Axis CRH-ACTH-adrenal glands
CRH, corticotropin-releasing hormone
Characteristics
- CNS stress response modulation (anxiety, food intake)
- Functions on periphery (BP, immune system, heart)
- a part of system of related peptides
- CRH-1R – neocortex, cerebellar cortex, subcortical structures of limbic
system, amygdala, ovaries, endometrium, skin
- CRH-binding protein
Hypothalamo-hypophyseal axis
- Fast ACTH secretion
Clinical significance
- Potential treatment of obesity
- CRH-R1 antagonists – anxiety and depression treatment
Regulation of secretion
- Neural control – various stressors
- Hypothalamo-hypophyseal axis
activation
- Sympathoadrenal axis activation
- ADH and oxytocin binding
- Ensuring requirements in
emergency situations
- Inflammation and cytokines
- IL-1B and hypothalamohypophyseal
axis activation
- Circadian rhythms - diurnal rhythms
Proopiomelanocortin
- POMC
Characteristics
-Adenohypophysis - short transcript
-CNS
-Placenta
-Skin
-Gonads
-GIT
-Liver
-Kidneys
-Adrenal medulla
-Lungs
-Lymphocytes
Stimulation of expression
-CRH, cytokines, ADH, catecholamines, VIP
Posttranslational modification
- Role of prohormone convertases (PCs)
long transcript with synthesis of
products regulating energy
metabolism
Functions of POMC-derived peptides
Adrenal glands - ACTH
- the only POMC hormone with effect on adrenal
glands
- MC2R receptor for melanocortin)
- Glucocorticoids, androgens, (mineralocorticoids)
- Mitogennic effect on adrenal glands (N terminal
peptide)
Skin pigmentation – ACTH, b-LPH, g-LPH
- MC1R
- Paracrine regulation (melanocytes, keratinocytes)
Regulation of appetite – a-MSH
- Inhibition of inhibitory effect of leptin
- Activation of MC3R and MC4R (hypothalamus)
Immune functions – a-MSH
- Inhibition of leukocyte migration
- Inhibition of macrophage functions
- Modulation of antigen-presenting and T cells
Analgesia – b-endorphin
- Circulating probably without effect on CNS
Placental POMC
- 2nd trimester
- Decrease 3 days after birth
- No correlation to ACTH/cortisol of mother
- Unknown physiological function
Ectopic synthesis of POMC/ACTH
- Mainly tumors with ability of posttranslational
changes
MSH – melanotropins
α-MSH: Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val
β-MSH: Ala-Glu-Lys-Lys-Asp-Glu-Gly-Pro-Tyr-Arg-Met-Glu-His-Phe-Arg-Trp-Gly-Ser-Pro-Pro-Lys-
Asp
γ-MSH: Tyr-Val-Met-Gly-His-Phe-Arg-Trp-Asp-Arg-Phe-Gly
- Pregnancy (+)
- Adrenal glands (hypofunction)
Clinical significance
-Synthetic analogues
-Afamelanotide – photoprotection
-Melanotan II – increased libido
-Bremelanotide – aphrodisiac effect (MC3R and MC4R)
ACTH
Secretion
-Circadian and ultradian rhythms
-Rise from 16:00 with peak before 19:00
-Lowest levels between 23:00 and 3:00
-Pulsatile secretion (ca 40/day, higher in males)
ACTH and stress
- Complex – peripherial and central stress adaptors
- Vasovagal and sympathetic activation (catecholamines), cytokine secretion
- Pain, infection, inflammation, bleeding, hypovolemia, trauma, hypoglycemia, psychological stress
- Higher amplitude of ACTH pluses
Secretion regulation
- Very complex - neuroendocrine control of stress response and homeostasis
- Regulatory molecules – CNS, hypothalamus (CRH, ADH, dopamine) – corticotropic cells
- Cytokines (IL-6, LIF), growth factors – adenohypophysis – local control (paracrine)
- Glucocorticoids
- Negative feedback mechanism – inhibition of CRH secretion, decrease of basal
ACTH secretion
- Modulation of somatostatin inhibitory effect (downregulation of R)
- Dopamine
- Physiological regulation of secretion – exercise (athletes – hypercortisolism)
Function
- Adrenal glands size,
structure and function
- Steroidogenesis stimulation
Clinical significance
- Deficiency ACTH
- Hypersecretion of ACTH
- Testing - insulin
Adrenal glands
Adrenal cortex - Steroid hormones
- Glucocorticoids
- Mineralocorticoids
- Androgens
Adrenal medulla
- Catecholamines
- Epinephrine (adrenaline)
- Norepinephrine (noradrenaline)
- Dopamine
Corticomedullary portal system
Function
- Stress response
- Na+, K+, ECT
- Blood pressure
Fetal adrenal gland and its importance
- Placental CRH stimulates production of DHEA,
corresponding sulphate and cortisol in fetal adrenal gl.
