Endocrine
system
INTERCELULAR COMMUNICATIONS
Synaptic
Autocrine
Paracrine
Tissue
Synapsis
Local
Contact
Distant
Endocrine
Neurocrine
Blood
Blood
• Endocrine organs (e.g. pituitary, thyroid, parathyroid, adrenal)
• Endocrine tissue within other organs
(pancreas, gonads, kidneys, placenta)
• Isolated endocrine cells (DNES, APUD)
• Neuroendocrine cells
• Common developmental scheme
- invagination of epithelial layer
- contact with original tissue lost during development
- absence of exocrine ducts
GENERAL PROPERTIES OF ENDOCRINE ORGANS
• C.t. capsule + septs
• Trabecules of glandular epithelium or follicles or clusters of glandular cells
• Capillary network
- Fenestrated capillaries
- Sinusoids
GENERAL PROPERTIES OF ENDOCRINE ORGANS
1. Negative feedback by change of metabolic state
Langerhans
islets
Insulin
High glycemia Low glycemia
2. Negative feedback by increased concentration of
secreted hormone
Hypothalamus Adenohypophysis Adrenal cortex
CRH ACTH
Cortisol
3. Nerve system – direct innervation
CNS (sympaticus)
Adrenal medulla
Adrenalin
CNS
Hypothalamus
Neurohypophysis
ADH
REGULATION OF HORMONE SECRETION
⚫ hormones are chemical messengers delivered by bloodstream to
target cells and tissues
⚫ chemical nature of hormone determines is function
⚫ classification
▪ water soluble
▪ water insoluble
▪ surface receptors
▪ nuclear receptors
GENERAL PROPERTIES OF HORMONES
• steroids – hydrophobic, intracytoplasmic or nuclear receptors (sex
hormones, corticosteroids)
• proteins and polypeptides – hydrophilic, plasma membrane receptors
(insulin, pituitary hormones, PTH, …)
• aminoacids and their amine derivatives (adrenalin, noradrenalin, thyroxin)
GENERAL PROPERTIES OF HORMONES
Testosterone
Insulin
Estradiol
Adrenalin
Growth hormone
Melatonin
hCG
GENERAL PROPERTIES OF HORMONES
ENDOCRINE GLANDS
PITUITARY GLAND (GL. PITUITARIA)
⚫ hypothalamus
⚫ sella turcica
⚫ fossa hypophysialis
⚫ optic chiasm
PITUITARY GLAND (GL. PITUITARIA)
Chiasma opticum
A. hypophysialis sup.
Diaphragma sellae
Dura mater
ANTERIOR LOBE
POSTERIOR LOBE
INFUNDIBULUM
HYPOTHALAMUS
A. hypophysialis inf.
A. hypophysialis inf.
Sella turcica of sphenoid bone
PITUITARY (GL. PITUITARIA)
• adenohypophysis - glandotropic hormones, prolactin, GH
• neurohypophysis - hypothalamic hormones - ADH, oxytocin
• anatomical and functional association with hypothalamus
• capillary systems and neuroendocrine secretion
PITUITARY GLAND (GL. PITUITARIA)
• adenohypophysis (pars distalis, pars tuberalis, pars intermedia)
• neurohypophysis (pars nervosa)
• infundibulum, eminentia mediana
PITUITARY GLAND (GL. PITUITARIA)
• Ectoderm of stomodeum (Rathke’s pouch)
• Neuroectoderm of ventral wall of diencephalon
EMBRYONIC DEVELOPMENT OF PITUITARY GLAND
~ week 3 ~ week 8
~ week 16~ week 11
~ week 6
• Physician, anatomist,embryologist,
zoologist
• One of founding fathers of modern
embryology
"For a long time I have observed in several animals ... a small irregularly rounded depression
which belongs to the mucous membrane of the mouth, of which it is clearly a thin-walled
outpocketing. ... Finally I saw that this depression represents the first step in the formation of
the pituitary gland" (p. 482).
