OH

CH3

O

CH3

Dehidroepiandroszteron

O

CH3

O

CH3

4-Androsztén-3,17-dion

Petefészek -Stratum granulosum

Ösztradiol (E2)

Tesztoszteron

Androszténdion

OH

HO

Aromatáz

HO

O

Ösztron (E1)

Ösztriol

HO

HO

OH

Koleszterin

Petefészek -Stratum granulosum

Ösztradiol (E2)

Tesztoszteron

Androszténdion

OH

HO

Aromatáz

HO

O

Ösztron (E1)

Ösztriol

HO

HO

OH

Koleszterin

O

OH

O

OH

H

5 -reduktáz

NADPH

Tesztoszteron Dihidrotesztoszteron (DHT)

C

CH3

O

HO O

C O

CH3

O

C O

CH3

OH

C

CH3

O

HO

OH

HO

O

O

O

O

OH

HO

OH

17--hidrox iláz

C17,20-l iáz

17--hidrox isz teroid dehidrogenáz

Pregnenolon

17--hidroxi-pregnenolon

Dehidroepiandroszteron

5-Androszténdiol Tesztoszteron

Androszténdion

17--hidroxi-progeszteron

Progeszteron

dehydroepiandrosterone (DHEA)

androstenedione

estrone (C18) estradiol (C18)

testosterone 5

dihydrotestosterone

androstenediol

3OHSDH

aromatase

5 reductase

17OHSDH

Synthesis of sex steroids

NAD(P)H NAD(P)+

17-hydroxysteroid dehydrogenase enzymes

17OHSDH-I

Petefészek -Stratum granulosum

Ösztradiol (E2)

Tesztoszteron

Androszténdion

OH

HO

Aromatáz

HO

O

Ösztron (E1)

Ösztriol

HO

HO

OH

Koleszterin

Petefészek -Stratum granulosum

Ösztradiol (E2)

Tesztoszteron

Androszténdion

OH

HO

Aromatáz

HO

O

Ösztron (E1)

Ösztriol

HO

HO

OH

Koleszterin

NADPH+H+

NADP+

estrone estradiol

reductase in

cytosol

placenta, ovaries,

adipose tissue

17OHSDH-III

androstenedione testosterone

NADPH+H+

NADP+

reductase in

ER

testis 17OHSDH-II

estrone estradiol

androstenedione testosterone

NAD+ NADH+H+

oxidation=inactivation

in ER

liver, intestine, placenta

Testis, Leydig cell

- P450c17 (17-hydroxylase/17,20 lyase)

- 17-hydroxysteroid dehydrogenase : NAD(P)H, not a cytochrome P450!

- NO P45021

mitochondrium inner membrane

cholesterol

pregnenolone

ER surface

pregnenolone

progesterone

P450scc

3OHSDH

cholesterol

17 OH-

pregnenolone

17 OH-

progesterone

DHEA

androstenedione

P45017

testosterone

androstenediol

cAMP

17OHSDH

cholesterol ester

LH, hCG

receptor

5 reductase

testosterone

dihydrotestosterone

NADPH

+ H+

NADP+

5 reductase

in target cells, on ER surface

T,DHT induce its synthesis

testis

spermatogenesis

psychosexual identity

protein synthesis in the

muscle

male voice

male-type hair growth

androgen effects

male external organs

development and function of

the prostate

male-type hair growth

male-type baldness

- more efficient (binds to A receptor with higher affinity, DHT-

A receptor complex is a better inducer)

- no way back to estrogens

5 reductase deficiency

(pseudohermaphroditismus masculinus)

XY, testis

normal plasma T, but DHT , T/DHT ratio

female or mixed external sex organs the newborn is

considered as a girl

pubertal virilization diagnosis

Regulation of testosterone synthesis

Hypothalamus

Adenohypophysis

GnRH

FSH LH

Sertoli cell Leydig cell

inhibin testosterone

spermatogenesis

dihydrotestosterone

5 reductase

inhibitors

Pulsatile

secretion 10AAs,

t1/2=2-5 min Long-acting

GnRH analogues

P450c17 inhibitors

A receptor

antagonists

AR Biol. effects

Prostate cancer

1966 Nobel prize for castration therapy : practically

androgen withdrawal

If receptor-positive: hormone-therapy

-Inhibit steroid biosynthesis

-receptor antagonist

BUT: androgen antagonist therapy favors androgen-

independent tumor growth

Aromatase reaction

testosterone

estradiol

(C18)

