Download Steroid hormons

Steroid hormons
Hormons
• are chemicals
released by cells
• Endocrine glands
• Higher stability
• chemical messenger
that transports a
signal from one cell
to another
– Paracrine
– Autocrine
Hormonal cascade – amplification of
signal
• CNS  target cell
• Stimuli
– Action potential
– Chemical signal
– Limbic system
• Hypothalamus
• Pituitary gland
• Target cell - hormon
Hormonal cascade – feed back
• t, noise, trauma
• Limbic system –
hypocampus
– ng hypothalamic releasing
hormon (corticotropin
releasing hormone)
• Pituitary gland receptor
– Adrenocorticotrope hormon
mg
– (ACTH és β-lipotropin) t1/2 is
longer, as t1/2 (CRH)
• Adrenal cortex – zona
fasciculata – receptor –
cortisol - mg
Various types of receptors
Hypothetical cell
Receptors:
Peptid hormons
Growth factors
Aminoacid derivatives
Hormons (epinephrine)
Steroid hormons +
receptors
Nucleus
Cell membrane
Cytoplasm
Thyroid hormons +
receptors
Steroid hormons
Steroid receptors
Biochemistry of steroid hormones
• Autoradiography of
Madhabananda Sar
and Walter E. Stumpf
• Guinea pig
endometrium +
radioactivly labelled
progesterone (15’)
Classification of steroid hormons
• Sex & progestagen
hormons
Classification of steroid hormons
• Sex & progestagen
hormons
Classification of steroid hormons
• Sex & progestagen
hormons
• Hormons of adrenal
cortex
Cross sectional view of adrenal
cortex
• Cortex
– Zona glomerulosa:
• mineralocorticoids
– Zona fasciculata:
• glucocorticoids +
androgens
– Zona reticularis:
• glucocorticoids +
androgens
Carbon skeleton
• Cyclopentanoperhydrophenanthrene
skeleton
• A, B, C, D - four fused
rings
A koleszterin
•
•
•
•
•
1.) transz, szék elnyújtott szalagszerű felépítés
1) 3-b-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
CH2
CH2
CH
CH
CH
CH2
18
12
CH2
CH2
CH2
CH
CH2
CH
CH
11
CH2
1
2
CH2
9
3
CH2
R1
D
14
10
A
CH2
17
13
C
19
R2
16
15
8
B
5
4
7
6
1,2-ciklopentano-perhidrofenantrén (szterán) - váz
szék
kád
CH3
CH3
C
CH3
D
Koleszterin, 5 (6)-kolesztén-3-b -ol
A
B
A
CH3
HO
CH3
C
A
HO
 szubsztituens TRANSZ
C3H8
D
CH3
B
B
H
CH3
C3H8
CH3
C3H8
CH3
H
H
C
H
H A
D
B
C
HO
A
B
Kolesztanol
CH3
CH3
C
H A
D
C
b szubsztituens CISZ
D
C3H8
H
HO
H
D
H
H
H
Koprosztanol
B
Kolesztanol
H
HO
H
Koprosztanol
A / B cisz, B / C, C / D transz
A / B transz, B / C, C / D transz
Via - D5-pregnenolonone …
CH3
O
HO
HO
Cholesterol
D-pregnenolon
Inactivation of steroind hormones
• Reduction
• glucuronidization
Steroid hormons Progesterones
Hormone
Progesterone
Secretion from
Corpus luteum
Secretion Signal
LH
Functions
Maintains (with estradiol) the uterine endometrium or implantation;
differentiation of mammary glands
Steroid hormons –
17ß-estradiol
Hormone
17β-Estradiol
Secretion from
Ovarian follicle;
corpus luteum;
(Sertoli cell)
Secretion Signal
FSH
Functions
Female: regulates gonadotropin secretion in ovarian cycle; maintains (with
progesterone) uterine endometrium; differentiation of mammary gland.
