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HYPOTHALAMUS AND ITS HORMONES
HORMONES OF THE PITUITARY
Jana Jurcovicova
ANATOMICAL NOTES
Pituitary has a coordinating role in regulation of peripheral endocrine glands.
It is connected with with part of diencephalon - hypothalamus to form
hypothalamo-pituitary complex.
Hypothalamus acts as a regulating and connecting center which enables
the control of endocrine functions by central nervous system.
Hypothalamus is located on the base of third ventricle and extends between
- mammilary bodies (caudally)
- optic chiasm (frontally)
- optic tract (laterally)
- thalamus (dorsally)
On its base is median eminence, an important structure where converge
regulatory pathways form hypothalamus into peripheral blood.
BASAL VIEW OF THE HYPOTHALAMUS
HYPOTHALAMO-HYPOPHYSEAL CONNECTION
Central part of neuroendocrine regulation
is hypothalamo-hypophyseal complex.
Structural components of this complex are
neurosecretory cells grouped into
secretory nuclei located around the third
ventricle. These secrete neuropeptides
into portal blood connecting
hypothalamus with adenopituitary. The
other cell groups secrete neuropeptides to
systemic circulation through posterior lobe
via long axons of magnocellular
hypothalamic neurons.
Pituitary is located in sella turcica and is
composed from 2 distinct structures adenopituitary and posterior pituitary
arcuate
nucleus and
other nuclei
adenopituitar
hormones
supraoptic and
paraventricular
nuclei
posterior
pituitary
hormones
ENDOCRINE HYPOTHALAMUS
Hypothalamic secretory nuclei synthesize neuropeptides regulating adenopituitary
secretion. These either exert either stimulatory or inhibitory effects.
There are 4 stimulatory - releasing hormones
and 2 inhibitory - statins
releasing hormones:
reproduction function activates gonadotropin releasing hormone
- GnRH
growth hormone activates growth hormone releasing hormone - GHRH
thyroid function activates thyrotropin releasing hormone – TRH,
adrenocortical function activates corticotropin releasing hormone – CRH.
inhibiting hormones (statins)
growth hormone inhibits somatostatin - SRIF (mild inhibitory activity also on TSH)
prolactin inhibits prolactostatin - dopamine
TOPOGRAPHY OF ENDOCRINE HYPOTHALAMUS
The highest endocrine activity resides in medial hypothalamus (tuberal region),
then lateral and proptic regions
Medial hypothalamus: arcuate nucleus (ARC) containis GHRH, somatostatin
and PIH, paraventricular nucleus (PVN) contains CRH and TRH.
Periventricular nucleus contains somatostatin.
Lateral hypotalamus: supraoptic nucleus (SON) contains neurohypophyseal
hormons arginin-vasopressin (AVP or ADH) and oxytocin, suprachiasmatic
jnucleus (SCN) which is a central pacemaker of daily rhythms
Preoptic region is rich in GnRH.
