Steroid hormons

Steroid hormons

HormonsHormons

• are chemicals are chemicals released by cellsreleased by cells

• Endocrine glandsEndocrine glands• Higher stabilityHigher stability

• chemical messenger chemical messenger that transports a that transports a signal from one cell signal from one cell to anotherto another – ParacrineParacrine– AutocrineAutocrine

Hormonal cascade – amplification of Hormonal cascade – amplification of signalsignal

• CNS CNS target cell target cell• Stimuli Stimuli

– Action potentialAction potential– Chemical signalChemical signal– Limbic systemLimbic system

• HypothalamusHypothalamus• Pituitary glandPituitary gland• Target cell - Target cell - hormonhormon

• t, noise, traumat, noise, trauma

• Limbic system – Limbic system – hypocampus hypocampus – ng hypothalamic releasing ng hypothalamic releasing

hormon (corticotropin hormon (corticotropin releasing hormone)releasing hormone)

• Pituitary gland receptorPituitary gland receptor– Adrenocorticotrope hormon Adrenocorticotrope hormon

g g – (ACTH és β-lipotropin) (ACTH és β-lipotropin) tt1/21/2 is is

longer, as longer, as tt1/21/2 (CRH) (CRH)

• Adrenal cortex – zona Adrenal cortex – zona fasciculata – receptor – fasciculata – receptor – cortisol - mgcortisol - mg

Hormonal cascade – feed backHormonal cascade – feed back

Various types of receptors

Hypothetical cell

Cytoplasm

Cell membrane

Nucleus

Steroid hormons + receptors

Steroid hormons

Steroid receptors

Receptors:Peptid hormonsGrowth factorsAminoacid derivativesHormons (epinephrine)

Thyroid hormons +receptors

Biochemistry of steroid hormones

• Autoradiography of Madhabananda Sar and Walter E. Stumpf

• Guinea pig endometrium + radioactivly labelled progesterone (15’)

Classification of steroid hormonsClassification of steroid hormons

• Sex & progestagen Sex & progestagen hormonshormons





• Hormons of adrenal Hormons of adrenal cortexcortex

Cross sectional view of adrenal cortex

• Cortex– Zona glomerulosa:

• mineralocorticoids

– Zona fasciculata: • glucocorticoids +

androgens

– Zona reticularis:• glucocorticoids +

androgens

Carbon skeletonCarbon skeleton

• Cyclopentano- perhydrophenanthrene skeleton

• A, B, C, D - four fused rings

A koleszterin

• 1.) transz, szék elnyújtott szalagszerű felépítés• 1) 3--OH membrán / H2O határ• 3.) 18/19 CH3, váz tömör• 4.) gátolja membrán fluiditását, gátolja a membrán befagyását• 5.) a lipoproteinek alkotórésze, szérum koncentráció – rizikótényező

“A koleszterin a biológia leginkább dekorált molekulája. 13 Nobel-díjjal tüntették ki ama tudósokat, akik munkásságuk nagy részét a koleszterinnek áldozták. 1784 óta, amikor először izolálták epekövekből, szinte hipnotikus hatást gyakorolt a tudomány különböző területein dolgozó tudósokra. A koleszterin Janus-arcú molekula. Vízben való oldhatatlansága, mely hasznos a sejtmembránokban, halálhozóvá is teszi.”

Michael Brown L Joseph Goldstein: Nobel Lettures 1985

Stereochemistry of steroid hormons

2

34

5

101

67

89 14

1312

11

15

16

17

19

18

R1

R2

A B

C D

szék kád

CH2

CH2CH2

CH

CHCH2

CH2

CH2

CHCH CH

CHCH2

CH2

CH2

CH2

CH2

1,2-ciklopentano-perhidrofenantrén (szterán) - váz

HO

Koleszterin, 5 (6)-kolesztén-3- -ol

HO

CH3

H

CH3 C3H8

HH

A

A

B

B

C

C D

D

DC

B

CH3 C3H8

HH

CH3

HO

H A

Kolesztanol

Koprosztanol

Kolesztanol

DC

BA

CH3 C3H8

HH

HO

CH3

H

DC

B

CH3 C3H8

H

H

CH3

HO

H A

Koprosztanol

CH3

CH3

H

A B

C DCH3 szubsztituens CISZ

szubsztituens TRANSZ

A / B cisz, B / C, C / D transz A / B transz, B / C, C / D transz

ViaVia55-pregnenolonone …-pregnenolonone …

OH OH

CH3

O

Cholesterol -pregnenolon

Inactivation of steroind hormonesInactivation of steroind hormones

• ReductionReduction• glucuronidizationglucuronidization

Steroid hormons - Steroid hormons - ProgesteronesProgesterones

Hormone Secretion from Secretion Signal Functions

ProgesteroneProgesterone Corpus luteumCorpus luteum LHLH Maintains (with estradiol) the uterine endometrium or implantation; Maintains (with estradiol) the uterine endometrium or implantation; differentiation of mammary glandsdifferentiation of mammary glands