Male: negative feedback inhibitor of Leydig cell synthesis of testosterone
Steroid hormonsk –
Testosteron
Hormone
Testosterone
Secretion from
Leydig cells of
testis; (adrenal
gland); ovary
Secretion Signal
LH
Functions
Male: required for spermatogenesis; converted to more patent androgen,
dihydrotestosterone, in some target tissues like prostate gland; secondary sex
characteristics (in some tissues testosterone is active hormone)
Steroid hormons –
Dehydroepiadrosteron
Hormone
Secretion from
Secretion Signal
Dehydroepian drosterone
Reticularis
cells of
adrenal cortex
ACTH
Functions
Various protective effects of adrenal cortex (anticancer, antiaging); weak
androgen; can be converted to estrogen; no receptor yet isolated.
Steroid hormons –
Cortisol
Hormone
Secretion from
Cortisol
Fasciculata
cells of adrenal
cortex
Secretion Signal
ACTH
Functions
Stress adaptation of adrenal cortex through various cellular phenotypic
expressions; regulates protein, carbohydrate, and lipid metabolism;
Immunosuppressive effects.
Steroid hormons –
Aldosteron
Hormone
Aldoszteron
Secretion from
Glomerulosa
cells of adrenal
cortex
Secretion Signal
Angiotensin
II/III
Functions
Causes sodium ion reabsorption in kidney via conductance channel; controls salt
and water balance; raises blood pressure by increasing fluid volume.
1,25-dihydroxy vitamine D3
Hormone
1,25-Dihydroxyvitamin D3
Secretion from
Secretion Signal
Functions
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
1,25-dihidroxi-vitamin D3
HO
OH
Classification: # of C atoms
• C27
– 1,25(OH)2D3
• C21
– progesteron, cortizol, aldosteron
• C19
– testosteron & dehydroepiandrosteron
• C18
– 17β-estradiol
Steroid hormons
Cholesterol C27
Pregnenolon C21
Progestagens C21
Mineralocorticoids C21
Glucocorticoids C21
Androgens C19
Estrogens C18
Characteristic substituents
• Glucocorticoids, mineralocorticoids
– C11
– OH, O
• Estrogens
– Lack of C19 methyl groups
– Ring „A” is aromatic
• Steroid receptors
– Estradiol Ring „A” - Rings B–C–D
• Other steroid hormons other than female hormones
– Ring „A” is coplanar to rings B–C–D
Sterical positions of ring „A” and
rings „B-C-D”
Sterical positions of ring „A” and
rings „B-C-D”
Receptors of steroidal hormones
•
•
•
•
Hydrophobic molecules
Plasma proteins
Free diffusion
„Target cells”: receptors: in
cytoplasm / nucleus
Receptors of steroidal hormones
• intracellular
– non-steroid component
• thyroid hormons
• Retinoic acid
• Vitamine D3
– Steroids
• cytoplasmic
– glucocorticoid
receptors
– aldosteron
• nucleus – chromatin
assotiated form
– Other receptors
Steroid Receptor Gene Superfamily
Steroid hormon receptors
• Kcortisol/receptor 109 M−1
• Kcortosol/CBG 107 M−1
• Cortisol receptor–complex
– (~ 300 kDa)
– dimer 90 kDA heat shock
protein
• heat shock
• Masking DNS-binding
domain
• Hormon – receptor
interaction - activation
• Hydrolysis of proteins,
– + charge aminoacids – DNA
• Ligand receptor complex
– translocation
• DNS binding site – HSE
hormone response element
• Regulation of gen
transcription
– Enhancement of
transcription – mRNA –
protein
– Repression – 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
hormones
• [cAMP]intracellular 
• [Ca2+] intracellular 
• [cAMP] intracellular 
– Acute
• Mobilisation of
cholesterol – mit.
membrane
– Chronic
• Steroidogen enzyme
transcription 
[cAMP]intracellular 
• Cholesterol –
pregnenolone
• Cytochrom P450 SCC
(side chain cleavage)
enzyme
22 OH - cholesterol
+
• NADPH + H ; O2
C27
22,20 diOH - cholesterol
Cyt450 SCC
C22
[cAMP]intracelluláris 
• Protein
inductionStAR
(Steroidogenic acut
regulatory protein)
• 30 kD,
phosphoprotein
• testis
• ovary
[cAMP]intracellular 
• Protein induction
• StAR (Steroidogenic
acut regulatory protein)
• Defective / nonfunctional StAR
– Lipoid congenital adrenal
hyperplasia (LCAH)
• Steroid synthesis of
adrenals and gonadsis
lowered
• Lipid deposition