SCHEMATIC DRAWING OF HYPOTHALAMIC
NUCLEI
AC: anterior commissure PO: preoptic nucleus SC: suprachiasmatic nucleus OC: optic chiasma TC: tuber cinereum AP: anterior pituitary
IN: infundibulum: posterior pituitary ME: median eminence AH: anterior hypothalamic nucleus SO: supraoptic nucleus TH: thalamus
PV: paraventricular nucleus (not to be confused with periventricular nucleus, which is not shown) DM: dorsomedial nucleus VM:
ventromedial nucleus AR: arcuate nucleus (associated with periventricular nucleus, which is not shown) LT: lateral nucleus PN: posterior
nucleus MB: mamillary body
SCHEMATIC CROSS SECTION OF
HYPOTHALAMUS
suprachiasmatic
Guyton and Hall, 2006
Ganong and Hall, 2006
CROSS-SECTION OF THE ROSTRO - MEDIAL
PART OF THE BRAIN
CROSS- SECTION OF THE MIDDLE PART OF
THE BRAIN
HISTOCHEMICAL STAINING OF
HYPOTHALAMIC NUCLEI
HYPOTHALAMIC HORMONES
SECRETED HORMONE
abbr
Thyrotrophic-releasing
hormone
(Prolactin-releasing
hormone)
TRH,
PRH
Parvocellular
neurosecretory
neurons
Stimulate thyroid-stimulating hormone (TSH) release from
anterior pituitary (primarily)
Stimulate prolactin release from anterior pituitary
Dopamine
(Prolactin-inhibiting
hormone)
DA
or
PIH
Dopamine neurons
of the arcuate
nucleus
Inhibit prolactin release from anterior pituitary
Growth hormone-releasing
hormone
GHR
H
Neuroendocrine
neurons of the
Arcuate nucleus
Stimulate Growth hormone (GH) release from anterior
pituitary
Somatostatin
(growth hormone-inhibiting
hormone)
SS,
GHI
H, or
SRIF
Neuroendocrine
cells of the
Periventricular
nucleus
Inhibit Growth hormone (GH) release from anterior pituitary
Inhibit thyroid-stimulating hormone (TSH) release from
anterior pituitary
Gonadotropin-releasing
hormone
GnR
H or
LHR
H
Neuroendocrine
cells of the Preoptic
area
Stimulate follicle-stimulating hormone (FSH) release from
anterior pituitary
Stimulate luteinizing hormone (LH) release from anterior
pituitary
Corticotropin-releasing
hormone
CRH
Parvocellular
neurosecretory
neurons
Stimulate adrenocorticotropic hormone (ACTH) release from
anterior pituitary
Magnocellular
neurosecretory
cells
Uterine contraction
Lactation (letdown reflex)
Magnocellular
neurosecretory
neurons
Increase in the permeability to water of the cells of distal
tubule and collecting duct in the kidney and thus allows
water reabsorption and excretion of concentrated urine
Oxytocin
Vasopressin
(antidiuretic hormone)
ADH
or
AVP
PRODUCED BY
EFFECT
HYPOTHALAMO – PITUITARY CONNECTION
Neurons of medial and preoptic hypothalamus end in the external
layer of median eminence. Here they secrete neurohormones into
primary plexus of portal vein system which converges along the
pituitary stalk into the long veins. The neurohormones are then
transported to adenopituitary secretory cells by veins of secondary
blood plexus.
The existence of releasing / inhibiting hormone dates back to early
70-ties of the last century, when in was first proved that
adenipotuitary is regulated by humoral factors coming from the
hypothalamus.
Many neurohormones are produced also in GIT and are released into
circulation. Therefore the concentration of releasing hormones in
portal blood must be higher than in peripheral blood system.
HYPOTHALAMO – PITUITARY CONNECTION
HYPOTHALAMO-PITUITARY REGULATION
DEVELOPMENT AND STRUCTURE OF PITUITARY
diencephalon
Rathke’s pouch
of pharynx
neural tissue
ectoderm
pars tuberalis
pars distalis
pars nervosa
anterior
posterior
pars intermedia
HYPOTHALAMO - PITUITARY SYSTEM
Nc. paraventricularis
Nc. supraopticus
Hypothalamic neurons
secreting releasing, inhibiting
hormones (nuclei:nARC, mPOA NPE)
Primary capilary
plexus
Chiasma
opticum
Neural lobe
Portal vein
Adenopituitary
Anterior lobe
Secretory
cells
Oxytocin
Vasopresin
ACTH, GH,
TSH, LH, FSH, Prolactin
INNERVATION OF ANTERIOR AND
POSTERIOR PITUITARY BY NEURONES OF
PARAVENTRICULAR AND SUPRAOPTIC
NUCLEI
