Ppathophysiology of endocrine
system III
Thyroid gland
Adrenal cortex na medulla
Endocrine system
• network of specialized endocrine glands in
the body that make the hormones
• CAVE many more organs/tissues produce
hormones
• discrete clusters of cells
• groups of hormone-producing cells are found in organs
that have other functions, such as the pancreas,
ovary, placenta, and testis
• DNES cells (diffuse neuro-endocrine system,
formerly APUD) in the gut, heart, kidney, liver,
skin, …
• Amine Precursor Uptake
• for high uptake of amine precursors including 5hydroxytryptophan
(5-HTP) and dihydroxyphenylalanine
(DOPA)
• Decarboxylase
• for high content of the enzyme amino acid
decarboxylase (for conversion of precursors to amines)
Survival of an organism is predicated upon
the ability of:
• (1) to maintain homeostasis
• = stable internal environment as a response to fluctuations
in external or internal conditions
• (2) and to carry out important life-history functions,
such as
• growth and maturation
• reproduction
• repair, healing, remodeling
• (migration)
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
- part of the APUD system (calcitonin)
- can give rise to medullary carcinoma
- no clin. consequences of deficiency/removal
Hormone synthesis by follicular cell
• upon nutritional iodide intake in thyrocytes by
the sodium-iodide symporter (NIS), it is
transported into the follicular lumen
• fabrication of thyroid hormones is conducted by
the enzyme thyroid peroxidase (TPO), an
integral membrane protein present in the apical
(colloid-facing) plasma membrane of thyroid
epithelial cells
• TPO catalyzes two sequential reactions:
• iodination of tyrosines on thyroglobulin (also known as
"organification of iodide") resultong in formation of monoand
diiodotyrosines
• synthesis of thyroxine (T4) or triiodothyronine (T3) from
two iodotyrosines
• a molecule of thyroglobulin contains 134 tyrosines,
although only a handful of these are actually used to
synthesize T4 and T3
• after pinocytosis of TG into thyrocytes, it fuses
with lysosomes, becomes hydrolysed by
proteases and T4, T3 diffuse into the cytoplasm
and then are released into the bloodstream
where they quickly bind to carrier proteins for
transport to target cells
• TBG – thyroid binding globulin (produced in liver)
Hormone synthesis by follicular cell - detail
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
• 99.9% bound to TBG (75%), transthyretin (15%) and albumin (10%)
• T3 free fraction 0.3%
• MIT and DIT are liberated into the cytoplasm, the iodines are removed
by a deiodinases (selenium-dependent enzymes), and they and the
tyrosines are reused
• free fraction of T4 and T3 is metabolically active, while bound fraction
is a ‘reserve’
• peripheral de-iodination (e.g. liver, kidneys, placenta, …)
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
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
Quantitatively
Molecular basis of T3/T4 action
• (1) genomic effects
• complexes thyroid
hormone/hormone-activated
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
• (2) fast immediate effects
• mitochondria?
