Ppathophysiology of endocrine
system I
HPA and HPT axis and chronobiology
Circadian rhythm
Adrenal cortex and medulla
Thyroid gland
Endocrine system
• network of specialized endocrine glands in
the body that make the hormones
• however, 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,
adipose tissue, 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
• mediated commonly by negative
feedbacks
• (2) and to carry out important
life-history functions, such as
• growth and maturation
• reproduction
• repair, healing, remodeling
• (migration in some species)
• mediated commonly by positive
feedbacks
Neuro-endocrine-immune (NEI) network
• Neuro-endocrine-immune interactions
involve multi-directional crosstalk that is
mediated by extrinsic (environmental,
social factors) and intrinsic
(resistance/tolerance to disease,
homeostasis and allostatic load,
reproductive status, behaviour) factors
• First-order interactions involve
• (1) direct interactions between the nervous and
immune systems
• e.g. sympathetic innervation of immune tissue
• activation of microglia or specific nuclei in brain
from cytokines
• (2) endocrine-immune interactions
• e.g. hormonal regulation of immunity
• cytokine/ chemokine activation of endocrine cells)
• (3) classic interactions between the nervous and
endocrine systems
• e.g. activation and modulation of hypothalamicpituitary
units
• neuromodulation by hormones
• (4) second-order interactions involve all three
systems interacting to produce a physiological
effect(s)
Horm Behav. 2017. Neuroendocrine-immune circuits, phenotypes,
and interactions. Ashley NT, Demas GE.
Mechanisms of endocrine diseases
• (1) hormone deficiency
• hereditary
• genetic defect
• acquired - destruction process in the gland
• infection
• infarction
• compression by tumour
• autoimmunity
• type II or IV hypersensitivity mostly – cellular or antibody cytotoxicity
• (2) hormone excess
• autotopic – in the very same gland
• tumours (adenomas)
• immunopathologic (type V hypersensitivity – stimulatory anti-receptor Ig)
• ectopic – elsewhere
• tumours
• exogenous (iatrogenic) – therapeutic use
• (3) hormone resistance
• abnormal hormone/molecule
• antibodies against hormone or receptor
• receptor defect
• post-receptor defect
CHRONOBIOLOGY
Homeostasis – feedback regulation – hierarchy
Hypothalamus – integration of signals form different parts of CNS
Biological rhythms
• most processes in the body has some cyclic character, however, the length of
the biological cycle is various
• circadian rhythm
• production of hormones throughout the day and regulation of respective processes
• ultradian – shorter than 24 hrs.
• e.g. appetite/satiety cycles, respiration adjustment, …
• infradian – longer than 24 hrs.
• lunar, seasonal, …
• principal biological rhythm – circadian – is generated autonomously by inner
“biological clock“
• nucleus suprachiasmaticus (SCN) in hypothalamus
• glandula pinealis in pituitary – guiding the production of melatonin in cooperation with
SCN
• nucleus paraventricularis (PVN) in hypothalamus
• releasing hormones
• tractus hypothalamo-hypophysialis (oxytocin and ADH)
• orexins
• mediators influenced by periodical activity of biological clock direct the activity
of peripheral endocrine glands and other organs incl.
• awakening/sleep
• alertness
• feeding and energy homeostasis
• reproduction
• immune functions and repair
• growth
• etc.
• synchronization depends on external cues via sensory receptors and cognition
• dark/light signals from the retina (and also skin)
• food intake – nutrient levels
• temperature – season
• less important in men
Circadian clock systems
• Circadian clock systems are present in all cells and organs and their
timing is determined by a transcriptional-translational feedback
loop of circadian genes which form proteins
• the key genes involved are CRY1, CRY2, PER1, 2, and 3, BMAL, and CLOCK
• CLOCK and BMAL1 form cytoplasmic heterodimers which, once within the nucleus start
the transcription of clock genes (PER1, PER1, PER3, CRY1, and CRY2)
• gene transcription is switched off by negative feedback of PER:CRY heterodimers which
inhibit the action of the CLOCK/BMAL1 heterodimers
• this cycle lasts approx. 24 hrs
• Individual cellular clocks are synchronized by the central body clock
(situated in the suprachiasmatic nucleus), which communicates with
them through humoral and neural signals including melatonin
• The circadian system controls both
• the circadian period, i.e., the length of the intrinsic clock
• the circadian phase, i.e., the clock timing
• An important determinant of the circadian system is light exposure
• in most humans, the circadian period is slightly longer than 24 hrs and without
regular resetting it tends to drift, leading to progressively later bedtimes and
wake times
Light is the most powerful external cue
synchronising the circadian rhythm
• light perception includes 3 types of retinal
photoreceptors:
• classical cones and rods
• and specialised retinal ganglion cells (RGCs)
producing a photopigment melanopsin
• this controls the production of melatonin
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) in 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
Molecular mechanisms of circadian rhythm
• a | The circadian timing system synchronizes clocks across the entire body to
adapt and optimize physiology to changes in our environment. Light is received
by specialized melanopsin-producing photoreceptive retinal ganglion cells
(ipRGCs) in the eye. These ipRGCs project through the retinohypothalamic tract
to the suprachiasmatic nucleus (SCN), among other brain regions. The SCN
relays timing information to other areas of the brain via direct projections (dark
green boxes) and indirect projections (light green boxes). Humoral signals and
the peripheral nervous system (that is, the sympathetic nervous system (SNS)
and parasympathetic nervous system (PNS)) convey information from the SCN
to orchestrate peripheral clocks. Feeding schedules and exercise can also
entrain central and peripheral clocks. Circadian rhythms are key regulators of
thermogenesis, immune function, metabolism, reproduction and stem cell
development. b | The mammalian molecular clock is composed of
transcriptional and translational feedback loops that oscillate with a near-24hour
cycle. The positive loop is driven by the heterodimerization of either
circadian locomotor output cycles protein kaput (CLOCK) or neuronal PAS
domain-containing protein 2 (NPAS2) with brain and muscle ARNT-like 1
(BMAL1) in the nucleus. The resulting heterodimers bind to enhancer boxes (Eboxes)
in gene promoters to regulate the transcription of clock-controlled genes
(CCGs), including those encoding period (PER) proteins and cryptochrome
(CRY) proteins. PER and CRY proteins accumulate in the cytoplasm during the
circadian cycle, eventually dimerizing and shuttling to the nucleus to inhibit
their own transcription, thus closing the negative-feedback loop. The auxiliary
loop includes the nuclear retinoic acid receptor-related orphan receptors (RORα
and RORβ) and REV-ERBs (REV-ERBα and REV-ERBβ), which are also
transcriptionally regulated by CLOCK–BMAL1 heterodimers. REV-ERBα (REV in
the figure) and RORα repress and activate the transcription of Bmal1,
respectively, by inhibiting and activating the ROR or REV-ERB response
elements (RREs). CLOCK–BMAL1 complexes also control the expression of
nicotinamide phosphoribosyltransferase (NAMPT), which is the rate-limiting
enzyme of NAD+ biosynthesis from nicotinamide (NAM). NAM is modified by
NAMPT to produce nicotinamide mononucleotide (NMN), which in turn is
converted to NAD+ by several adenyltransferases. Thus, NAMPT oscillations
control circadian fluctuations in NAD+ levels, which in turn modulate sirtuin 1
(SIRT1) activity and signalling. High levels of NAD+ promote SIRT1 activation.
SIRT1 interacts directly with CLOCK–BMAL1 to deacetylate BMAL1 and inhibit
CLOCK-driven transcription. Between tissues and cell types, CCGs and other
molecular and cellular rhythms may be expressed with different acrophases
(phase of peak expression), amplitudes and even periodicities. ArcN, arcuate
nucleus; DmH, dorsomedial hypothalamus; DR, dorsal raphe; IGL,
intergeniculate leaflet; LC, locus coeruleus; LH, lateral hypothalamus; LHb,
lateral habenula; MA, medial amygdala; mPOA, medial preoptic area; NAc,
nucleus accumbens; PVN, paraventricular nucleus of the hypothalamus; PVT,
paraventricular nucleus of the thalamus; RMTg, rostromedial tegmental
nucleus; Sptm, septum; SPZ, subparaventricular zone; VLPO, ventrolateral
preoptic nucleus; VTA, ventral tegmental area.
Froy O Endocrine Reviews 2010;31:1-24
©2010 by Endocrine Society
Coordination of signals from central and peripheral „clocks“
Disturbances of circadian rhythmicity
• aetiology/causes
• mutations/genetic variability in clock genes
• interindividual variability
• chorotype “owls” vs. “larks”
• aging
• external factors
• shift work
• jet lag
• exposure to light during evening and night
• social factors
• infection – sleeping sickness (Trypanozoma brucei)
• psychiatric and neurological diseases
• depression
• neurodegenerative
• obesity and abnormal food intake
• blindness (total without light perception)
• preserved circadian rhythm
• perception of light by skin resp. subcutaneous fat cells?
