Steroid hormons
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Transcript of 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
Classification of steroid hormonsClassification of steroid hormons
• Sex & progestagen Sex & progestagen hormonshormons
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
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89 14
1312
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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
Hormone Secretion from Secretion Signal Functions
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
Hormone Secretion from Secretion Signal Functions
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
Hormone Secretion from Secretion Signal Functions
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
Hormone Secretion from Secretion Signal Functions
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
Hormone Secretion from Secretion Signal Functions
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
Hormone Secretion from Secretion Signal Functions
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