steroid and thyroid hormonesbiochemie.lf2.cuni.cz/anglicky/biox2letni/prednasky/steroid...
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Steroid and Thyroid
Hormones
Srbová Martina
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Hormones are chemical messengers that transport
signals from one cell to another
There are 3 major chemical classes of hormones
• steroid hormones - i.e. progesterone
• peptide and protein hormones - i.e. insulin
• amino acid derivatives - epinephrine
Chemical Classification of
Hormones
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Classification of Hormones Endocrine hormones: act on cells distant from the site
of their release
Paracrine hormones act only on cells close to the cell
that released them
Autocrine hormones act on the same cell that released
them
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Mechanism of Hormone
Action
Peptide hormones and
catecholamines bind
to cell surface
receptors
Steroid and thyroid
hormones act via
intracellular
receptors
All hormone action is receptor mediated
Copy from Devlin T.M.: Textbook of Biochemistry with Clinical Correlations
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Mechanism of Hormone Action
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Regulation of hormone release
Negative feedback
Positive feedback (ovulation, childbirth)
Cyclic changes (cirkadian rythm, our development)
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Hormonal cascade
Signal amplification
Environmental or
internal signal
Systemic effects
CNS
Limbic system
Hypothalamus
Anterior pituitary
Target „gland“
Electrical-chemical signal
Electrical-chemical signal
Releasing hormones (ng) - liberins
Anterior pituitary hormone (μg) -tropines
Ultimate hormone (mg)
The gonads, the thyroid gland,
the adrenal cortex
Inhibiting hormones - statins
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CNS
Systemic effects
Hormonal cascade
Negative feedback
system
Short feedback
loop
Long feedback
loop
Limbic system
Hypothalamus
Anterior pituitary
Target „gland“
Releasing hormones
Anterior pituitary
hormones
Ultimate hormone
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Steroid hormones
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Steroids are lipophilic molecules.
All steroids, except calcitriol, have cyclopentanoperhydrophenanthrene structure (sterane).
Structure of Steroid
Hormones
The parental precursor of
steroids - cholesterol
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Transport of Hormones
in the Bloodstream Are not water soluble so have to be carried in the blood complexed to
specific binding globulins.
Only the free fraction is biologically active usually less than 10%
• Albumin is non-specific
• Corticosteroid binding globulin
(CBG) - transcortin
• Sex hormone binding globulin
(SHBG)
• Androgen binding protein (ABP)
Carrier-
bound
hormone
Endocrine
cell
Free
hormone
Hormone
Receptor
Hormone
degradation Biological
effects
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Hormone half life
Steroids and thyroid hormone, which are bound to plasma proteins, have a long half life
(~ hours)
Peptides and catecholamines are water-soluble, they are transported dissolved in plasma
generally have a very short half life (~ seconds to minutes)
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• Because steroid hormones initiate protein synthesis their effects are produced more slowly, but are more long-lasting than those produced by other hormones.
Mechanism of Steroid
Hormone Action
Copy from Devlin T.M.: Textbook of Biochemistry with Clinical Correlations
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Model of typical steroid hormone receptor
1. Variable domain – interacts with other transcription factors
2. DNA-binding domain – „zinc finger“
3. Domain for dimerization – a site of dimerization of two receptor-hormone complexes
4. Hormone- binding domain
Intracellular receptors
1 2 3 4 H2N- - COOH
„zinc finger structure“
Copy from Devlin T.M.: Textbook of Biochemistry with Clinical Correlations
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Biosynthesis of Steroid
Hormones
Peptide hormones are encoded by specific genes;
steroid hormones are synthesized from the
enzymatically modified cholesterol.
Thus, there is no gene which encodes steroid
hormone.
The regulation of steroidogenesis involves control of
the enzymes which modify cholesterol into the
steroid hormone.
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Hormonal Stimulation of Steroid Hormone
Biosynthesis
• Hormone stimulation depends
on the cell type and receptor
(ACTH for cortisol synthesis,
FSH for estradiol synthesis, LH
for testosterone synthesis etc.)
St AR
StAR – steroidogenic acute regulatory protein
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Biosynthesis of Steroid
Hormones
Critical step is the cell activity in mobilizing
cholesterol stored in a droplets, transport of
cholesterol to mitochondria.
The rate-limiting step is the rate of cholesterol side
chain cleavage in mitochondria by enzymes
known as the cytochrome P450 side chain
cleavage enzyme complex.
