BIOSYNTHESIS OF STEROID HORMONES

Transcription

1 BIOSYNTHESIS OF STEROID HORMONES Sri Widia A Jusman Department of Biochemistry & Molecular Biology FMUI sw/steroidrepro/inter/08 1

2 STEROID HORMONES Progestins (21 C) Glucocorticoids (21 C) Mineralocorticoids (21 C) Androgens ( 19 C) Estrogens (18 C) sw/steroidrepro/inter/08 2

3 Steroid class Source Stimulated by Example Progestins Corpus luteum, placenta LH Progesterone Glucocorticoids Adrenal cortex ACTH Cortisol Mineralocorticoids Androgens Adrenalcortex (zona glomerulosa) Leydig cells (major) Adrenal cortex (minor) Angiotensin II, ACTH LH, ACTH Aldosterone Testosterone Estrogens Ovarian follicle FSH Estradiol sw/steroidrepro/inter/08 3

4 Synthesized from its precursor cholesterol, in adrenal cortex (mineralocorticoids, glucocorticoids, androgens) testes, ovaries ( sex hormones) skin, liver, kidney (calcitriol / vit D3)l Secreted from sites of synthesis transported to the target organ cross the cell membrane of target organ bind to specific receptors in cytoplasma or nucleus Transported in blood bound to globulin corticosteroid-binding globulin (CBG), sex hormonebinding globulin (SHBG) sw/steroidrepro/inter/08 4

5 Cholesterol for synthesis of steroid hormones Plasma cholesterol Synthesis in situ from acetyl CoA via mevalonate and squalene Cholesterol in adrenal is esterified and stored in cytoplasmic droplets Stimulation of adrenal by ACTH activated esterase free cholesterol is transported into mitochondria mitochondrial cytochrome P450 cleave the cholesterol side chain convert into pregnenolone sw/steroidrepro/inter/08 5

6 CH, AA Fatty acid Acetyl CoA Aceto acetyl CoA Statin - HMG CoA HMG CoA reductase Biosynthesis of cholesterol Mevalonate Squalene - Cholesterol Bile acid Cholesterol Bile acids Membrane structure Steroid hormones Vitamin D sw/steroidrepro/inter/08 6 Fig 1. Biosynthesis of cholesterol

7 Cleavage of the side chain of cholesterol involved sequential hydroxylation at C22 and C20 then followed by side chain cleavage give 21 C steroid All mammalian steroid hormones are formed from cholesterol via pregnenolone through a series of reaction in mitochondria or endoplasmic reticulum adrenal cells sw/steroidrepro/inter/08 7

8 ADRENAL STEROID HORMONES Mineralocorticoids Glucocorticoids Androgens sw/steroidrepro/inter/08 8

9 Cholesterol (C27) Pregnenolone (progestin)(c21) 17OH-Pregnenolone (C21) Progesterone (C21) 17OH-Progesterone (C21) Dehidroepiandrosterone (DHEA)(C19) Deoxycorticos terone (C21) Corticosterone (C21) 11Deoxycortisol (C21) Cortisol (C21) Androstenedione (C19) Aldosterone (C21) GLUCOCORTICOID ANDROGEN MINERALOCORTICOID Fig 2. Biosynthesis of adrenal steroid hormones sw/steroidrepro/inter/08 9

10 ANDROGEN SYNTHESIS Major androgen in adrenal cortex is DHEA Most of 17OH-pregnenolone followed the glucocorticoid pathway Adrenal androgen production increased markedly if glucocorticoid synthesis is impaired in adrenogenital syndrome (congenital adrenal hyperplasia) sw/steroidrepro/inter/08 10

11 Congenital adrenal hyperplasia Incidence 1/ Caused by deficiency of hydroxylases required for synthesis of glucocorticoid Glucocorticoid level are deficient ACTH release disinhibited causes adrenal hyperplasia and stimulation of desmolase overproduce of progestin - diverted into androgen synthesis The disorder produces ambiguous external genitalia in girls or pubertal precox in boys sw/steroidrepro/inter/08 11

