterol holesterol ester + + P450scc pregnenolone camp + ATH (adrenal gland) LH (testis, ovary) X StAR Steroidogenic Acute Regulatory Protein congenital lipoid adrenal hyperplasia angiotensin II K + E (adrenal cortex, z.glomerulosa) a 2+ ic

10 Synthesis of steroid hormones in the adrenal gland P450c17 H P450c17 H NAD+ NADH pregnenolone Pregnenolon 3HSDH 17 hydroxylase 17,20 lyase H 17-Pregnenolon 17H-pregnenolone H H Dehidroepiandroszteron dehydroepiandrosterone (DHEA) P450c21 Progesteron progesterone 21 hydroxylase H 2 H 17-hidroxi-progeszteron 17H-progesterone H 2 H 4 -Androsztén-3,17-dion androstenedione H 11-deoxikortikoszteron 11deoxycorticosterone 11-deoxikortizol 11deoxycortisol

11 H 2 H H 2 H H P450c11 11-deoxikortikoszteron 11deoxycorticosterone 11hydroxylase H 2 H H 11-deoxikortizol 11deoxycortisol H H 2 H H P450c18 corticosterone kortikoszteron H 18hydroxylase/ dehydrogenase H 2 H H cortisol kortizol Encoded by YP11B1 in z. fasciculata und reticularis aldosterone Aldoszteron Encoded by YP11B2 only in z. glomerulosa

12 Synthesis of mineralocorticoids z. glomerulosa - YP11B2 encodes for an enzyme with all three activities of 11-Hase, 18- Hase/dehydrogenase aldosterone synthase - YP17A1 not expressed mitochondrium inner membrane cholesterol P450 scc pregnenolone corticosterone P D P cholesterol pregnenolone 3HSDH progesterone P deoxycorticosterone (D) ER surface aldosterone encoded by YP11B2 aldosterone

13 Synthesis of glucocorticoids and weak androgens z. fasciculata and reticularis - YP17A1 (17-hydroxylase/17,20 lyase) - YP11B1 (11-hydroxylase, only) mitochondrium inner membrane cholesterol P450 scc pregnenolone cholesterol pregnenolone progesterone D 17Hase 3HSDH P450c21 YP17A1 17 Hpregnenolone 17 Hprogesterone 11deoxycortisol ER surface 17,20lyase DHEA dehydroepiandrosterone androstenedione D P450c11 corticosterone corticosterone 11deoxycortisol cortisol cortisol encoded by YP11B1 z. fasciculata: 21Hase is preferred z.reticularis: 17,20lyase is preferred DHEAS: more water soluble, inactive produced only in z. reticularis

14 Aldosterone effects Receptor: mineralocorticoid receptor (steroid receptor type I) - intracellular localization - receptor activation modulates the gene expression of certain proteins - promiscuity - prereceptor specificity Target epithelial cells and effects Lumen Na+ K+ Na+ Na+ K+ K+ kidney: cortical collecting ducts ATPase Na+ K+ K+ Interstitial space Na+/K+ ATPase Na+ channel K+ channel number/activity increases Na+ reabsorption K+ secretion Intercalated cells in collecting ducts: H+ ATPase transcription increases H+ secretion ther epithelial cells (colon, excretory ducts of sweat gland and salivary gland) NS: salt craving

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16 Signs of excess aldosterone : hypertension low K+ (hypokalemia) low H+ (alkalosis) Signs of aldosterone deficiency: loosing salt and water elevated K+ (hyperkalemia) elevated H+ (acidosis)

17 Steroid receptors Steroid hormones are similar MR and GR are similar and promiscuous

18 Prereceptor specificity I plasma concentration (in relative units) mineralocorticoid activity aldosterone D corticosterone cortisol

19 Prereceptor specificity II Mineralocorticoid target cells: 11bH-steroid dehydrogenase 2 or: cortisol (active) corticosterone (active) cortisone (inactive) 11 dehydrocorticosterone (inactive) NAD + NADH+ H + BUT: aldosterone and D are not substrates! Deficiency R: licorice components may inhibit: AME (Apparent Mineralocorticoid Excess) hypertension, low K + but: low level of mineralocorticoids and cortisol/cortisone is elevated in urine Partial def. in essential hypertension, salt-sensitivity

20 ortisol (F) ortisone (E) interconversions: Prereceptor ligand metabolismus 11bHSDH2: Dehydrogenase - ortisol inactivation, ofactor: NAD+, ER cytosolic surface Epitelial MR target cells ER lumen cytosol 11bHSDH1: Reductase- ortisol activation, ofactor: NADPH+H+, ER luminal surface, Liver, Adipose tissue, Lung

21 Regulation of aldosterone secretion in glomerulosa cells N stores of aldosterone hypovolemia Na + neural system stress adenohypophysis K + E K + induced a 2+ influx renin-angiotensin system angiotensin II acetylcholine (ATH) MSH-peptides AT II receptor Ah receptor ATH receptor a 2+ a 2+ camp ANP cgmp atrial muscle cholesterol esterase activity, cholesterol transport into the mitochondrium, P450scc and P synthesis, mitochondrial NADPH hypervolemia aldosterone synthesis and secretion

22 Effects of cortisol carbohydrates: glucose oxidation gluconeogenesis (P, PEPK, gl-6-phosphatase, fru-1,6- bisphosphatase, ASAT) glycogen synthesis, liver glycogen pancreas: glucagon, insulin lipids: proteins: lipoprotein lipase hormone-sensitive lipase, plasma FFA distribution:omentum>retroperitoneum >abdominal wall >limbs mesenchymal cell adipocyte, and not osteoblast proteolysis (substrate for gluconeogenesis) others: immunosuppression RB count negative a2+ balance (absorption in intestine, excretion in kidneys ), osteoporosis impaired wound healing

23 Disease states Excess cortisol - ushing-syndrome impaired glucose tolerance/dm obesity of the visceral type muscle atrophy, thin limbs livid (purple) striae osteoporosis propensity for infections Lack of cortisol adrenal cortex insufficiency low blood pressure, dehydration, K+ increases, Na+ decreases impaired hair growth exhaustion

24 Regulation of cortisol secretion stress RH from hypothalamus adenohypophysis ATH (essential for the adrenal cortex) camp ATH receptor cholesterol esterase activity, LDL-cholesterol uptake, cholesterol transport into the mitochondrium, P450scc and P450 17, P450 21, P synthesis synthesis and secretion of cortisol Diurnal rhythm, ca 1 year hypothalamus RH rhythm eating habits light cycle and sleeping cycle vertebral rhythm, if constant ATH is added after removal of the hypophysis

25 ongenital adrenal hyperplasia defect in cortisol synthesis classical form is rare (1:14 000), but mild forms are more common (1: ) most frequent forms: partial or complete deficiencies of 21- hydroxylase (90%), or 11-hydroxylase no cortisol to suppress ATH secretion hyperplasia + production of excess androgens, starts in utero

26 ongenital adrenal hyperplasia II cholesterol * pregnenolone * 17H-pregnenolone progesterone 17H-progesterone 21Hase deficiency D corticosterone 17Hase deficiency hypertension DHEA androstenedione deoxycortisol 11bHase deficiency (YP11B1) cortisol no cortisol, no androgens def. i.u. sexual development def. i.u. sexual development aldosterone elevated ATH loosing salt