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http://en.wikipedia.org/wiki/Pre
gnenolone
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http://chemistry.gravitywaves.com/CHE452/21_Adrenal%20Steroid17.htm
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Steroidogenic Enzymes Common name „Old“ name Current name
Cholesteroldesmolase
(Side-chain cleavage enzyme)
P450SCC CYP11A1
3b-hydroxysteroid dehydroge-
nase
3 b-DH 3 b-DH
17a-hydroxylase/17,20 lyase P450C17 CYP17
21-hydroxylase P450C21 CYP21A2
11b-hydroxylase P450C11 CYP11B1
Aldosterone synthase P450C11AS CYP11B2
Aromatase P450aro CYP19
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Steroid Hormone Classes
Glucocorticoids
Mineralocorticoids
Progestagens
Androgens
Estrogens
Vitamin D
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Steroid hormones
Steroid hormones play important roles in:
- carbohydrate regulation (glucocorticoids)
- mineral balance (mineralocorticoids)
- reproductive functions (gonadal steroids)
Steroids also play roles in inflammatory responses, stress responses, bone metabolism, cardiovascular fitness, behavior, and mood.
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Composed of 3 layers (zones):
• outer zone (zona glomerulosa) produces aldosterone (mineralocorticoid)
• middle zone (zona fasciculata) produces cortisol (glucocorticoid)
• inner zone (zona reticularis) produces dehydroepiandrosteron (androgen)
Steroid Hormones of the
Adrenal Cortex
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Regulation of Adrenal Steroid
Hormones Synthesis Steroid
hormone
Steroid producing
cells
Signal Second messenger Signal system
Cortisol Zona fasciculata ACTH cAMP, IP3, Ca 2+ Hypothalamic-pituitary
Aldosteron Zona glomerulosa Angiotensin II,III IP3, Ca 2+ Renin-angiotensin
Decreased blood pressure, salt depletion renin
Angiotensinogen
Angiotensin I
Angiotensin II
Angiotensin III
angiotensin converting enzyme
aminopeptidase
Renin-angiotensin system
Factors that stimulate renin release
Aldosteron
Na+, H2O resorption
excretion of K+, H+
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Transport of Adrenal
Steorid Hormones in the
Bloodstream
CORTISOL
70% is bound to corticosteroid
binding globulin (transcortin)
22% of cortisol is bound to albumin
8% free cortisol
ALDOSTERONE
60% of aldosterone is bound to
albumin
10 % is bound to transcortin
A small amount of aldosterone is
bound to other plasma
proteins
Transcortin is produced in the liver and its synthesis is increased by
estrogens.
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Cortisol - effects
proteins
Proteolysis
Amino acids
concentration
in the blood
rises Amino acids
glucose Fatty acids
lipids
lipolysis
Immunosupresive
effect antiinflammatory
effect
bone
degradation
protein synthesis
high
concentration
gluconeogenesis
cortisol
Stress adaptation
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Cortisol
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Congenital Adrenal Hyperplasia CAH
(adrenogenital syndrome)
Autosomal recessive disease
Insufficient amounts of steroidogenic enzymes – deficiency of end
products, the accumulation of intermediates
21 – hydroxylase deficiency (90% of cases)
cortisol production ACTH – adrenal hyperplasia, androgens
(virilization)
In children with the more severe form of the disorder (mineralocorticoid
deficiency), symptoms often develop 1. – 4. weeks after birth.
Acidosis, hyperkalemia, hyponatremia
Since 2006 newborn screening
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Cushing’s syndrome
Glucocorticoid excess
Use of glucocorticoids
Pituitary adenoma, adrenal adenoma
Hyperglycemia - ↑gluconeogenesis
Protein catabolic effects– thinning of the skin, osteoporosis, negative
N balance
Redistribution of fat- buffalo hump
Resistence to infections and inflammatory responses is impaired
Hypernatremia, hypokalemia, hypertension,edema
http://cushingsmoxie.blogspot.cz/2012_04_30_archive.html
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Steroid Hormones of the
Gonades
• Hormones that affect the development of the
reproductive organs and sexual characteristics.
Steroid
hormone
Steroid producing
cells
Signal Second
messenger
Signal system
Testosterone Leydig cells LH cAMP Hypothalamic-pituitary
Estradiol Granulosa cells FSH cAMP Hypothalamic-pituitary
Progesterone Corpus luteum LH cAMP Hypothalamic-pituitary
Regulation of Sex Hormones Synthesis
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Testes
Leydig cells produce:
• testosteron
Sertoli cells produce:
•dihydrotestosterone (DHT) – but most of conversion of testosterone to DHT occurs outside the testes
• estradiol – a small amount of testosteron is also converted into estradiol by aromatization
– inhibits testosteron synthesis
• inhibin – polypeptide hormone, which inhibits FSH releasing
FSH binds to the Sertoli cells and stimulates the synthesis of androgen-binding protein (ABP). ABP binds testosterone (produced by Leydig cells) and transports it to the site of spermatogenesis
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Ovaries
Estradiol is the main hormone produced during the follicular phase of the menstrual cycle. Responsible for maintenance of the female reproductive system and the development of female secondary sex characteristics Estrogens are formed by aromatisation of androgens After ovulation progesterone is made by follicular cells, which now constitute the corpus luteum. Involved in preparing and maintaining the uterus
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FOLLICLE OVULATION CORPUS LUTEUM
Uterine endometrium Menstruation
Follicular phase Luteal phase
Menstrual cycle
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Transport of Sex Hormones in
the Bloodstream Testosterone & estradiol bind to sex hormone binding globulin (SHBG). Affinity of SHBG for testosterone is higher than for estradiol
.