12 Pituitary ACTH Cholesterol Progestin Side chain cleavage blocked Corticosteroid Androgen Fig 3. Overproduce androgen in congenital adrenal hyperplasia sw/steroidrepro/inter/08 12

13 Progestin Synthesis is initiated by side chain cleavage of cholesterol by mitochondrial desmolase produced pregnenolone converted to progesterone by microsomal and cytoplasmic enzyme Progesterone the major end product in corpus luteum & placenta Other endocrine gland convert pregnenolone & progesterone to other steroid hormones sw/steroidrepro/inter/08 13

14 Corticosteroids Distinguished from progestins by the presence of additional OH groups The OH groups are introduced by monooxygenase reaction The reaction require cytochrome P450 sw/steroidrepro/inter/08 14

15 ADRENAL ANDROGEN Adrenal androgen was synthesized from cleavage of 2 carbon side chain of 17-OHpregnenolone (C21) - forming 19 C adrenal androgen dehidroepiandrosterone (DHEA) a weak androgen Synthesis occurred in zona reticulata of adrenal cortex sw/steroidrepro/inter/08 15

16 DHEA converted to androstenedione another weak adrenal androgen Androstenedione were reduced forming testosterone primarily in extra adrenal tissues Androstenedione can be converted into estrogen in the peripheral tissues particularly in adipose tissue sw/steroidrepro/inter/08 16

17 Androgen also synthesized in the theca cells at the periphery of ovarian follicle Androstenedione produced by the adrenal cortex about 3 mg/day far less potent than testosterone but the major source of androgen activity in girls and women sw/steroidrepro/inter/08 17

18 Boys and men produce small amount of estrogen (65 ug of estrone from androstenedione; 45 ug of estradiol from testostesrone) catalyzed by aromatase In male - a small quantity of estradiol is synthesized in testes, but most estrogen produced in adipose tissue, liver, skin, brain Testosterone precursor of 2 other hormones DHT & estradiol sw/steroidrepro/inter/08 18

19 DHEA (C19) Androstenedione (C19) aromatase Testosterone ( C19) ANDROGEN Estrone (C18) Estriol (C18) aromatase Estradiol (C18) ESTROGEN Fig 3. Synthesis of estrogen from androgen sw/steroidrepro/inter/08 19

20 cholesterol pregnenolone progesterone DHEA androstenedione androstenediol Testosterone Estrone Dihydrotestosterone (DHT) Estriol Estradiol Fig 3. Major pathways for synthesis of gonadal steroids sw/steroidrepro/inter/08 20

21 TESTOSTERONE Synthesized in Leydig cells of the testes and ovary in response to LH The pathway of synthesis similar to synthesis in adrenal cortex Cholesterol pregnenolone OH-pregnenolone DHEA androstenedione testosterone In target cells: testosterone reduced into DiOHtestosterone (DHT) sw/steroidrepro/inter/08 21

22 ESTROGEN & PROGESTERONE Estrogen synthesized in the ovarian follicle & corpus luteum stimulated by FSH Women of reproductive age produce most of their estrogen in the granula cells of the ovarian follicle and the placenta during pregnancy Postmenopausal women still have estrone derived from the adrenal androgen androstenedione sw/steroidrepro/inter/08 22

23 In peripheral tissue - estrogens are synthesized from androgens In men aromatisation of testosterone estradiol - 80 % from this pathway In women adrenal androgens were the main substrate for synthesis of estradiol 50 % of estradiol in pregnant women produced from this pathway sw/steroidrepro/inter/08 23

24 Synthesis of estrone from androstenedione was the major pathway in post menopausal women Activity of aromatase was found in adipose tissue, liver and skin Increased activity of aromatase was found in estrogenisation in liver disease, aging and obesity sw/steroidrepro/inter/08 24