Rathke, H. : Ueber die Entstehung der glandula pituitaria. Arch, f . Anat,, Phys. und wiss. Med. S. 482-85. 1838
MARTIN HEINRICH RATHKE (1793 – 1860)
~6th week
EMBRYONIC DEVELOPMENT OF PITUITARY GLAND
A = fossa
B = hypothalamus
C = eminentia mediana
D = adenohypophysis
EMBRYONIC DEVELOPMENT OF PITUITARY GLAND
HYPOTHALAMUS
• small region of diencephalon
• complex neuroarchitecture
• core of the limbic system
• complex functions
- regulation of temperature, emotions, eating
behavior, circadian rhythms
- hormonal regulation controlled by various stimuli
(osmoreception, concentration of nutrients,
electrolytes, systemic functions - pain)
• neurosecretion from hypothalamic nuclei
- n. supraopticus, n. paraventricularis
- magnocelullar neurons - tractus hypothalamohypophysialis
- oxytocin and ADH through
neurohypophysis
- parvocelullar neurons - capillaries in eminentia
mediana - statins and liberins regulating
secretion from adenohypophysis through
hypothalamo-hypophyseal portal system
Tractus hypothalamo-hypophysialis
- axons of magnocelullar neurons in nucleus supraopticus
and paraventricularis
- terminating on fenestrated capillaries in neurohypophysis
- synthesis of prohormones → maturation during axonal
transport
- capillary plexus from arteria hypophysialis inferior
(branch of a. carotis interna → sinus cavernosus
Hypophyseal portal system
- parvocellular neurons e.g. in nucleus arcuatus,
preopticus, paraventricularis and nuclei tuberales
- axonal transport onto primary capillary plexus in
eminentia mediana (from anterior and posterior
superior hypophyseal arteries) → hypophyseal portal
veins → secondary capillary plexus in adenohypophysis
→ inferior hypophyseal portal veins → vv. jugulares
internae
MECHANISM OF NEUROSECRETION
ncl. paraventricularis
ncl. supraopticus
Tractus hypothalamo-hypophysealis
posterior lobe
secondary capillary plexus of anterior lobe
primary capillary plexus at e. mediana
anterior lobe
MECHANISM OF NEUROSECRETION
• synthesis and transport of effector hormones from n.
supraopticus and n. paraventricularis via tractus
hypothalamo-hypohesialis to neurohypophysis
• synthesis of liberins a statins, their secretion to
capillaries of eminentia mediana and further
transport through portal system to adenohypophysis
Primary capillary at
eminentia mediana
Hypophyseal veins
A. hypophysyalis inf.
A. hypophysyalis sup.
Hypophyseal portal veins
Hypophyseal veins
Capillaries of secondary plexus at pars distalis
A. carotis int.
CAPILLARY SYSTEMS OF HYPOPHYSIS
• elevated part of tuber cinereum (detachment of infundibulum p. nervosa)
• neurohemal area - hematoencephalic barrier is open here
• fenestrated capillaries with large perivascular spaces
EMINENTIA MEDIANA
• Nonmyelinated nerve fibers
- axons of neurosecretory cells
(c.a. 100 000) of hypothalamic
nuclei (n. supraopticus and
paraventricularis)
• Pituicytes (neuroglia)
- astrocyte-like (intermediate
filamets, GFAP)
- local control of secretion from
neuroscretory termini
- Herring bodies – neurosecretory
endings – dilatation close to
capillaries
• Hormones
- oxytocin (OT)
- antidiuretic hormone (ADH,
vasopresin)
NEUROHYPOPHYSIS (POSTERIOR LOBE)
NEUROHYPOPHYSIS (POSTERIOR LOBE)
NEUROHYPOPHYSIS (POSTERIOR LOBE)
Oxytocin
• nonapeptide
• magno-cellular supraoptic and paraventricular nuclei of the
hypothalamus
• OR - G-coupled receptor
• lactation reflex
• uterine contraction
• social behavior
