Download Steroid and Thyroid Hormones

Steroid and Thyroid
Hormones
Srbová Martina
Chemical Classification of
Hormones
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
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
Mechanism of Hormone
Action
All hormone action is receptor mediated
Peptide hormones and
catecholamines bind
to cell surface
receptors
Steroid and thyroid
hormones act via
intracellular
receptors
Copy from Devlin T.M.: Textbook of Biochemistry with Clinical Correlations
Mechanism of Hormone Action
Regulation of hormone release



Negative feedback
Positive feedback (ovulation, childbirth)
Cyclic changes (cirkadian rhythm, our development)
Hormonal cascade
Signal amplification
CNS
Environmental or
internal signal
Electrical-chemical signal
Limbic system
Electrical-chemical signal
Hypothalamus
Releasing hormones (ng) - liberins
Inhibiting hormones - statins
Anterior pituitary
Anterior pituitary hormone (μg) -tropines
Target „gland“
The gonads, the thyroid gland,
the adrenal cortex
Ultimate hormone (mg)
Systemic effects
CNS
Limbic system
Hormonal cascade
Negative feedback
system
Hypothalamus
Long feedback
loop
Releasing hormones
Anterior pituitary
Anterior pituitary
hormones
Target „gland“
Ultimate hormone
Systemic effects
Short feedback
loop
Steroid hormones
Structure of Steroid
Hormones
Steroids are lipophilic molecules.
All steroids, except calcitriol, have
cyclopentanoperhydrophenanthrene
structure (sterane).
The parental precursor of
steroids - cholesterol
Transport of Hormones
in the Bloodstream
Are not water soluble so have to be carried in the blood complexed to
specific binding globulins.
Carrier-
•
•
•
bound
hormone
Albumin is non-specific
Corticosteroid binding globulin
(CBG) - transcortin
Sex hormone binding globulin
(SHBG)
Endocrine
cell
Free
hormone
Hormone
degradation
• Androgen binding protein (ABP)
Only the free fraction is biologically active usually less than 10%
Hormone
Receptor
Biological
effects
Hormone half life
Steroids and thyroid hormone, which are
bound to plasma proteins, have a long half life
(~ hours)
Peptides and catecholamines are watersoluble, they are transported dissolved in plasma
generally have a very short half life (~ seconds
to minutes)
Mechanism of Steroid
Hormone Action
•
Because steroid hormones initiate
protein synthesis their effects are
produced more slowly, but are
more long-lasting than those
produced by other hormones.
Copy from Devlin T.M.: Textbook of Biochemistry with Clinical Correlations
Intracellular receptors
Model of typical steroid hormone receptor
H2N-
1
2
3
- COOH
4
1.
Variable domain – interacts with other transcription factors
2.
DNA-binding domain – „zinc finger“
3.
4.
Domain for dimerization – a site of dimerization of two
receptor-hormone complexes
Hormone- binding domain
„zinc finger structure“
Copy from Devlin T.M.: Textbook of Biochemistry with Clinical Correlations
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 individual
hormone.
The regulation of steroidogenesis involves control of
the enzymes which modify cholesterol into the
steroid hormone.
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
Biosynthesis of Steroid
Hormones

Critical step is the cell activity in mobilizing
cholesterol stored in a droplets, transport of
cholesterol to mitochondrion.

The rate-limiting step is the rate of cholesterol side
chain cleavage in mitochondrion by enzymes
known as the cytochrome P450 side chain
cleavage enzyme complex.
http://en.wikipedia.org/wiki/Pre
gnenolone
http://chemistry.gravitywaves.com/CHE452/21_Adrenal%20Steroid17.htm
Steroidogenic Enzymes
„Old“ name
Current name
P450SCC
CYP11A1
3b-hydroxysteroid dehydrogenase
3 b-DH
3 b-DH
17a-hydroxylase/17,20 lyase
P450C17
CYP17
21-hydroxylase
P450C21
CYP21A2
11b-hydroxylase
P450C11
CYP11B1
P450C11AS
CYP11B2
P450aro
CYP19
Common name
Cholesteroldesmolase
(Side-chain cleavage enzyme)
Aldosterone synthase
Aromatase
Steroid Hormone Classes
Glucocorticoids
Mineralocorticoids
Progestins
Androgens
Estrogens
Vitamin D
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.
Steroid Hormones of the
Adrenal Cortex
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)
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
Renin-angiotensin system
Factors that stimulate renin release
Decreased blood pressure, salt depletion
Angiotensinogen
renin
Angiotensin I
converting enzyme
 Na+, H2O resorption
Angiotensin II
Aldosteron
 excretion of K+, H+
aminopeptidase
Angiotensin III
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.
Cortisol - effects
Stress adaptation
proteins
Amino acids
Proteolysis
lipids
lipolysis
concentration
in the blood
rises
cortisol
gluconeogenesis
high
concentration
Fatty acids
protein synthesis
Immunosupresive
effect
Amino acids
antiinflammatory
effect
bone
degradation
glucose
Cortisol
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, hypekalemia, hyponatremia
Since 2006 newborn screening
Cushing’s syndrome

Glucocorticoid excess
Use of glucocorticoids
Pituitary adenoma, adrenal adenoma

Lost of diurnal pattern of ACTH and cortisol secretion

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
Steroid Hormones of the
Gonades
•
Hormones that affect the development of the
reproductive organs and sexual characteristics.
Regulation of Sex Hormones Synthesis
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
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 androgenbinding protein (ABP). ABP binds testosterone (produced by Leydig
cells) and transports it to the site of spermatogenesis
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
Menstrual cycle
FOLLICLE
OVULATION
CORPUS LUTEUM
Uterine endometrium
Follicular phase
Menstruation
Luteal phase
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.
Calcitriol - 1,25 (OH)2-D3
Liver
OH
Diet
25-hydroxylase
HO
Vitamin D3
cholecalciferol
UV from
sunlight
HO
25(OH) D3
Kidney
1α- hydroxylase
Skin
OH
HO
7
7-dehydrocholesterol
HO
OH
1,25(OH)2 D3
(active hormone form)
Calcitriol - 1,25 (OH)2-D3

1a-hydroxylation is the rate-limiting step in calcitriol
synthesis
Regulation of 1a-hydroxylase
Activation
Inhibition
Hypocalcemia
Parathroid hormone
Hypophosphatemia
Calcitriol
Calcitriol
- increases uptake of Ca2+ and phosphate from the
intestine
- stimulates calcium binding protein synthesis
- increases reabsorption of Ca2+ by the kidney
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
Thyroid Hormones
Thyroid Hormones

3,5,3´-triiodothyronine (T3)

Thyroxine (T4)
3,5,3´,5´-tetraiodothyronine
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)
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.
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
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
Degradation of thyroid
hormones



Deiodation
Oxidative deamination
Conjugation with glucuronate, sulfate
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)