• plasma membrane
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 clinical 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 insulindependent
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
self-sustained circannual
oscillators
• migratory restlessness
• hibernation
• seasonal moulting
• seasonal breeding
Thyroid function assessment
• Thyroid scintigramms (marker 99Tc)
• A) normal thyroid
• B) Graves disease, diffuse increased uptake
in both thyroid lobes,
• C) Plummers disease (TMNG, toxic
multinodular goitre)
• D) toxic adenoma
• E) thyroiditis
• serum
• hormones
• TSH, T4, T3, fT4, fT3, rT3
• antibodies
• anti-thyroglobulin (anti-TG), antithyroid
peroxidase antibodies (anti-
TPO)
• calculated indexes
• fT4/fT3, fT3/rT3
• ioduria (morning urine)
• 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)
• usually diffuse form
• toxic (hyperthyroidism, thyrotoxicosis)
• nodular or diffuse form
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 (Graves-Basedow’s
disease)
• stimulation by anti-TSH
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
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
• (1) genomic – mediated by cytosolic receptors (cGR) upon binding to
GC responsive elements (GREs)
• (2) fast 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 hormone-activavable 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
• evident in many of anti-inflammatory and immunosuppressive
effects
• nonspecific interactions with the cell membrane
• specific interactions with cytosolic GRs (cGRs)
• or membrane-bound GRs (mGRs)
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
signaling 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 (i.e. lipids and proteins)
Tissue/organ Physiologic effects Effects of overproduction
Liver hepatic gluconeogenesis ( Glc)
(stimulation of key enzymes – pyruvate carboxylase, PEPCK,
G6Pase)
impaired glucose tolerance/diabetes mellitus
hepatic lipogenesis ( FA and VLDL)
(stimulation of key enzymes acetyl-CoA-carboxylase 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 tolerance/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 cortisol
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 overeating-induced 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 overactivation
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 cortisol
concentration
• mainly in kidney
• by degrading cortisol 11βHSD2 enables tissue-specific 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
• 11βHSD2 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
Disorders of adrenal gland
• hyper-corticalism
• usually selective
• primary vs. secondary
• Cushing syndrome
• Conn syndrome
• adrenal hyperandrogenism
• DHEA producing adrenal adenoma
• hypo-corticalism
• usually generalised
• Addison syndrome
• dissociation of adrenal function
• abnormality of steroid biosynthesis
• if serious – CAH (congenital
adrenal hyperlasia)
Glucocorticoid excess: Cushing’s syndrome
• Etiology
• primary
• GC overproduction by adrenal tumor (adenoma or carcinoma)
• GC overproduction by ectopic tissue (embryonic origin, commonly ovary or testes)
• secondary
• ACTH-producing pituitary tumor (Cushing’s disease)
• excess CRH from the hypothalamic tumor
• extra-hypophyseal/ectopic ACTH production
• typically mediastinum (i.e. small cell lung carcinoma)
• low CBG
• iatrogenic
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
Adrenocortical insufficiency - etiology
• destructive process usually affecting all zones of the cortex
• decreased production of cortisol, aldosterone and adrenal androgens
• adrenal insufficiency occurs when at least 90% of the adrenal cortex has been destroyed
• prior to that can be latent and manifest in stress
• (1) primary generalized (Addison's disease)
• chronic or acute manifestation (Addison’s crisis)
•  ACTH
• causes
• autoimmune destruction (type II hs) - gradual destruction of the adrenal cortex
• TBC
• necrosis (Waterhouse-Friderichsen syndrome)
• acute adrenal insufficiency due to massive haemorrhage into the adrenal gland, more often bilateral, caused by meningococcus infection
• rare: congenital, haemochromatosis, adrenalectomy, X-linked adrenoleukodystrophy (X-ALD), amyloid, thrombosis, …
• (2) primary in dissociation of adrenal function
• see further
• (3) secondary to inadequate secretion of ACTH
• hypopituitarism
• 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
Congenital adrenal hyperplasia (CAH)
• frequency 1/8000 – 10000 new-borns – postnatal
screening
• a group of inherited disease that impair cortisol
synthesis, with compensatory increases in ACTH
leading to hyperplastic adrenals
• spectrum of enzymatic deficiencies ranges from mild
to complete and from a single activity to several
activities
• steroid 21-hydroxylase deficiency (21OHD)
accounts for over 90% of CAH cases
• much rarer
• 11-Beta hydroxylase deficiency
• 17a-hydroxylase deficiency
• 3-Beta-hydroxysteroid dehydrogenase deficiency
• congenital lipoid adrenal hyperplasia
• p450 oxidoreductase deficiency
• abnormalities of primary and secondary sex
differentiation
• for 21-hydroxylase deficiency:
• females will most likely have ambiguous or atypical
external genitalia (masculinization or virilization),
although they are genetically female and will have
normal internal reproductive organs
• males will not have ambiguous genitalia
• both genders can experience other symptoms such as
early onset of puberty, fast body growth, and premature
completion of growth leading to short stature, if they are
not diagnosed and treated in early life
Adrenal medulla
• paragangliomas form
in nerve tissue in the
adrenal glands and
near certain blood
vessels and nerves
• paragangliomas that
form in the adrenal
glands are called
heochromocytomas
pheochromocytomas
and paragangliomas
may be benign or
malignant cancer