Progesterone binds to transcortin.
• Before puberty - the level of SHBG is about the same in males and females .
• At the puberty - there is a small decrease in the level of circulating SHBG in females and larger decrease in males, insuring relatively greater amount of the unbound, biologically active sex hormones.
• In adults, males have half of the amount of SHBG than females.
• Testosterone lowers SHBG levels in blood, whereas estradiol raises SHBG levels.
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HO
Vitamin D3
cholecalciferol
Diet
HO
OH
25(OH) D3
Liver
25-hydroxylase
OH HO
OH
1,25(OH)2 D3 (active hormone form)
Kidney
1α- hydroxylase
HO 7
7-dehydrocholesterol
UV from
sunlight Skin
Calcitriol - 1,25 (OH)2-D3
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1a-hydroxylation is the rate-limiting step in calcitriol synthesis
Calcitriol
- increases uptake of Ca2+ and phosphate from the intestine
- stimulates calcium binding protein synthesis
- increases reabsorption of Ca2+ by the kidney
Regulation of 1a-hydroxylase
Activation Inhibition
Hypocalcemia
Parathroid hormone
Hypophosphatemia
Calcitriol
Calcitriol - 1,25 (OH)2-D3
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Hormone Catabolism and
Excretion
• Inactivation of steroids involves reductions and conjugation to glucuronides or sulfate to increase their water solubility.
• Most are catabolized by the liver and kidneys.
• 70% of the conjugated steroids are excreted in the urine, 20 % leave in feces and rest exit through the skin.
3
estron-3sulfate
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Thyroid Hormones
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3,5,3´-triiodothyronine (T3)
Thyroxine (T4)
3,5,3´,5´-tetraiodothyronine
Thyroid Hormones
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Biosynthesis of thyroxine • The main synthetized thyroid hormone is thyroxine, but
triiodothyronine is tentimes more potent
• Precursor molecule for synthesis thyroid hormones is tyrosine derivative
• Biosynthesis is perfomed on tyrosine residues bound in protein of thyroid gland – thyreoglobulin
• The first step is transport of iodide into follicle cells of thyroid gland
• Active transport of iodide into the follicle cell is mediated iodide pump (the concentration outside is 25times lower than inside)
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Transport of thyroid
hormones by blood
The main transporting protein is thyroxine binding globulin (TBG). Its
affinity for T4 is 10 times higher than for T3 .
The further proteins, binding thyroid hormones, are thyroxine binding
prealbumin and albumin.
More than 99% of T4 is bound on plasma proteins.
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Control of thyroid hormone
synthesis and secretion
Pituitary hormone thyreotropin (TSH)
upregulates activity of iodide pump of
follicle cells of thyroid gland
Endocytosis of iodinated
thyreoglobulin and following secretion
of T3 and T4 is also upregulated by
TSH
Production of TSH is upregulated by
TRH and controled by thyroid
hormones via negative feedback
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Thyroid Hormones
Bind to intracellular receptor, increase expression of numerous metabolic
enzyme
Stimulate metabolism and influence development and maturation
stimulate the consumption of oxygen
increase metabolic rate
regulate thermogenesis
Hyperthyroidism, excessive secretion of thyroid hormones, causes
high body temperature, weight loss, irritability, and
high blood pressure
Hypothyroidism, low secretion of thyroid hormones, causes weight
gain, lethargy, and intolerance to cold
during fetal and immediate postnatal periods results
in irreversible physical and metal retardation cretinism
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Degradation of thyroid hormones
Deiodation
Oxidative deamination
Conjugation with glucuronate, sulfate
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Literature
Devlin, T. M. Textbook of biochemistry: with clinical correlations. 6th edition.
Wiley-Liss, 2006.
Marks´ Basic Medical Biochemistry, A Clinical Approach, third edition, 2009
(M. Lieberman, A.D. Marks)
Color Atlas of Biochemistry, second edition, 2005 (J. Koolman and K.H.
Roehm)