BIOSYNTHESIS OF STEROID HORMONES

DR. SUMREENA MANSOOR ASSISTANT PROF OF BIOCHEMISTRY

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Chemical nature of the adrenal hormones Outline the steps involved in steroid biosynthesis in adrenal cortex Transport of adrenocortical steroids Adrenocortical hormone metabolism

INTRODUCTION 
Introduction

Structure, Nomenclature, Synthesis  Adrenocorticoids Glucocorticoids, Mineralocorticoids  Male Sex Hormones Androgens  Female Sex Hormones Estrogens and Progestins
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Composed of 3 layers (zones) ` Outer zone (zona glomerulosa) produces aldosterone (mineralocorticoid) ` Middle zone (zona fasciculata) produces cortisol (glucocorticoids) ` Inner zone (zona reticularis) produces androgens (precursors DHEA. Androstenedione) .

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A SPECIAL NOMENCLATURE DESCRIBES THE CHEMISTRY OF STEROIDS  COMMON C-17 COMPOUND (CYCLOPENTANOPERHYDROPHENANTHREIN RING) .

STRUCTURES OF STEROIDS Structure and Nomenclature of the Steroid Nucleus CH 12 19 11 3 18 17 16 CH 3 1 2 C 13 D 8 14 15 7 A 3 4 10 5 9 B 6 MEDC 603 Steroids 4/6/2011 9 .

STRUCTURES OF STEROIDS Structure and Nomenclature of the Steroid Side-chain CH3 CH3 CH3 20 21 22 23 26 24 25 27 CH3 CH3 MEDC 603 Steroids 4/6/2011 10 .

 Additional carbons can be added at C-10. C-13 and side chain on C-17 Number bonds and location of double o o Methyl groups at C-10 and C-13 .

 Glucocorticoids (Cortisol C-21) (aldosterone C-21)  Mineralocorticoids  Androgens  (DHEA C-19) ALL THESE HORMONES ACT VIA GENE EXPRESSION AND REGULATE GLUCONEOGENESIS . Na+. K+ and H+ BALANCE .

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mineralocorticoids and androgens result into disease or serious life threatening complications . Glucocorticoids essential for adaptation to stress. Synthetic analogs are used as potent anti-inflammatory agents  Excessive or deficient plasma levels of these glucocorticoids.

estradiol. desoxy cholic acid.) MEDC 603 Steroids 4/6/2011 16 .) ormones (testosterone.CHOLESTEROL C C C 3 3 3 C C 3 3 O cholesterol liver various tissues Bile Acids (cholic acid. etc. etc. progesterone cortisol.

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GLUCOCORTICOID BIOSYNTHESIS .

SEVERAL ENZYMES ARE INVOLVED IN THE BIOSYNTHESIS OF ADRENAL STEROID HORMONES    Plasma cholesterol is the main precursor ACTH stimulated esterase release free cholesterol CHOLESTEROL TRANSPORTED TO INNER MITOCHONDRIAL MEMBRANE BY (STAR: STEROIDOGENIC ACUTE REGULATORY PROTEIN) AND UNDERGOES SEQUENTIAL HYDROXYLATIONS AT C-22 AND C-20 BY CYTOCHROME P-450 SIDE CHAIN CLEAVAGE enzymes(p-450scc)form PREGNANOLONE .

ADRENAL STEROID HORMONES  All mammalian steroids are formed from pregnanolone. in mitochondria and (SER) by following enzymes  Hydroxylases and NADPH  Dehydrogenases zona glomerulosa  Isomerase  Lyase .

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C-21 and C-11 positions First two reactions are rapid  . (cortisol C-21)  Only requires three hydroxylases for sequential addition of OH group on C-17.(Zona fasciculata).

HYDROXYLASE MITOCHONDRIA Cortisol .Cholesterol Mit.5 ISOMERASE Progesterone In Zona fasiculata Cytoplasmic 17 ±HYDROXYLASE (SER) Cytoplasmic 21 11 ±HYDROXYLAS (SER) . Scc enzyme Pregnenolone Cytoplasmic 3 -Of DH 4.