Steroid hormons – Steroid hormons – 17ß-estradiol17ß-estradiol


17β-Estradiol17β-Estradiol Ovarian follicle; Ovarian follicle; corpus luteum; corpus luteum; (Sertoli cell)(Sertoli cell)

FSHFSH Female: regulates gonadotropin secretion in ovarian cycle; maintains (with Female: regulates gonadotropin secretion in ovarian cycle; maintains (with progesterone) uterine endometrium; differentiation of mammary gland. progesterone) uterine endometrium; differentiation of mammary gland. Male: negative feedback inhibitor of Leydig cell synthesis of testosteroneMale: negative feedback inhibitor of Leydig cell synthesis of testosterone

Steroid hormonsk – Steroid hormonsk – TestosteronTestosteron


TestosteroneTestosterone Leydig cells of Leydig cells of testis; (adrenal testis; (adrenal gland); ovarygland); ovary

LHLH Male: required for spermatogenesis; converted to more patent androgen, Male: required for spermatogenesis; converted to more patent androgen, dihydrotestosterone, in some target tissues like prostate gland; secondary sex dihydrotestosterone, in some target tissues like prostate gland; secondary sex characteristics (in some tissues testosterone is active hormone)characteristics (in some tissues testosterone is active hormone)

Steroid hormons – Steroid hormons – DehydroepiadrosteronDehydroepiadrosteron


Dehydroepi- Dehydroepi- an drosteronean drosterone

Reticularis Reticularis cells of cells of adrenal cortexadrenal cortex

ACTH Various protective effects of adrenal cortex (anticancer, antiaging); weak Various protective effects of adrenal cortex (anticancer, antiaging); weak androgen; can be converted to estrogen; no receptor yet isolated.androgen; can be converted to estrogen; no receptor yet isolated.

Steroid hormons – Steroid hormons – CortisolCortisol


CortisolCortisol Fasciculata Fasciculata cells of adrenal cells of adrenal cortex cortex

ACTHACTH Stress adaptation of adrenal cortex through various cellular phenotypic Stress adaptation of adrenal cortex through various cellular phenotypic expressions; regulates protein, carbohydrate, and lipid metabolism; expressions; regulates protein, carbohydrate, and lipid metabolism; Immunosuppressive effects. Immunosuppressive effects.

Steroid hormons – Steroid hormons – AldosteronAldosteron


Aldoszteron Aldoszteron Glomerulosa Glomerulosa cells of adrenal cells of adrenal cortex cortex

Angiotensin Angiotensin II/III II/III

Causes sodium ion reabsorption in kidney via conductance channel; controls salt Causes sodium ion reabsorption in kidney via conductance channel; controls salt and water balance; raises blood pressure by increasing fluid volume. and water balance; raises blood pressure by increasing fluid volume.

1,25-dihydroxy vitamine D1,25-dihydroxy vitamine D33


1,25-Dihydroxy-1,25-Dihydroxy-vitamin D3vitamin D3

Vitamin D arises in skin cells after exposure to UV light and successive hydroxylations occur in liver and kidney to yield active form of hormone

PTH (stimulates kidney proximal tubule hydroxylation system)

Facilitates Ca2+ and phosphate absorption by intestinal epithelial cells; induces intracellular calcium-binding protein

OH

OHOH

1,25-dihidroxi-vitamin D3

Classification: # of C atomsClassification: # of C atoms

• C27C27– 1,25(OH)1,25(OH)22D3 D3

• C21C21– progesteron, cortizol, aldosteron progesteron, cortizol, aldosteron

• C19C19– testosteron & dehydroepiandrosteron testosteron & dehydroepiandrosteron

• C18C18– 17β-estradiol 17β-estradiol

Steroid hormons

Progestagens C21

Mineralocorticoids C21 Glucocorticoids C21 Androgens C19

Estrogens C18

Cholesterol C27 Pregnenolon C21

Characteristic substituentsCharacteristic substituents

• Glucocorticoids, mineralocorticoidsGlucocorticoids, mineralocorticoids– CC1111 – OH, OOH, O