• 50% subjects suffer from non-24-hour sleep-wake
disorder (N24SWD, „free-running“)
• consequences
• T2DM, cardiovascular diseases,
immunopathology, cancer
• a concept of chrono-pharmacology
THE ADRENALS
Anatomy and histology of adrenals
Cortisol profile & regulation
Major steroid biosynthetic pathways
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-activatable state
• GR/Hsp (+ other proteins) complexes
• protect GRs from degradation by proteasome
• increase the affinity of GRs for GCs (~100)
• blocking the action of other proteins (e.g. MAPK) bound to the 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 facilitates 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) trans-repression = 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 to non-genomic action of GCs
• affinity of steroid receptors (for GC, aldosterone, estradiol) is
not specific!!
• e.g. GCs bind avidly to MR in the brain, not in kidney though
(degraded, see further)
• (B) non-genomic effects - evident in many of antiinflammatory
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 co-regulators [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 subcutaneous 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 synthase)
muscle atrophy, weakness, steroid myopathy
Pancreas
(β cells)
 insulin secretion
(suppression 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
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 hyperplasia)
Glucocorticoid excess: Cushing’s syndrome
• Etiology
• primary
• GC overproduction by adrenal tumor (adenoma or carcinoma)
• adrenal hyperplasia
• 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 or CRH 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
pheochromocytomas
• paragangliomas may
be benign or malignant
cancer
THE THYROID
Anatomy and histology of the thyroid, HPT axis
Physiology 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 mono- and 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
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 – HPT axis
• 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
• (3) reproduction
Mexican axolotl (Ambystoma mexicanum) – T3
effects and regeneration
Physiologic effects of T3/T4
• (4) 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
• hypothyroidism – combined dyslipidaemia
(hypertriglyceridemia, hypercholesterolemia),
NAFLD
• 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
• hyperthyroidism – worsening of DM
compensation or T2DM
• protein metabolism
• (5) other effects
• cardiovascular, CNS, immune systém, …
DISEASES OF THE THYROID GLAND
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
• morning urine - ioduria
• serum
• hormones
• TSH, T4, T3, fT4, fT3, rT3
• antibodies
• anti-thyroglobulin (anti-TG), antithyroid
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
Goiter
• 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
• remote, inland, mountain regions 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
• South America – Andes
• Central Africa
• iodine prophylaxis !!!
Cretinism
• develops due to pre- and/or postnatal iodine and thus
T3/T4 deficiency
• (A) neurological form
• mental retardation, deafness, spastic palsy
• prenatal deficiency of T3 (critical esp. between 12th – 18th week of
gestation)
• (B) myxoedema form
• grave growth retardation, face malformation, myxoedema,
hypogonadisms, sterility
• postnatal deficiency of T3
• other etiological factors considered incl. toxins
Global data on iodine status
Taylor, P., Albrecht, D., Scholz, A. et al. Global epidemiology of hyperthyroidism and hypothyroidism. Nat Rev Endocrinol 14, 301–316 (2018)
Thyroid endocrinopathies – functional aspects
• Hyperthyroidism (thyrotoxicosis)
• common in iodine-replete
populations
• Graves’ disease (toxic diffuse goitre)
• younger adults
• autoimmune
• common in iodine-deplete
populations
• toxic multi-nodular goitre (Plummer’s
disease)
• older adults
• toxic adenoma
• rare
• thyroiditis
• de Quervaine – acute (following
respiratory infection, painful, selflimiting
course of hyperthyroidism
• post-partum
• primary and/or metastatic follicular
carcinoma
• TSH-producing tumour of the pituitary
• drug-induced
• amiodarone, lithium, INF-, anti-viral
• Hypothyroidism
• autoimmune thyroiditis (Hashimoto)
• for both autoimmune – Graves and
Hashimoto - predominance of women,
middle age
• hypothalamic or pituitary - rare
• drug-induced
• amiodarone, lithium, INF-, anti-viral
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]
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
• typically Hashimoto thyroiditis
• usually transitory
hyperthyroidism in acute
phase, then cessation of
function
• predominance of women,
middle age
A. During Hashimoto's thyroiditis, self-reactive CD4+
T lymphocytes recruit B cells and CD8+ T cells into
the thyroid. Disease progression leads to the death
of thyroid cells and hypothyroidism. Both
autoantibodies and thyroid-specific cytotoxic T
lymphocytes (CTLs) have been proposed to be
responsible for autoimmune thyrocyte depletion.
B. In Graves' disease, activated CD4+ T cells
induce B cells to secrete thyroid-stimulating
immunoglobulins (TSI) against the thyroidstimulating
hormone receptor (TSHR),
resulting in unrestrained thyroid hormone
production and hyperthyroidism.