HYDROXYLASE MITOCHONDRIAL 11 MITOCHONDRIAL 18.HYDROXYLASE Aldosterone .5 ISOMERASE Progesterone In Zona glomerulosa Cytoplasmic 21 ±HYDROXYLASE .Cholesterol Mit. Scc enzyme Pregnenolone Cytoplasmic 3 -Of DH 4.

activated to turn on pathways Cholesterol Pregnenolone Progesterone Progesterone 21-hydroxylase 11-Deoxycortisone Aldosterone Progesterone 21-hydroxylase 11-Deoxycortisol Cortisol General pathways for the synthesis of aldosterone and cortisol in the adrenal cortex .

Scc enzyme Pregnenolone Cytoplasmic 17 ±HYDROXYLASE 17 -Hydroxypregnenolone Cytoplasmic 2C Side chain cleavage In Zona reticularis Dehydroepiandrosterone .Cholesterol Mit.

ANDROGEN SYNTHESIS DHEA acts as prohormone converted to testosterone (the most Potent androgen) .

Pregnenolone D EA Androstenedione Androstenedion Pathway for formation of androgens in the adrenal cortex. .

Cholesterol Progesterone Pregnenolone Androstenedione Progesterone Testosterone (pathway ends here in testes) Estrone (produced in both male and female adipose cells) Estradiol (pathway continues to here in ovaries) In obese men. overproduction of estrogen in fat cells can cause gynecomastia = excessive male breast development Pathways for the synthesis of testosterone (testes) and the estrogens estradiol (ovaries) and estrone (adipose cells) .

the adrenal gland requires cholesterol. which is then converted biochemically into steroid hormones. Interruptions in the delivery of cholesterol include Smith-LemliOpitz syndrome and abetalipoproteinemia. To form cortisol. .

` Congenital adrenal hyperplasia Most common in various forms: ` 3 -hydroxysteroid dehydrogenase .

Active androgen and estrogen  Salt excretion in urine  Female like genitalia  .3 -hydroxysteroid dehydrogenase No Glucocorticoids. Mineralocorticoids.

glucocorticoids and Corticosterone absent  Excessive Androgen masculinization of external genitalia .17 -hydroxylase  No sex hormone and Cortisol  Mineralocorticoids-----Hypertension  Female like genitalia 21-hydroxylase  Mineralocorticoids.

 11 -hydroxylase  Mineralocorticoids and glucocorticoids absent  Deoxycorticosterone causes fluid retention  Excessive Androgen masculinization of external genitalia .

` Autoimmune destruction of the adrenal cortex is cause by an immune reaction against the enzyme 21-hydroxylase .

rifampicin. phenytoin) .g.g.` Some medications interfere with steroid synthesis enzymes (e. while others accelerate the normal breakdown of hormones by the liver (e. ketoconazole).

excess Cortisol is produced by adrenal gland tumors. . or adrenal glands with nodular adrenal hyperplasia.. ` In adrenal Cushing's. hyperplastic adrenal glands.

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A.   Secretion of steroid hormones Little storage and released into plasma when made Cortisol release by ACTH release .

a. (i)   Plasma transport Glucocorticoids (Cortisol) Bound form with corticosteroid binding globulin (CBG) or called transcortin Much less is bound with albumin Half life (with transcortin) is 1.5±2 hours .B.

TRANSPORT AND METABOLISM OF ADRENAL STEROID (ii) Free form(8%) biologically active form b.    Mineralocorticoids(aldosterone) No specific transport protein Very weak association with albumin Corticosterone and 11deoxycortiscosterone bind with CBG Metabolism and excretion rates depend on the presence or absence of carrier proteins F .

Reduction of Cortisol (80%) and Corticosterone. 11 deoxycortisol (20%) to dihydro and tetrahydro metabolites .A. GLUCOCORTICOIDS (i).

(ii) (iii) (iv) (v) METABOLISM AND EXCRETION OF ADRENAL STEROID Conjugation with glucoronoid and sulfate These modifications take place in liver and convert these to water soluble compounds Most of these are reabsorbed by entero hepatic circulation All there are excreted via A. 70 % in urine B. 10 % via skin . 20 % in feces C.

Mineralocorticoids Excreted in urine very rapidly in the form of tetrahydroaldosterone & 3glucoronoid which are formed in liver Androgens DHEA and androstenedione as 17keto compounds .B. C.

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