Special pathophysiology
of endocrine system
Thyroid and adrenal glands
Mechanisms of endocrine diseases
• (1) hormone deficiency
• destruction process in the gland
• hereditary
• genetic defect
• acquired
• infection
• infarction
• compression by tumour
• autoimunity (type II hypersensitivity mostly –
cellular or antibody cytotoxicity)
• (2) hormone excess
• autotopic – in the very gland
• tumours (adenomas)
• immunopathologic (type V hypersensitivity –
stimulatory anti-receptor Ig)
• ectopic – elsewhere
• tumours
• exogenous (iatrogenic) – therapeutic use
• (3) hormone resistance
• abnormal hormone
• antibodies against hormone or receptor
• receptor defect
• post-receptor defect
The Thyroid
Pathophysiology of thyroid gland
Hormone synthesis by follicular cell
The sodium-iodide symporter
“Organification” of TG & coupling
of thyrosines, liberation of T3/T4
Secretion of thyroid hormones
• upon stimulation by TSH, droplets
of iodinated thyroglobulin return to
the follicular cell by endocytosis
• the droplets fuse with lysosomes,
forming an endosome
• proteases from the lysosomes
breakdown peptide bonds between
the iodinated residues and
thyroglobulin molecules to yield
T3, T4, MIT and DIT
• free T3 and T4 cross the cell
membrane and are discharged into
the capillaries
• T4 limitedly de-iodinated
• bound to TBG (75%), transthyretin
(15%) and albumin (10%)
• MIT and DIT are liberated into the
cytoplasm, the iodines are
removed by a deiodinase, and
they and the tyrosines are reused
• peripheral de-iodination
• liver, kidneys, others
Summary Peripheral modulation of T4 and T3 levels
• activity: T3 10× >> T4 > rT3
• enzymatic conversion by deiodinases
• activation (by D1 and D2): T4 → T3
• inactivation (by D3):T4 → rT3 (→ T2)
• tissue and organ specificity
Summary Control of the T3/T4 production
• hypothalamus:
• TRH
• somatostatin
• pituitary:
• TSH
• binding of TSH to TSH-R
stimulates:
• synthesis of the iodide
transporter
• thyroid peroxidase
• synthesis of thyroglobulin
• rate of endocytosis of colloid
• thyroid autoregulation
• iodide uptake and transport
Quantitatively Molecular basis of T3/T4 action
• complexes thyroid
hormone/hormoneactivated
nuclear
receptors act as
transcription factors
• modulation of gene
expression
• in contrast to
steroid hormone
receptors, thyroid
hormone receptors
bind DNA already in
the absence of
hormone, usually
leading (in inactive
state) to
transcriptional
repression
Thyroid hormone receptors
• encoded by two genes,
designated alpha and beta
• further, the primary transcript
for each gene can be
alternatively spliced, generating
4 different alpha and beta
receptor isoforms): α-1, α-2, β-
1 and β-2
• different forms of thyroid
receptors have patterns of
expression that vary by tissue
and by developmental stage
• THR bind to a short, repetitive
sequences of DNA called
thyroid or T3 response
elements (TREs)
• T3 bind to a TRE as monomers,
as homodimers or as
heterodimers with the retinoid X
receptor (RXR)
• the heterodimer affords the
highest affinity binding - the
major functional form of the
receptor
• change from co-repressor
complex binding (T3 absence)
to co-activator complex binding
(T3 presence)
T3 action on gene transcription
Physiologic effects of T3/T4
• (1) development
• profound effects on the terminal stages of
brain differentiation, including
synaptogenesis, growth of dendrites and
axons, myelination and neuronal migration
(esp. in the fetal period)
• the net effect of pregnancy is an increased
demand on the thyroid gland
• in the normal individuals, this does not appear
to represent much of a load to the thyroid