STRUCTURES OF ARGININE VASOPRESSIN
AND OXYTOCIN
LIST OF PITUITARY HORMONES
STRUCTURE OF PROOPIOMELANOCORTIN
PC1 – PROHORMONE CONVERTASE1
PC2 – PROHORMONE CONVERTASE2
REGULALION OF ENDOCRINE HYPOTHALAMUS
Feedback regulations
Neural inputs
- mainly from higher CNS centers
Inputs from peripheral blood - leptin, ghrelin, insulin, cytokines ,
adenopituitary hormones, plasma levels of glucose, osmolality, steroid
hormones (gonadal steroids and corticosteroids)
Light -
photoperiod for the synchronization of circadian rhythms
Stress – various stress stimuli depending on the character of stressor
FEEDBACK REGULATIONS
REGULATION OF HYPOTHALAMIC
HORMONES BY SHORT LOOP AND
ULTRASHORT LOOP FEEDBACK
REGULATION OF HYPOTHALAMIC
HORMONES BY COMPLEX FEEDBACK
SDDDDDDDDDDD
NEURAL STIMULI OF THE HYPOTHALAMUS
NEURON
synaptic buttons
myelin
Ranvier
cleft
axon
dendrites
oligodendroglia
nucleus
mitochondrion
vesicles with mediator
exocytosis
synapse
postsynaptci
receptots
NEUROTRANSMITTER SYSTEMS REGULATING
HYPOTHALAMIC SECRETION
DOPAMINE
nigrostriatal pathway
SEROTONIN
mesocortical pathway
v
tuberoinfundibular pathway
NORADRENALINE
NEUROTRANSMITTES REGULATING INDIVIDUAL
RELEASING HORMONES
Although many findings come from animal studies and cannot be
applied to human physiology absolutely, the principal regulatory
mechanisms are equal.
It is generally accepted that central noradrenaline plays a pivotal
role in stimulation of GHRH, CRH, AVP a TRH.
The effect of noradrenaline on GnRH is unequivocal.
Central serotonin stimulates the secretion of GHRH and also
pituitary prolactin via its not yet known releasing hormone.
Central dopamine participates in the inhibition of GnRH and in
stimulation of CRH. CRH is also stimulated by acetylcholine.
BLOOD BORNE STIMULI OF THE HYPOTHALAMUS
BLOOD BRAIN BARRIER (BBB)
Neurotransmitters and other molecules affecting neurosecretory activity of the
hypothalamus (toxins, inflammatory agents) are found also in the circulation.
Hypothalamus is protected from these influences by blood brain barrier (BBB).
BBB is a complex mechanism regulating exchange of mediators between blood and
CNS. It functions as protection from harmful stimuli (toxins) and also as transport
system (for example glucose) into brain.
BBB represented by tight junctions between endothelial capillary cells which are 100
times tighter than junctions in peripheral veins. These junctions are formed by
ineractions of transmembrane proteins (claudins, occludins), adhesion molecules and
cytoplasmic proteins (zona ocludens) bound to cytoskeletal actin filaments.
BBB undergoes dynamic change during maturation, aging, under the influence of
toxins or stress.
For neuroendocrine secretion it is important that not all areas in brain are protected by
BBB. These are: pineal gland, posterior pituitary, median eminence, and region around
the third ventricle: area postrema, subcommissural organ, subfornical organ and
organom vasculosum laminae terminalis
BRAIN ENDOTHELIAL CELL – CELL
TIGHT JUNCTIONS
transmembrane
molecules
linked to actin
skeleton
adhesion
molecules
Engelhardt and Sorokin, 2009
AREAS WITHOUT BLOOD BRAIN BARRIER
OVLT - organum vasculosum laminae terminalis; SFO – subfornical organ; ME – median eminence;
SCO – subcomissural organ; PG – pineal gland; PL – posterior lobe; AP - area postrema;
MODULATION OF ADENOPITUITARY
RESPONSIVENESS TO HYPOTHALAMIC
REGULATION
HYPOTHALAMIC REGULATION OF FOOD INTAKE
PHYSIOLOGY OF GROWTH HORMONE - GH
INCREASES PROTEIN SYNTHESES
DECREASES UTILIZATION OF CARBOHYDRATES IN MUSCLE
STIMULATES OSTEOBLAST GROWTH AND IGF-I
HIGH LEVELS ARE DIABETOGENIC
STIMULATES IMMUNE SYSTEM
REGULATION OF GROWTH HORMONE (GH )
SECRETION
GROWTH HORMONE CHANGES DURING THE DAY
Guytom and Hall, 2006
NORMAL FUNCTIONS OF GH PRODUCED BY THE
BODY
Main pathways in regulation of growth and etabolism
Effects of growth hormone on the tissues is anabolic.