Vasopressin
• nonapeptide
• retention of water
• effective in collecting duct and distal convoluted
tubule (aquaporin translocations)
• blood pressure regulation by affecting t. media
• diabetes insipidus, hypernatremia, polyuremia
HORMONES OF NEUROHYPOPHYSIS (POSTERIOR LOBE)
Chromophilic cells
Acidophils
- Somatotropic (STH, somatotropin), 50%
- Mammotropic (LTH, prolactin), 10-25%
Basophils
- Thyrotrophic (TSH), 3-5%
- Gonadotrophic (FSH, LH), 10-15%
- Corticotropic (POMC, ACTH, MSH), 15-25%
Nonglandotropic
- direct effect on target tissues
Glandotropic
- regulation of other endocrine glands
Chromophobic cells
• undifferentiated cells
• degranulated (“empty“) chromophils
• stromal cells
Folliculo-stellate cells (FS-cells)
• unclear function, putative stem cells
• cytokine production
ADENOHYPOPHYSIS (ANTERIOR LOBE)
Capillaries Acidophils
Basophils
Chromomphobes
ADENOHYPOPHYSIS (ANTERIOR LOBE)
ADENOHYPOPHYSIS (ANTERIOR LOBE)
Acidophils producing GH Basophils producing glandotropic hormones
ADENOHYPOPHYSIS (ANTERIOR LOBE)
ADENOHYPOPHYSIS – FUNCTIONAL LINK TO HYPOTHALAMUS
”FLAT PEG”
• FSH
• LH
• ACTH
• TSH
• Prolactin
• Endorhins
• Growth hormone
REGULATION BY HYPOTHALAMIC HORMONES
• gonadoliberin → FSH a LH
• corticoliberin → cortikotropin
• thyreoliberin → thyreotropin
• prolactin releasing hormone (?)→ prolactin
• somatoliberin → somatotropin
• follistatin FSH a LH
• somatostatin somatotropin, TSH
• dopamin prolactin
Pro-opio-melanocortin (POMC)
ADENOHYPOPHYSIS– HORMONES
rough ER → pre-prohormon
produced by various tissues
cleavage to
• ACTH (target: adrenal cortex → cortisol)
• MSH (target: melanocytes - mostly in paracrine way)
• lipotropin (lipolysis, steroidogenesis)
• endorphins
FSH (folitropin), LH (lutropin)
• gonadotropic cells of adenohypophysis stimulated by GnRH
• glycoproteins, 30kDa
• heterodimer, two noncovalent bound subunits (a/ - common for - LH, FSH, TSH,
hCG, b/ - specific)
• FSH receptor (testes, ovarium, uterus) G-protein coupled receptor
- glycosylated extracellular domain of 11 leucine rich repeats specific to FSH
- after ligand binding, activation of G-protein and cAMP signaling
- alternative activation of MAPK cascade (ERK)
- complex signaling response (prostaglandins, PLPc, NO)
FSH LH
ovarium follicle development (FSHR in m. granulosa
cells)
ovulation, development of
corpus luteum, production of
androgens in thecal cells
testes spermatogenesis, FSHR in Sertoli cells production of testosterone in
Leydig cells (expression of LHR)
extragonadal FSHR in secretory endometrium of luteal phase
uterus (endometrial functions, embryoendometrial
interactions)
uterus, seminal vesicles,
prostate, skin... unknown
function
ADENOHYPOPHYSIS– HORMONES
TSH, thyrotropin
• thyrotropic cells of adenohypophysis stimulated
by TRH
• production of T4 (thyroxin) a T3 (triiodothyronin)
by thyroid gland
• glycoprotein, 28,5 kDa, heterodimer, two
noncovalent bound subunits (a, b)
• TSH receptor on thyroid follicular cells
• G-protein signaling → adenylylcyklase → cAMP
- cAMP → iodide channels (pendrin), transcription
of thyreoglobulin, endo- and exocytic pathway
• cross-reactivity with hCG → in pregnancy alterations
in synthesis of thyroid hormones
(gestational hyperthyroidism)
ADENOHYPOPHYSIS – HORMONES
GH, somatotropin, growth hormone
• somatotropic cells of adenohypophysis stimulated by GHRH (somatocrinin)
• several molecular isoforms (alternative splicing), ~20-24 kDa