- DHEA/DHEAS is in placenta converted to estrogen
(preparation and promotion of birth)
- Cortisol upregulates ACTHR, but also prostaglandin
and uterotonics in placenta (birth)
- Cotisol is necessary for maturation of fetal lungs
- Progesterone inhibits placental CRH
Adrenal gland hormones
Functional architecture of adrenal gland allows transport of steroid hormones into medulla and influences activity of
enzymes connected to catecholamine synthesis.
ERLipiddroplets
15 %
75 %
10 %
Adrenal medulla
Adrenaline secerning cells
(90 %)
Noradrenaline secerning cells
(10 %)
Dopamine secerning cells
(?)
Secretory vesicles contain apart from catecholamines also ATP, neuropeptides – adrenomedullin, ACTH, VIP, calcium,
magnesium and chromogranines.
Medulla - NA Cortex
Adrenal medulla
Preganglionic sympathetic neurones
Sympathetic nervous ganglion – medulla
acetylcholine
Cholinergic receptors of chromaffin cells
(feochromocytes)
Catecholamines release
Catecholamine synthesis is regulated by negative feedback loop through
effect of noradrenaline.
Adrenaline synthesis is influences by steroid hormone production in
adrenal cortex.
Noradrenaline conversion takes place in cytoplasm. It is then transported
into vesicles by ATP-controlled transport (monoamine transporter VMAT1).
Catecholamines secretion
Is determined by direct sympathetic stimulation:
1. Binding of Ach on nicotinic cholinergic receptors
(ligand-gated ion channels)
2. Rapid Na+ influx and depolarization
3. Activation of voltage-gated Ca2+ ion channels
4. Influx of Ca2+ ions
5. Secretory vesicles associated with voltage-gated Ca2+
ion channels
6. Exocytosis – intersticium
7. Modulation of NA release by NA itself through a2-AR
(inhibition)
8. Transport to target organs
Constitutive secretion
- Spontaneous
- Ca2+ independent
Regulated secretion
- Ca2+ dependent
- Complex system of sorting and „packaging“
Transport and metabolization of
catecholamines
- Very short half-life in circulation (cca 2 min)
- Binds to albumin (50 %) with very low
affinity
- Reuptake (up to 90 % - nerve endings, 10 %
uptake extraneuronal tissues) and
degradation
- Catechol-O-methyltransferase (COMT) –
metadrenaline, normetadrenaline
- Monoaminooxidase (MAO) – deamination
- Aldehyde dehydrogenase
- Direct filtration (kidneys)
- Final degradation product is
vanillylmandelic acid (A, NA) and
homovanillic acid (DOP)
Physiological effects of catecholamines
Physiological effects of catecholamines are mediated through G-protein-coupled adrenergic receptors. Catecholamines from
adrenal medulla cannot cross HEB and affect peripherial tissues.
Adrenergic receptor G protein Secondary messenger Ligand
a1-adrenergic
a1A, a1B, a1D
Mainly GQ/11 Activation of PLCa, PKC, increased
concentration of intracellular Ca2+ ions
Noradrenaline > adrenaline >>
(isoprenaline)
a2-adrenergic
a2A, a2B, a2C
Mainly Gai and
G0
Decreased activity of AC (antagonistic
effect to k b-AR). Activation of K+ ICH,
inhibition of Ca2+ ICH. Activation of
PLCb or PLA2.
adrenaline = noradrenaline >>
isoprenaline
b1-adrenergic Gas Activation of AC and increased cAMP
concentration
Isoprenaline > adrenaline =
noradrenaline
b2-adrenergic Gas Activation of AC and increased cAMP
concentration
Isoprenaline > adrenaline >>
noradrenaline
b3-adrenergic Gas Activation of AC and increased cAMP
concentration
Isoprenaline = noradrenaline >
adrenaline
D1 family
D1, D5
Gas
GOlf
Activation of AC and increased cAMP
concentration
dopamine
D2 family
D2, D3, D4
Gai Inhibition of AC and decreased cAMP
concentration
dopamine
Main effects of catecholamines - overview
Mediated by a-AR Mediated by b-AR
Vasoconstriction Vasodilatation
(+) inotropy (+) chronotropy
Smooth muscle relaxation (GIT) (+) dromotropy
Sphincter contraction (GIT) (+) inotropy
Mydriasis Smooth muscle relaxation (GIT)
Stimulation of saliva and tear secretion Musculus detrusor relaxation
Bronchoconstriction Bronchodilatation
Ejaculation Calorigenesis, thermogenesis
Gluconeogenesis (liver) Glycogenolysis
(-) insulin secretion Lipolysis
Thrombocytes aggregation (+) renin secretion
(+) Na+ reabsorption (kidneys) (+) glucagon secretion
Pilomotor muscle contraction Accommodation of distance vision
Clinical relevance
- Antagonistic effect of various
a2AR subtypes
- A – decresed blood pressure
- B – increased blood
pressure (vasoconstriction)
- Wide use of agonists and
antagonists in clinical practice:
- Cardiology
- Ophthalmology
- Internal medicine
Physiological effects of catecholamines
Catecholamine secretion stimuli
- Sympathetic stimulation (generally)
- Stress response (physical, psychical stress)
- Bleeding and blood loss
- Hypoglycemia
- Trauma
- Surgery
- Fear
- „fight or flight“
Acute response to stress stimuli
- e.g. bronchodilatation, sphincter contraction,
tachycardia, peripherial vasoconstriction and
increased peripherial resistance, inhibition of
motility (GIT)
Ensuring energy requirements
- Mobilisation of substrates – liver, muscles,
adipose tissue
- Glycogenolysis, lipolysis
- Effect – increased glycemia, concentration of
glycerol, FFA
Regulation of adrenergic receptors
- Chronic stimulation = changes in sensitivity (biological
response) of target tissues
- Desensitization of AR (phosphorylation)
- Internalization of AR
- Upregulation:
- Glucocorticoids
- Thyroid hormones
- Different upregulation of various AR receptors!
Clinical relevance
- Changes in target tissue sensitivity during chronic
administration of agonists/antagonists
- Chronic application of b-agonists – asthma
- Chronic application of a-agonists – tachyphylaxis
(intranasal decongestants)
- Feochromocytom
Biochemical aspects
- Monitoring of catecholamine secretion - urine
Dopamine
Functions of dopamine outside of CNS :
- Hormone, paracrine and autocrine factor
- Cannot cross HEB!
- Regulation of ECF volume and ion balance
- increased GFR
- natriuretic effect
- Immune function
- (-) lymphocyte activation
- Endocrine pancreas
- (-) insulin secretion
- Heart
- (+) inotropy
- (+) systolic blood pressure
- (0) diastolic blood pressure
Clinical relevance
- i.v. application in newborns
- Treatment of acute kidney damage?
- Cardiogenic shock
- Septic shock
DR
Family D1 Family D2
D1 D5 D2 D3 D4
(-) ion
transport
in GIT
(-) Na+ and
water in
kidneys
Relaxation
of smooth
muscle
(-)
sympathetic
n.s. (CNS)
Blood pressure regulation
Chromogranin A
Characteristics
- Acidic glycoprotein
- Precursor protein for:
- Vasostatin-1
- Vasostatin-2
- Pancreastatin
- Catestatin
- Parastatin
- Chromaffin cells of AM
− b-cells of pancreas
- Paraganglia
- ECL cells
eNOS
Functions and relevance
- Cardioprotective effect (catecholamines)
- Autoantigen – DM1
- Hormone secerning CgA - marker
Adrenomedullin - AMD
Characteristics
- Hormone, neuromodulator,
neurotransmitter
- Peptide (partial homology with CGRP)
- Receptors – combination of CALCR +
RAMP2/3 – AM1/2
- Found in:
- CNS
- Blood vessels
- Myocardium
- Tumour tissue
Functions
- Vasodilatation (cAMP, NO)
- Cardioprotection
- Protection during oxidative stress
- Protection from hypoxic damage -
angiogenesis
Hormones of adrenal cortex
Hormones of adrenal cortex = cholesterol
derivates
⁻ C21 steroids with two carbon chain in
position C17
⁻ Mineralocorticoids
⁻ Glucocorticoids
⁻ C19 steroids with keto- or hydroxyl group
in position C17
⁻ Androgens
⁻ C18 steroids with 17-keto or hydroxyl
group without angular methyl group in
position C10
Source of cholesterol – cholesterol esters or plasma membrane
STAR (Steroid Acute Regulatory) proteins
- Transfer of cholesterol into inner
mitochondrial membrane
Regulation of synthesis
- Acute (minutes) versus chronic
Synthesis and secretion of steroid hormones
Glucocorticoids - pulsatile character under ACTH stimulation (cortisol – 10 – 20 mg/day)
Mineralocorticoids – ACTH only basal secretion, RAAS – angiotensin II (aldosterone – 100 – 150 mg/day)
Androgens – ACTH (DHEA, DHEAS, androstenedione – 100 – 150 mg/day)
Different expressions of enzymes catalyzing steps in steroid conversions are responsible for
synthesis of various steroid hormones in individual zones of adrenal cortex.
Regulation of synthesis and secretion
Glucocorticoids
- ACTH – GaS – activation of AC and
PAK
- Phosphorylation of cholesterol ester
hydrolase
- Increased availability of cholesterol
- Increased STAR synthesis
Mineralocorticoids
- Angiotensin II and extracellular K+
- ACTH (only basal and acute
secretion)
- RAAS system
- Renin (juxtaglomerular cells)
- Conversion of angiotensinogen
- Angiotensin II stimulates
aldosteron synthesis and
secretion
- Inhibition also by somatostatin and
dopamine
Circadian and pulsatile secretion of ACTH and cortisolMaximuminearlymorning
Increasedfrequencyandamplitudeofpulses,lossof
circadiansecretion
Glucocorticoid metabolism
- Lipophilic
- Conjugates
- Binding to CBG proteins (transcortin, cortisol-binding
globulin) and albumin
- Half-life 70 – 90 min
Cortisol-
CBG
- Up to 80 %
Free cortisol
- Up to 10 %
Cortisol-
albumin
- 20 – 50 %
estrogens
cirrhosis
Detoxication
- Liver
- Kidney
- Reduction, oxidation, hydroxylation and conjugation
- Glucuronides and sulphates
Local glucocorticoid metabolism
- Tissues with different expression of isoforms of 11bhydroxysteroid
dehydrogenase type I (conversion
cortisone to cortisol)
- Liver, adipose tissue, lungs, skeletal muscle,
smooth muscles of blood vessels, gonads, CNS
- Tissues with different expression of isoforms of 11bhydroxysteroid
dehydrogenase type II
- Tubular system
Conversion of cortisol to cortisone is essential for
prevention of cortisol binding to mineralocorticoid
receptor.
Effects of glucocorticoids
All tissues express glucocorticoid receptors, which
causes their wide array of effects.
1. Binding of GC on corresponding receptor
2. Conformational change and dissociation of
receptor from complex HSP70 and HSP90
3. Migration to nucleus
4. Binding on GRE together with activating
protein (AP1)
Glucocorticoids affect intermedial metabolism,
stimulate proteolysis and gluconeogenesis, inhibit
proteosynthesis (mainly in muscles) and stimulate
mobilization of FFAs.
Specific effects of glucocorticoids
System Induced gene expression Suppressed gene expression
Immune system Inhibitor of NF-κB, haptoglobin, TCR, p21,
p27, p57, lipocortin
Interleukins, TNF-α, interferon-g, Eselectin,
COX-2, iNOS
Metabolism PPAR-g, glutamine synthase, glycogen
synthase, Glu-6-phosphatase, leptin, gfibrinogen,
cholesterol 7a-hydroxylase
Tryptophan hydroxylase,
metalloproteases
Bone tissue Androgene receptor (AR), calcitonin receptor
(CTR), alcalic phosphatase, IGFBP6
Osteocalcin, collagenase
Ion channels and transporters ENaC-α, -β a –g, SGK, aquaporin 1
Endocrine system Basic FGF, VIP, endothelin, RXR, GHRH
receptor, receptors for natriuretic peptides
GCR, prolactin, POMC/CRH, PTHrP,
ADH
Growth and development Surfactant proteins A, B, C Fibronectin, a-fetoprotein, NGF,
erythropoietin, G1 cyclins and CDKs
Effects of glucocorticoids - overview
Cardiovascular system:
- Increased sensitivity to catecholamines (a2-AR)
- Increased sensitivity to angiotensin II
- Inhibition of NO-mediated vasodilatation
- Stimulation of angiotensinogen synthesis
- HSD11B2-activity-dependent increase in Na+
retention in distal tubulus and increased K+ excretion
- Increased GFR
- Increased resorption of Na+ in proximal tubulus
Increasedbloodpressure
Immune system:
- Decrease in lymphocyte count (T more than B)
based on redistribution to spleen, lymphatic nodes
and bone marrow
- Increased number of neutrophils
- Decreased number of eosinophils and basophils
- Inhibition of monocyte-macrophage differentation
- Inhibition of immunoglobulin synthesis
- Inhibition of cytokine synthesis
- Inhibition of histamine and serotonin secretion
from mast cells
- Inhibition of prostaglandine synthesis
Anti-inflammatoryand
immunosuppressiveeffect
Glucocorticoids – clinical aspects
Field Utilization
Endocrinology Substitution therapy
Dermatology Dermatitis
Haematology, hematooncology Leukemia, lymphoma, haemolytic anemia,
immune thrombocytopenic purpura
Gastroenterology Ulcerative colitis, Crohn’s disease
Internal medicine, Infectious diseases Chronic active hepatitis, transplantation,
nephrotic syndrome, vasculitis
Neurology Cerebral edema, increased intracranial
pressure
Pneumology Asthma, angioedema, anaphylaxis,
sarcoidosis, obstructive pulmonary
diseases
Rheumatology Systemic lupus erythematosus, arteritis,
rheumatoid arthritis
Glucocorticoids are
characteristic by not only
glucocorticoid, but also
mineralocorticoid activity and
by ability to affect axis CRHACTH-GC
by feedback loop.
Long-term glucocorticoid
application:
- Steroid diabetes
- Secondary osteoporosis
- Dexamethasone test
- Metyrapone test
- CRH stimulation test
Glucocorticoids – clinical aspects
Cushing syndrom Addison disease
Mineralocorticoids – regulation of aldosteron secretion
Effects of mineralocorticoids
Main effects of aldosterone
- Stimulation of epithelial Na
transport
- Distal tubulus and
collecting duct
- Distal colon
- Salivary glands
Mechanism of effect
- (+) synthesis of Na+ IK
- (+) synthesis of Na+/K+-ATPase
- (+) activity of Na+/K+-ATPase
- (+) synthesis of H+-ATPase
- (+) synthesis of Cl-/HCO3
-
exchanger
Receptors
- Limited distribution
- Keratinocytes
- Neurons (CNS)
- Myocytes
- Smooth muscle cells in large
blood vessels
Adrenal gland androgens
Androgens produced in adrenal glands represent more than 50 % of circulating androgens in premenopausal women.
In men dominates the testicular production.
- DHEA is important precursor for sex hormones synthesis
- Conversion by enzymes from b-hydroxysteroid
dehydrogenase group and aromatase in peripherial
tissues
- Possible presence of CASH (cortical androgenstimulating
hormone)
Possible functions of adrenal gland androgens
- Libido and its „regulation“
- Cardioprotective effects in men
- Possible protective role from ovarial and breast
carcinoms in premenopausal women
- Neuroprotection
- Effect on synthesis and secretion:
- IGF-1
- Testosterone and dihydrotestosterone
- Estradiol
Clinical aspects
- Congenital adrenal hyperplasia (CAH)
- prenatal virilization (high androgen concentration in
utero)
- Deficit of 21b-hydroxylase, „salt wasting form“
- Deficit of 11β-hydroxylase, „hypertensive form“
- Deficit of 3β-hydroxysteroid dehydrogenase II
- Deficit of 17α-hydroxylase
- Congenital lipoid adrenal hyperplasia
- Defective conversion of cholesterol to pregnenolone
- Adrenogenital syndrome
- Hyperaldosteronism
- Primary hyperaldosteronism
- Secondary hyperaldosteronism with increased renin
level
- Secondary adrenal insufficiency (ACTH)
- Tertiary adrenal insufficiency (CRH)
- Hyporeninemic hypoaldosteronism
- Pseudohypoaldosteronism
Apparent mineralocorticoid excess syndrome
- Inhibition or absence of 11β-hydroxysteroid
dehydrogenase II
Watch out for liquorice ☺