• EstrogensEstrogens– Lack of CLack of C1919 methyl groups methyl groups– Ring „A” is aromaticRing „A” is aromatic

• Steroid receptorsSteroid receptors– Estradiol Ring „A” - Rings B–C–DEstradiol Ring „A” - Rings B–C–D

• Other steroid hormons other than female hormonesOther steroid hormons other than female hormones– Ring „A” is coplanar to rings B–C–DRing „A” is coplanar to rings B–C–D

Sterical positions of ring „A” and Sterical positions of ring „A” and rings „B-C-D”rings „B-C-D”

Sterical positions of ring „A” and Sterical positions of ring „A” and rings „B-C-D”rings „B-C-D”

Receptors of steroidal hormonesReceptors of steroidal hormones

• Hydrophobic molecules• Plasma proteins• Free diffusion• „Target cells”: receptors: in

cytoplasm / nucleus

Receptors of steroidal hormonesReceptors of steroidal hormones

• intracellularintracellular– non-steroid component non-steroid component

• thyroid hormonsthyroid hormons

• Retinoic acidRetinoic acid

• Vitamine DVitamine D33

– SteroidsSteroids• cytoplasmiccytoplasmic

– glucocorticoid glucocorticoid receptorsreceptors

– aldosteronaldosteron

• nucleus – chromatin nucleus – chromatin assotiated formassotiated form

– Other receptorsOther receptors

Steroid Receptor Gene SuperfamilySteroid Receptor Gene Superfamily

Steroid hormon receptorsSteroid hormon receptors

• KKcortisol/receptorcortisol/receptor 10 1099 M M−1−1

• KKcortosol/CBGcortosol/CBG 10 1077 M M−1−1

• Cortisol receptor–complex Cortisol receptor–complex – (~ 300 kDa) (~ 300 kDa) – dimer 90 kDA heat shock dimer 90 kDA heat shock

proteinprotein

• heat shock heat shock • Masking DNS-binding Masking DNS-binding

domaindomain• Hormon – receptor Hormon – receptor

interaction - activationinteraction - activation

• Hydrolysis of proteins, Hydrolysis of proteins, – + charge aminoacids – DNA+ charge aminoacids – DNA

• Ligand receptor complexLigand receptor complex– translocation translocation

• DNS binding site – HSE DNS binding site – HSE hormone response elementhormone response element

• Regulation of gen Regulation of gen transcriptiontranscription– Enhancement of Enhancement of

transcription – mRNA – transcription – mRNA – proteinprotein

– Repression – in given casesRepression – in given cases

Biochemistry of steroidal hormones

• The hormon receptor complex:

• Receptor – Homodimer formation

– DNS hormone response elements

– Glucocortikoid RE:

– 5’AGAACAnnnTGTTCT3’

– 3’TCTTGTnnnACAAGA5’

– Transcription factor:

– gens

Biosynthesis of steroid Biosynthesis of steroid hormoneshormones

• [cAMP]intracellular • [Ca2+] intracellular

• [cAMP] intracellular – Acute

• Mobilisation of cholesterol – mit. membrane

– Chronic• Steroidogen enzyme

transcription

[cAMP][cAMP]intracellularintracellular

• Cholesterol – Cholesterol – pregnenolonepregnenolone

• Cytochrom PCytochrom P450450 SCC SCC

(side chain cleavage) (side chain cleavage) enzymeenzyme

• NADPH + HNADPH + H++; O; O22

22 OH - cholesterol

22,20 diOH - cholesterol

Cyt450 SCC

C27

C22

[cAMP][cAMP]intracellulárisintracelluláris

• Protein Protein inductionStAR inductionStAR ((StSteroidogenic eroidogenic aacut cut rregulatory protein)egulatory protein)

• 30 kD, 30 kD, phosphoproteinphosphoprotein

• testistestis• ovaryovary

[cAMP][cAMP]intracellularintracellular

• Protein inductionProtein induction• StARStAR ( (StSteroidogenic eroidogenic

aacut cut rregulatory protein)egulatory protein)• Defective / non-Defective / non-

functional StARfunctional StAR– LLipoid ipoid ccongenital ongenital aadrenal drenal

hhyperplasia (yperplasia (LCAHLCAH))• Steroid synthesis of Steroid synthesis of

adrenals and gonadsis adrenals and gonadsis loweredlowered

• Lipid depositionLipid deposition

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Steroid hormons