• broad spectrum of target cell types and physiological circuits
- transcription of DNA, translation of RNA, proteosynthesis
- lipid use (fatty acid mobilization, conversion to acetyl-CoA)
- inhibition of direct use of glucose, stimulation of glukoneogenesis
- transmembrane transport of aminoacids
- proteosynthesis in chondrocytes and osteoblasts, proliferation, osteogenesis
• GHR in various tissues
- RTK, JAK-STAT
• somatomedins
- small proteins (MW 7,5 kDa), IGF-like
- produced by liver
• various pathologies associated with GH
ADENOHYPOPHYSIS – HORMONES
ADENOHYPOPHYSIS – HORMONES
Hypophyseal tumors
• compression of surrounding structures
(e.g. optic chiasma)
• hyperfunction of endocrine component
- prolactinoma - galactorrhea
- hypogonadism (alterations of GnRH)
- gigantism - acromegaly
- nanism
CLINICAL LINKS
Corticotrophs
hypofunction
Corticotrophs
hyperfunction
CLINICAL LINKS
Harvey W. Cushing
1912
1855
Thomas Addison
Cushing’s syndrome
PITUITARY GLAND SUMMARY
Anatomy Microscopic anatomy Hormones and target tissues
Anteriorlobe(adenohypophysis)
pars distalis
superior
hypophyseal
arteries
→ primary
capillary plexus at
eminentia
mediana
→ hypophyseal
portal veins
→
secondary
capillary plexus in
adenohypophysis
trabecular epithelium in cords and clusters,
reticular fibers; agranular folliculo-stellate
cells with so far unclear function
chromophobes
undifferentiated cells
degranulated chromophilic cells
stromal cells
lack hormonal activity
chromophils
acidophilic
nonglandotropic
mammotropic
cells
smallpolypeptides
dopamin (PIH)
⊥
PRF (?) → prolactin
mammary gland in
gravidity and lactations
somatotropic
cells
somatostatin (GHIH)
⊥
GHRH → somatotropin
(STH)
directly liver and growth
plates
other tissues via
somatomedins
basophilic
glandotropic
corticotropic
cells
glycoproteins
CRH → ACTH, MSH
adrenal cortex
→ cortisol
melanocytespars tuberalis
thyrotropic
cells
TRH → TSH
thyroid
→ thyroxin, T3
pars
intermedia Rathke’s cysts
gonadotropic
cells
GnRH → FSH (ICSH), LH
gonads
→ androgens, estrogens,
progesterone
Posteriorlobe
(neurohypophysis)
eminentia
mediana →
infundibulum
inferior
hypophyseal
arteries
→
capillary plexus in
neurohypohysis
nonmyelinated axons
of hypothalamic neurons n. supraopticus,
n. paraventricularis (tractus
hypothalamohypophysialis),
pituicytes
smallpeptides
ADH
tubulus reuniens, ductus
colligens
t.media of vessels
oxytocin
myometrium of uterus
during gravidity
myoepithelium of
lactating mammary gland
pars nervosa
• epithalamus
• c.t. capsule continuous to pia mater
• thin c.t. septa
• non-myelinated nerve fibers
• pinealocytes (95%, large, pale, round nuclei)
• interstitial neuroglia (astrocytes, dark,
elongated nuclei)
• acervulus cerebri
• melatonin
EPIPHYSIS (C. PINEALE)
EPIPHYSIS (C. PINEALE)
EPIPHYSIS - ACERVULUS CEREBRI
• pinealocytes
- star-like, modified neurons in trabecules
- association with fenestrated capillaries
- neurosecretory dilatations
- nonvisual photoreception
EPIPHYSIS (C. PINEALE)
• thickening of caudal part of
ependyma that does not
contribute to development of
choroid plexus at the roof of
diencephalon
• neuroectoderm
EMBRYONIC DEVELOPMENT OF EPIPHYSIS
Anolis
Parietal eye
SphenodonSphenodon
• Follicular cells → thyroid hormones (T3, T4)
• C cells → calcitonin
C.t. capsule, septs
Lobes → lobuli - follicles
Follicles (50 µm -1 mm)
- separated by interstitial loose collagen c.t.