gland, but in females with subclinical
hypothyroidism, the extra demands of
pregnancy can precipitate clinicial disease
• (2) growth
• T3 is a critical determinant of postnatal
linear bone growth and mineralisation
• growth-retardation observed in thyroid
deficiency
• the growth-promoting effect of thyroid
hormones is intimately intertwined with that of
growth hormone and IGF
Physiologic effects of T3/T4
• (3) metabolism
• increase in basal metabolic
rate and thermoregulation
• increase body heat production
from increased O2 consumption and
rate of ATP hydrolysis
• lipid metabolism
• fat mobilization → increased
concentrations of FFA in plasma
• oxidation of FFA
• plasma concentrations of
cholesterol and triglycerides
are inversely correlated with thyroid hormone levels
• carbohydrate metabolism
• stimulate almost all aspects of carbohydrate metabolism, including
enhancement of insulin-dependent entry of glucose into cells (via
GLUT4) and increased gluconeogenesis and glycogenolysis to
generate free glucose
• protein metabolism
• (4) other effects
• cardiovascular, CNS, reproductive system
CHRONOBIOLOGY OF THE
THYROID
Circadian rhythm
„Molecular clock“
• inner biological rhythmicity is caused by negative and positive
feedbacks between transcription of clock genes (CGs), their
translation, postransl. modification and degradation
• their products - proteins – then serve as transcription factors of
other hundreds of genes (CCGs) n n. suprachiasmaticus and
peripherally
• they synchronize the body according to external environment
• hypothalamus
• clock genes (CGs)
• Clock
• BMal1 (Mop3), BMal2
• Per1, Per2 (Period)
• Cry1, Cry2 (Cryptochrome)
• Rev – Erb-α
• CK1Є CK1δ (caseinkinase)
• clock-controlled genes (CCGs)
• Per 3
• AVP (arginin vasopresin)
• Dbp (D-element binding
protein)
• peripheral organs
Seasonal clocks - analogy with circadian
clocks
• in long-lived species
there is evidence for
the existence of selfsustained
circannual
oscillators
• migratory
restlessness
• hibernation
• seasonal moulting
• seasonal breeding
Thyroid function assessment
• serum
• hormones
• TSH, T4, T3, fT4, fT3, rT3
• antibodies
• anti-thyroglobulin (anti-TG), anti-thyroid
peroxidase antibodies (anti-TPO)
• calculated indexes
• fT4/fT3, fT3/rT3
• thyroid ultrasound
• radionuclide thyroid scan – iodine
(123I) or pertechnatate (Tc-99)
• detection of nodules and to assess
thyroid function
• fine needle aspiration
DISEASES OF THE THYROID
GLAND
Goiter (struma)
• abnormal enlargement of the
thyroid gland that is not
associated with inflammation
or cancer
• presence of a goiter does not
necessarily mean that the
thyroid gland is
malfunctioning
• gland that is producing too
much hormone
(hyperthyroidism)
• too little hormone
(hypothyroidism)
• or the correct amount of
hormone (euthyroidism)
• presence of goiter indicates
there is a condition present
which is causing the thyroid
to grow abnormally
Types of goiter
• simple (non-toxic, euthyroid)
• causes
• endemic
• caused by a deficiency of iodine in the diet (inland and highland areas of all
continents)
• sporadic
• “strumigens” in the diet (e.g. cabbage, soybeans, peanuts, peaches,
strawberries, spinach, and radishes)
• form
• usually diffuse
• toxic (hyperthyroidism, thyrotoxicosis)
• form
• nodular or diffuse
Endemic goiter
• inland, mountainous
districts all over the
world
• affects almost 13% of
population
• another 30% are in a risk
of a manifest deficit
• Himalayas – Pakistan,
India and Nepal, China,
Thailand and Vietnam,
Indonesia, New Zealand,
Europe, Andes, Africa
• cretinism
• neurologic form
• myxedematous form
• iodine prophylaxis !!!