C19 OHase X 2,

H2O leaves spontaneously

localization: sER

Ovaries (granulosa cells), Placenta,

adipose tissue, bones

3OHSDH

Ovaries – Two-cell theory

- P450c17 (17-hydroxylase/17,20 lyase)

- NO P450c21, 17hydroxysteroid dehydrogenase , aromatase

theca interna interstitial cells

- 17hydroxysteroid dehydrogenase, aromatase

- NO P450c17 , P450c21

Substrate dependent

granulosa cell

cholesterol

pregnenolone pregnenolone

progesterone

P450scc

3OHSDH

cholesterol

17 OH-

pregnenolone

17 OH-

progesterone

DHEA

androstenedione

P45017

cholesterol

pregnenolone pregnenolone

progesterone

LDL-cholesterol,

from plasma

P450scc

diffusion progesterone

androstenedione testosterone

estrone estradiol

aromatase

17OHSDH

in luteal phase, after

vascularization

- 17-hydroxylase/17,20 liase

- NO 21-hydroxylase, 17-

hydroxysteroid dehydrogenase,

aromatase

Cholesterol → Androstenedione

LH stimulates

- 17-hydroxysteroid dehydrogenase,

aromatase

- NO 17-hydroxylase/17,20 liase ,

21-hydroxylase:

Substrate dependent!

Androstenedione → Estradiol

FSH stimulates

Theca interna cells

Granulosa cells

Ovaries: follicular phase

Corpus luteum: LH surge – differentiation in lutein cells

17 hydroxylase/17,20-liase↓

Cholesterol→ progesterone,

Less androgens

aromatase↓

vascularization – cholesterol source

Cholesterol→ progesterone,

Less estrogens from less androgens

Lutein cells

SERM: Selective Estrogen Receptor Modulator

Interactions with ER – conformational change

Can be both agonists and antagonist

Tissue-specific interactions with co-activators/co-repressors

History:

1960s : clomifene („E – antagonist”)

1986: ERalpha cloned

tamoxifen, raloxifen – synthetic SERMs

2007: naturally occurring SERMs (27-OH-chol)

Tamoxifen: agonist in bones (prevents osteoporosis)

antagonist in breast tissue (breast cancer therapy)

pitfall: partial agonist in endometrium – increases risk for endometrial

cancer

Placenta

like the granulosa cell 3OHSDH P450scc cholesterol pregnenolone progesterone

androstenedione testosterone

estrone estradiol

aromatase

17OHSDH androstenediol DHEA DHEAS

maternal/fetal

adrenal cortex

z.reticularis

sulfatase

In the absence of SF-1 (steroidogenic factor-1, a TF), placenta lacks several

enzymes for de novo synthesis of steroid hormones (CYP45017)

Placental steroid synthesis is dependent on fetal and maternal precursors

estriol

16OH-DHEA

fetal

adrenal

cortex +

liver

3OHSDH

Inactivation of maternal steroids in the placenta

17OHSDH-II

estrone estradiol

androstenedione testosterone

NAD+ NADH+H+

oxidation=inactivation

ER

vascular endothelial cells

mother

11OHSDH2

mother cortisol cortisone

NAD+ NADH+H+

oxidation=inactivation

syncytiotrophoblast

Regulation of female sex steroid hormone synthesis

Hypothalamus

Adenohypophysis

GnRH

FSH LH

ovaries

E E/P

oocyte

uterus, endometrium

GnRH test

clomifene

Ovulation induction diagnosis

GnRH

secretion proliferation

menstruation

implantation

gonadotropin test

(FSH+LH)

FSH+LH

E, P test