- simple epithelium (flat to cubic, according
to their secretory activity)
- colloid
Capillary network from thyroid arteries
THYROID GLAND (GL. THYROIDEA)
THYROID GLAND - FOLLICLES
Follicular cells and C-cells (parafollicular)
C-cells
THYROID GLAND - FOLLICLES
Capillaries around thyroid follicles
FOLLICLES OF THYROID GLAND
T3 and T4
T3 synthesis from T4
• T4 half-life in blood 6.5 days, T3 2.5 (T4 is a reservoir for T3)
• deiodination by tissue specific deiodinase enzymes generates T3
Critical for brain development
Metabolism (nitrogen balance, proteosynthesis, lipolysis)
T4 synthesis in thyroid
• sodium-iodide symporter transports two Na+ and one I- across the
basement
• I− is moved across the apical membrane into the colloid of the follicle.
• thyroperoxidase oxidises 2 I− → I2.
• thyroperoxidase iodinates the tyrosyl residues of thyroglobulin
• (TSH) stimulates the endocytosis of the colloidal content
• endocytic vesicles + lysosomes, lysosomal enzymes cleave T4 from the
iodinated thyroglobulin
• exocytosis
THYROID GLAND – T3 AND T4 HORMONES
THYROID GLAND – T3 AND T4 HORMONES
C cells of thyroid
Calcitonin
- inhibition of osteoclasts
Neuroendocrine cells
- pale staining
- epithelial basis, under basal
lamina no contact with colloid
- derived from neural crest
- associate with ultimobranchial
body, (derivative of the
4th pharyngeal pouch)
THYROID GLAND - CALCITONIN
• endodermal proliferation of pharyngeal floor
• ductus thyreoglossus originates between
tuberculum impar and copula
• bilobed civerticulum, lobus pyramidalis
• obliterated d. thyreoglossus – foramen caecum
• ectopic thyroid tissue
EMBRYONIC DEVELOPMENT OF THYROID GLAND
6 mm, 130 mg
c.t. capsule and septs
Capillary network
Cords and clusters of glandular cells
- Chief
- Oxyphilic
- Adipose
PARATHYROID GLAND (GL. PARATHYREOIDEA)
• Chief
- most abundant
- small cells (7-10µm, big nucleus
- mildly acidophilic
- PTH – calcium metabolism
• Oxyphylic
- large, polyhedral,
- strongly acidophilic
- round nucleus
- glycogen
PARATHYROID GLAND (GL. PARATHYREOIDEA)
PARATHYROID GLAND (GL. PARATHYREOIDEA)
• 84 aminoacids
• stimulates resorption by osteoclasts
• enhances resorption of calcium and magnesium in
distal tubules and thick ascending limb
• enhances absorption in the intestine (via vD3)
PARATHYROID HORMONE (PTH, PARATHORMONE, PARATHYRIN)
PTH vs. CALCITONIN
• glandulae parathyroideae
superiores from endoderm of
4th pharyngeal pouch
• glandulae parathyroideae
inferiores from dorsal
process of 3rd pharyngeal
pouch
- together with thymus
descend to lower poles of
thyroid
• ectopic PTH gland in thymus
or mediastinum
EMBRYONIC DEVELOPMENT OF PARATHYROID GLAND
c.t. capsule, septs
capillary plexus
ADRENAL GLAND (CORPUS SUPRARENALE)
cortex
- mesoderm
- mesothelium, coelomic epithelium
medulla
- neural crest
ADRENAL GLAND DEVELOPMENT
ADRENAL CORTEX
• Zona glomerulosa (1/10)
- thin layer under c.t. capsule
- relatively small cells in coiled glomeruli
- not so abundant lipid droplets
- mineralocorticoids
• Zona fasciculata (6/10)
- radially arranged trabecules
- lipid droplets in cytoplasm
- glucocorticoids
• Zona reticularis (3/10)
- branched trabecules
- small, acidophilic cells
- lipofuscin
- androgen precursors
ADRENAL CORTEX
• Steroids produced incortex =
CORTICOSTEROIDS
• Steroidogenic cells
- SER, lipid droplets,
mitochondria
- mineralocorticoids
- glucocorticoids
• Aldosteron – zona glomerulosa
• Cortisol – zona fasciculata
• Androgens, estrogens,
progesteron – zona reticularis
ADRENAL CORTEX HORMONE
ADRENAL HORMONES
Clusters of glandular cells in reticular c.t.