Increased height during childhood is the most widely known effect of GH. Height is
stimulated by at least two mechanisms:
1.Through receptor mechanism GH directly stimulates division and multiplication of
chondrocytes and osteoblasts.
2.GH also stimulates the production of insulin-like growth factor 1 (IGF-1, formerly
known as somatomedin C), a hormone homologous to proinsulin The liver is a
major target organ of GH for this process and is the principal site of IGF-1
production. IGF-1 has growth-stimulating effects on a wide variety of tissues. IGF-1
is generated within target tissues, thus it is an endocrine and paracrine hormone.
IGF-1 also has stimulatory effects on osteoblast and chondrocyte activity to
promote bone growth.
GH Increases calcium retention, and strengthens the mineralization of bone
GH increases muscle mass through sarcomere hyperplasia
GH promotes lipolysis, release of FFA from fat tissue and enhanced production of
acetyl-CoA
GH inncreases protein synthesis by increased transport of aminoacids into cells
GH decreases glucose uptake in skeletal muscle and fat – hyperglycemic effect
GH increases glucose production by the liver
GH (in excess) promotes insulin resistance
GH stimulates the immune system
INSULIN-LIKE GROWTH F-1 (IGF-1) AND GROWTH
IGF-1
[U/ml]
10
6
4
2
1
gigantism / acromegaly normal
treatment - somatostatin
GH-deficit
(treatment – GH administration)
PHYSIOLOGY OF PROLACTIN - PRL
STIMULATES LACTATION (MILK PROTEIN CASEIN)
STIMULATES IMMUNE SYSTEM (DIRECT EFFECT ON IMMUNE CELL
PROLIFERATION)
ANTIGONADAL ACTION (PROGESTERONE)
HORMONE LEVELS DURING PREGNANCY AND
LACTATION
A- HCG
B-ESTROGENS
C-PRL
D-PROGESTERONE
EFFECT OF BREST FEEDING ON PRL RELEASE
PRL levels in
women after brest
feeding on days
2, 4 ,6, post
partum
A- good lactation
B- medium
lactation
C- poor lactation
F - before feeding
G - after feeding
THE PINEAL GLAND
Known over 2000 years
Producing hormone of the night –MELATONIN
It aggregates pigment granules containing melanin, and thus makes
the skin lighter.
Pineal gland EPIPHYSIS has a shape of a pine cone
HISTOLOGY OF PINEAL GLAND
The pineal is consists of connective tissue , blood vessels, glial cells,
and pinealocytes (which secrete melatonin).
Pinealocytes have larger, lighter staining nuclei
glial cells have small darker staining nuclei.
With age, calcified formations appear in the pineal gland (brain sand or
corpora aranacea ).
CIRCADIAN REGULATION OF MELATONIN
PRODUCTION
LIGH
HINDBRAIN
EYE
EYE
SPINAL CORD
ß-adrenergic receptors
N-acetyl
transferases
α -adrenergic receptors
dark period
Synthesis of
Superior
cervicale
ganglion
24-HOUR SECRETION OF MELATONIN IN
HEALTHY AND ARTHRITIC RATS
pg/ml
MELATONIN
250
200
150
100
50
0
**
**
MAEN AC
MEAN cFA
**
+
**
14
18
22
2
hour
+
6
10
CIRCADIAN SYNCHRONIZATION
CIRCADIAN OSCILATOR - SCN
Principle of the circadian rhythmicity of the SCN are feedback
mechanisms of clock genes
SYNCHRONIZATION of the internal environment is the light/dark cycle
Synhesis and release of melatonin is regulated from SCN, but
synchronized by light/dark cycle.
RHYTHM of melatonin secretion is indicator of CIRCADIAN
PACEMAKER
EFFECTS OF MELATONIN:
improves quality of sleep
activates immune system
antioxidant (prevents oxidative stress)