Thyroid endocrinopathies from the
functional point of view
• Hyperthyroidism
• Graves’ disease (toxic
diffuse goitre)
• autoimmune
• toxic nodular goitre
(Plummer’s disease)
• toxic adenoma
• thyroiditis
• primary and/or
metastatic follicular
carcinoma
• TSH-producing
tumour of the
hypophysis
• Hypothyroidism
• hypothalamic or
pituitary
• autoimmune
thyroiditis
(Hashimoto)
Toxic goiter
• nodular (Plummer’s
disease)
• autonomous
function of one or
more thyroid
adenomas in a part
of the gland
• diffuse (GravesBasedow’s
disease)
• stimulation by antiTSH
antibodies
(type V hs) [LATS =
long-acting thyroid
stimulators]
Hyperthyroidism (thyrotoxicosis)
• predominance of
women, middle age
Grave’s disease
• hyperthyroidism +
• infiltrative
ophthalmopathy
• ~1/2 od the cases,
independent on
hyperthyroidism
• involves periorbital
connective tissue,
ocular muscles and
fat
• infiltrative
dermopathy
• ~1/5 of cases
• pretibial myxedema
Ophthalmopathy
Hypothyroidism
• often results of
(auto)immune
destruction of the
thyroid
• de Quervain
thyroiditis
• Hashimoto thyroiditis
• usually transitory
hyperthyroidism in
acute phase, then
cessation of function
• predominance of
women, middle age
The Adrenals
Pathophysiology of adrenals
Major steroid biosynthetic pathways
• p450 enzymes are in mitochondria, each catalyses several reaction steps
• 3βHSD (hydroxysteroid dehydrogenase) is in cytoplasm, bound to endoplasmic
reticulum
• 17βHSD and p450aro are found mainly in gonads
Cortisol profile & regulation Glucocorticoid (GC) receptor
• GCs have receptor (GR) existing in two isoforms
• cytoplasmic (cGR)
• membrane bound (mGR)
• therefore, GCs have several modes of action
• genomic – mediated by cytosolic receptors (cGR) upon
binding to GC responsive elements (GREs)
• non-genomic – mediated by cGR, mGR and non-specific
effects by interaction with other proteins and cell membranes
• receptor activation
• cGR has 3 domains: N-terminal transactivation domain /
DNA-binding domain / ligand-binding domain
• following synthesis GRs are located in the cytoplasm in the
complexes with molecular chaperons
• Hsp-70 – newly synthesized, helps further folding of the
nascent GR
• Hsp-90 – helps to full maturation and achieving hormoneactivavable
state
• GR/Hsp (+ other proteins) complexes
• protect GRs from degradation by proteasome
• increase affinity of GRs for GCs (~100×)
• blocking action of other proteins (e.g. MAPK) bound to
complex
• upon binding of GC in cytoplasm → conformational
changes and release from inhibitory complexes with
Hsp → translocation to nucleus and homodimerisation
• binding to hormone responsive elements (HREs)
• short specific sequences of DNA located in promoters
• phosphorylation
• induction of transcription
• binding to HRE facilitate binding of TF to TATA box
• complex hormone-receptor - HRE thus function as an
enhancer
GC action – genomic effects
• (A) genomic effects – via cGR –
majority of metabolic effects are
achieved by genomic effects
• GC responsive genes represent ~ 20%
of all coding genes, indispensable for
life
• GR knock-out animals are not viable!!
• effects:
• (1) transactivation = binding to GREs
• short specific sequences of DNA
located in promoters →
gene transcription [I]
• (2) transrepression = binding to negative
GRE (nGRE) [II]
or interaction with other TF [III] or their
coactivators [IV]
• repression of transcription or blocking
action of other TF
on gene transcription (such as AP-1,
NFkB, ...)
• the whole sequence of events following
binding of GCs to cGRs takes at least
20-30min – late effects compared to
the action of peptide hormones or
non-genomic action of GCs
• affinity of steroid receptors (for GC,
aldosteron, estradiol)
is not specific!!
• e.g. GCs bind avidly to MR in brain, not in
kidney though (degraded)
• (B) non-genomic effects – many of
anti-inflammatory and
immunosuppressive effects
Steroid hormone receptor signalling
• GR act as hormone dependent
nuclear transcription factor
• upon entering the cell by
passive diffusion, the hormone
(H) binds the receptor[1], which
is subsequently released from
heat shock proteins [2], and
translocates to the nucleus [3]
• there, the receptor dimerizes
[4], binds specific sequences in
the DNA [5], called Hormone
Responsive Elements or HREs,
and recruits a number of coregulators
[7] that facilitate
gene transcription
• this latter step can be
modulated by certain cellular
signalling pathways [10] or
receptor antagonists (like
tamoxifen [11])
• subsequent gene transcription
[8] represents a genomic effect
of GC
• action is terminated by
proteasomal degradation [9],
• other, non-genomic effects are
mediated through putative
membrane-bound receptors [6]
Metabolic effects of GC – increased turnover
of free and stored substrates
Tissue/organ Physiologic effects Effects of overproduction
Liver −hepatic gluconeogenesis (↑↑↑↑ Glc)
(stimulation of key enzymes – pyruvate
carboxylase, PEPCK, G6Pase)
impaired glucose
tolerabce/diabetes mellitus
hepatic lipogenesis (↑↑↑↑ FA and VLDL)
(stimulation of key enzymes acetyl-CoAcarboxylase
and FA synthase)
steatosis/steatohepatitis
Adipose
tissue
−lipolysis in subscutaneous fat (↑↑↑↑ FFA)
(activation of HSL and inhibition of LPL)
insulin resistance in the muscle
(competition of FFA with Glc for
oxidation)
↓Glc uptake
(down-regulation of IRS, inhibition of PI3K, Glut4
translocation)
insulin resistance by interference
with insulin post-receptor
signalling
−adipocyte differentiation in visceral fat
(expression of GR and 11βHSD1 different in
adipose and visceral fat)
truncal (abdominal) obesity,
metabolic syndrome
Skeletal
muscle
↓ Glc uptake
(down-regulation of IRS, inhibition of PI3K, Glut4
translocation)
insulin resistance by interference
with insulin post-receptor
signalling
−proteolysis, ↓↓↓↓ proteosynthesis (↑↑↑↑ AA)
(counteracting effect of IGFs, activation of
ubiquitin-mediated degradation, induction of
myostatin and glutamine synthetase)
muscle atrophy, weakness, steroid
myopathy
Pancreas
(β cells)
↓↓↓↓ insulin secretion
(supression of GLUT2 and K+ channel, apoptosis)
impaired glucose
tolerabce/diabetes mellitus
Peripheral modulation of GC availability
• peripheral tissue-specific modulation of cortisol availability by enzymes catalysing
interconversions of active and inactive forms of GCs
• (a) 11β hydroxysteroid dehydrogenase type 1 (11βHSD1)
• act as a reductase regenerating cortisol from cortisone → ↑ intracellular corticol concentration
• mainly in liver and adipose tissue
• expression of 11βHSD1 is higher in visceral than subcutaneous fat! → visceral fat is therefore more flexible pool of energy
substrate
• often co-localises with GR (e.g. in liver and adipose tissue) and thus locally amplifies the GC action
• 11βHSD1 overexpressing mice develop obesity, while 11βHSD1 knock-out mice are protected from overeatinginduced
obesity
• liver and fat-tissue specific inhibitors of 11βHSD1 could be used for treatment of metabolic syndrome and obesity
• pathology associated with 11βHSD1
• Cushing syndrome – higher expression of 11βHSD1 in visceral fat – normally first source of substrate, but higher
suppression with GC, while enhanced GC action leads to lipolytsis in adipose tissue, the fat cumulates in visceral
• congenital deficiency of 11βHSD1 (apparent cortison reductase deficiency) → compensatory over-activation of HPA
axis → adrenal androgen excess, oligomenorhea, hirsutism in women
• overexpression of 11βHSD1 in subcutaneous tissue (congenital or acquired) leads to lipodystrophy
• 11βHSD1 plays a role in the pathogenesis of polycystic ovary syndrome
• regulation: starvation, cortisol, other hormones
• (b) 11β hydroxysteroid dehydrogenase
type 2 (11βHSD2)
• act as a dehydrogenase degrading cortisol to
cortisone → ↓ intracellular corticol concentration
• mainly in kidney
• by degrading cortisol 11βHSD2 enables tissuespecific
preferential action of aldosterone on MR
even though concentration of plasma cortisol
>>> aldosterone
• pathology associated with 11βHSD2
• congenital deficiency of 11βHSD2
(apparent mineralocorticoid excess) →
monogenic form hypertension
• 11βHSDě is expressed in placenta (maintains lower
cortisol in fetal circulation than in maternal) –
deficient action contributes to pregnancy pathologies
(preeclampsia, IUGR, ...) and possibly to fetal
metabolic programming
Summary – availability of GCs GC action on immunity
• suggested to be mediated via:
• genomic effects [I]
• transactivation and
transrepression of many
immunoproteins
• non-genomic effects
• cGR by sequestering proteins
[II]
• e.g. kinases (MAPK) →
blockade of action
• mGR [III] - multi-protein
complexes with other
membrane receptors →
blockade of action
• e.g. growth factors
• alternatively, induction of
apoptosis
• direct interactions of GC with
cellular membranes [IV] →
intercalation into membrane
→ stabilisation
• inhibition of Na/Ca exchange
• increase of proton leak in
mitochondria → less ATP
• ↓ATP-dependent
processes in immune
system (cytokinesis,
migration,
phagocytosis, antigen
processing and
presentation, Ig
synthesis,
cytotoxicity, …)
GCs and immune system
Glucocorticoid effects on primary and secondary immune cells
Monocytes /
macrophages
↓ Number of circulating cells (↓ myelopoiesis, ↓ release)
↓ Expression of MHC class II molecules and Fc receptors
↓ Synthesis of pro-inflammatory cytokines (e.g. IL-1, -2, -6, TNFα) and
prostaglandins
T cells ↓ Number of circulating cells (redistribution effects)
↓ Production and action of IL-2 (most important)
Granulocytes ↑ Number of circulating neutrophils
↓ Number of eosinophile and basophile granulocytes
Endothelial cells ↓ Vessel permeability
↓ Expression of adhesion molecules
↓ Production of IL-1 and prostaglandins
Fibroblasts ↓ Proliferation
↓ Production of fibronectin and prostaglandins
Examples of multiple action of
GCs on immunity
Balance of Th1/Th2 immune responses - Th2
shift as a consequence of stress
Summary – effects of GC on immunity
Glucocorticoid excess: Cushing’s
syndrome
• Etiology
• primary adrenal tumor
• ACTH-producing
pituitary tumor
(Cushing’s disease)
• ectopic ACTH production
• small cell lung
carcinoma
• excess CRH from the
hypothalamus tumor or
by an ectopic CRHproducing
tumor
Cushing’s disease
Adrenocortical insufficiency
• Etiology
• primary adrenal disease
(Addison's disease)
• destructive process
usually affecting all zones
of the cortex
• decreased production of
cortisol, aldosterone and
adrenal androgens
• secondary to inadequate
secretion of ACTH
• Sheehan's syndrome
• after severe postpartum
hemorrhagic or
infectious shock,
ischemic damage to the
pituitary
• Symptoms
• weakness (↑K)
• anorexia, hypotension
(↓Na)
• nausea, diarrhea or
constipation (↑Ca)
• vomiting (hypoglycemia)
• abdominal pain
(lymphocytosis)
• weight loss
• hyperpigmentation (POMC
→ MSH → melanocytes)
Addison’s disease
• autoimmune destruction (type II hs)
• gradual destruction of the adrenal cortex
• adrenal insufficiency occurs when at least 90%
of the adrenal cortex has been destroyed
• TBC
• necrosis (Waterhouse-Friderichsen
syndrome)
• acute adrenal insufficiency due to massive
haemorrhage into the adrenal gland, more
often bilateral, caused by meningococcus
infection
Mineralocorticoid regulation Hyperaldosteronism
• increased secretion of
aldosterone
• etiology
• primary
hyperaldosteronism
• unilateral adenoma
(Conn's disease)
• 70%, benign tumor
• bilateral adrenal
hyperplasia
• secondary
hyperaldosteronism
• ↑ RAAS
• ↑ ACTH
• tertiary
hyperaldosteronism
• decreased aldosterone
clearance – liver disease