- chromaffin cells – modified postganglionic neurons
- ganglionic cells
- capillaries, venules, nerve fibers
- adrenaline and noradrenaline
Neural crest origin
ADRENAL MEDULLA
ADRENAL MEDULLA
arteriae suprarenales (3) → arterial
plexus in cortex under c.t. capsule →
radially oriented fenestrated sinusoid
capillaries continuous with medullar
capillaries → medullar veins → v.
suprarenalis
three arterial regions
1) c.t. capsule and superior parts of cortex
2) radial capillaries of cortex continuing to
medulla
3) medullar capillaries from aa. perforantes
c.t. capsule
z. glomerulosa
z. fasciculata
z. reticularis
medulla
cortical arteriole
capsular arteriole capsular venule
medullar artery
capillaries of z.
glomerulosa
arteria
perforans
capillaries of z.
fasciculata
capillaries of z.
reticularis
venules of z.
reticularis
medullar
capillaries
medullar veins
→ Medullary cells influenced by cortical hormones
ADRENAL VASCULARISATION
Region (zone) Hormone Target tissue Hormonal effect Control
Cortex
Zona
glomerulosa
Mineralocorticoids
(aldosteron)
Kidney
Increaed renal reabsorption
of Na+ and water
Synergic to ADH
Excretion of K+
renin-angiotensin system,
high level of K+ low level of
Na+
Zona
fasciculata
Glucocorticoids
(hydrocortison)
Most cells
Release of aminoacids from
muscles and lipids from fat
tissue, peripheral utilization
of lipids, antiinflammatory
effects
Stimulation by ACTH
Zona
reticularis
Androgens
(dehydroepiandrosterone)
Most cells
In adult males not
significant
Children and women growth
of bones, muscles,
hematopoiesis
Stimulation by ACTH
Medulla Epinefrine, norepinefrine Most cells
Increased heart activity,
centrlaization of circualtion,
bronchodilatation,
glycogenolysis, regualtion og
glycemia
Sympaticus
Adrenal hormones
Adrenal cortex
ACTH
Cortisol
- glycogen lysis
- stabilization of glucose levels
- suppression of immune system
Pituitary gland
Adrenal medulla
Adrenaline
- blood pressure,
vasoconstriction, heart rate…
Fight or FlightChronic stress
STRESSHypothalamus
CNS
(sympaticus)
Paul Langerhans
1847 – 1888)
ISLETS OF LANGERHANS
Laguesse E. Sur la formation des ilots de Langerhans dans le
pancreas. Comptes Rend SocBiol 1893;5 (Series 9k.819-20
On July 27, 1921, Sir Frederick Banting and Charles Best
succeeded in isolating insulin from canine pancreases and
thereby discovered the first effective treatment for diabetes
mellitus.
ISLETS OF LANGERHANS
B-cells producing insulin
Ab-anti insulin –Alexa Fluor
A-cells producing glucagon
Ab-anti glukagon –Texas Red
ISLETS OF LANGERHANS
HEALTHY DIABETES TYPE I
Thank you for
attention
pvanhara@med.muni.czComments and questions: