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ANTER!R #T$TAR% &!R'!NE(
There are 6 major hormones produced by the anterior pituitary, which can be grouped
according to structure.
Luteinizing hormone, follicle stimulating hormone and thyroid stimulating hormone
These are glycoproteins with 2 subunits - and . hey all have 204 amino acids. he
subunit is common to all these hormones in one species. The subunit gives specificity
of binding to receptors and so site of action. The carbohydrate portion of the -subunit
affects specificity and half-life.
rowth hormone and prolactin
These two hormones belong to a family of polypeptide hormones. They share elements of
their structure and differ only by ! amino acids, " having #$# amino acids and
prolactin having #$$.
%drenocorticotrophic hormone
This is a polypeptide derived from the pro-opiomelanocortin &'()*+ precursor
molecule, which also gives rise to products such as melanocyte stimulating hormone,
lipotrophic hormone and -endorphin. ,t has -$ amino acids.
Thyroid (timulatin) &ormone or Thyrotrophin
T." is released from the anterior pituitary gland in response to thyroid releasing
hormone from the hypothalamus and causes the synthesis and secretion of
triiodothyronine &T-+ and thyro/ine &T0+ by the thyroid gland.
This is acheived by stimulation of the thyroid follicular cells by binding of T." to
the receptor on the basal surface of the cell and activation of adenylate cyclase.
This leads to iodide upta1e. T- and T0 e/ert negative feedbac1 on both the
pituitary production of T." and the hypothalamic production of T2".
(ther factors affecting release of T2" from the hypothalamus incluse blood
levels glucose and the body3s metabolic rate.
.omatostatin inhibits T." secretion and oestrogen has been shown, in rats, to
reverse the negative feedbac1 affect of T- and T0 on the T." response to T2".
4ffects of T." deficiency5
)etabolism 6ody weight increases
(/ygen consumption
7hat can go wrong
'roblems at the level of the hypothalamo-
pituitary a/is can cause deficiency of T."
decreases
"eat production
decreases
6asal metabolic rate
decreases
*8.
,mpaired mentality
'oor memory and
concentration
9rowsiness
)otor nervous
system
%ctivity decreases
.ympathetic nervous
system
%ctivity decreases
*ardiovascular
6radycardia
2educed output and
blood pressure
, tract
%ctivity decreased
*onstipation
resulting in secondary hypothyroidism
which is normally less severe than that
caused by disease of the thyroid gland itself.
*ongenital problems such as pituitary
hypoplasia of aplasia may affect any of the
pituitary hormones. There may be a loss of
midline structures as in septo-optic
dysplasia, which also causes loss of optic
nerves.
The effects are due to lac1 of production of
thyroid hormones. Treatment is by
administration of oral thyro/ine.
"yperthroidism has the opposite symptoms to hypothyroidism including increased o/ygen
consumption, increased metabolism, weight loss, heat intolerance, sweating, insomnia and
nervousness. The most common form is raves3 disease, an autoimmune condition in
which thyroid stimulating immunoglobulins e/ist that mimic the action of T." but with
no normal feedbac1 control. This results in continual production of thyroid hormones and
an enlarged thyroid gland. Treatment is with anti-thyroid drugs or by thryoid gland
surgery. ,t is rare to see overproduction of T." due to a pituitary adenoma.
*onadotrophins+luteini,in) hormone and -ollicle stimulatin) hormone
The hypothalamo-pituitary-gonadal a/is is different in males and females.
,n females n2" is secreted from the hypothalamus in a cyclical way leading to a
cyclical secretion of L" and :." from the pituitary, which maintains the menstrual cycle.
L" acts on the ovarian follicle and it induces ovulation and maintains the corpus
luteum.
:." causes development of the ovarian follicle and stimulates secretion of
oestradiol and progesterone.
The se/ steroids feed bac1 to inhibit release of n2" and therefore L" and :.".
%t sustained high levels however, oestradiol causes a sharp increase in L"
secretion lin1ed to ovulation. This is an e/ample of positive feedbac1.
,n males n2" causes the release of L" and :." from the anterior pituitary, as in
females.
L" acts on the Leydig cells of the testes to produce testosterone.
:." acts on the .ertoli cells of the testes to maintain spermatogenesis as well as
production of se/-hormone binding globulin.
,n males and females :." stimulates the production of inhibin, which has a negative
feedbac1 effect on the hypothalamus and pituitary.
7hat can go wrong
,nsufficient n2" causes a fall in gonadotrophin production, which leads to
amenorrhoea, due to lac1 of ovulation, in women and impotence and infertility in men.
This is sometimes seen when nutrient inta1e is too low, as in anore/ia nervosa, or when
e/cessive e/ercise is underta1en. ,t may also be due to a prolactin secreting tumour
because prolactin has effects on the hypothalamo-pituitary-gonadal a/is. The problems
caused by lac1 of n2" may be treated by administration of n2", gonadotrophins such
as recombinant :.", or se/ steroids.
*ro.th hormone
rowth hormone release from the anterior pituitary is under the control of two
hypothalamic hormones.
"2" acts to stimulate release of " while somatostatin acts to inhibit release of
".
" e/erts its effects directly and also indirectly through insulin-li1e growth
factors &,:s+ # and 2. The effects include promotion of growth of bone, soft
tissue and viscera as well as having affects on protein synthesis, lipolysis and
glucose transport and metabolism. ,:# provides negative feedbac1 to the
pituitary and hypothalamus.
(ther factors affecting "2" and somatostatin secretion include sleep, e/ercise,
stress and blood glucose levels. (estradiol also acts to increase sensitivity of
tissues to ".
7hat can go wrong
% " secreting tumour may be present in the pituitary gland leading to e/cessive height
due to e/tra " during childhood. 4/cessive production of " in adulthood,after the
growing ends of the bones have fused, leads to the condition of acromegaly and this can
be seen as enlarged feet, hands and jaw caused by thic1ening of the bones as well as
thic1ening of the soft tissue.
,nsulin resistance also develops, due to downregulation of the insulin receptors caused by
increased insulin production in response to increase glucose concentrations. This gives
the symptoms of diabetes mellitus. Treatment of acromegaly is usually surgery to remove
the tumour. The dopamine agonist bromocriptone is sometimes administered and
somatostatin analogues may also be used.
"yposecretion if " in childhood leads to pituitary dwarfism and a characteristic fat
distribution concentrated around the face and abdomen caused by a loss of metabolic
function.This may be due to a number of reasons, for e/ample irradiation of the
hypothalamo-pituitary area, surgery of the pituitary gland or trauma severing the lin1
between hypothalamus and pituitary gland, which result in lac1 of hypothalamic or
pituitary hormone secretion. The syndrome of hypopituitarism and the importance of "
in adults has only recently been recognised. .ymptoms of lac1 of " include increased
abdominal adiposity, reduced strength and e/ercise capacity, reduced bone density,
elevated cholesterol and impaired psychological well-being. " deficiency in both adults
and children can be treated successfully using recombinant human ".
#rolactin
'2L acts to initiate and maintain mil1 secretion by the mammary glands. ,t wor1s
with other hormones such as o/ytocin, which actually causes mil1 ejection, and
oestradiol, progesterone, glucocorticoids, ", thyro/ine and insulin, which
prepare the mammary gland for mil1 production.
(ther functions are unclear but e/perimental animals have been shown to produce
'2L in response to stress. '2L may also play a part in fertility and maternal
behaviour.
'2L secretion is under inhibitory control of dopamine. This means that if the lin1
between the hypothalamus and pituitary is severed '2L secretion increases,
unli1e all other pituitary hormones, where production would decrease without
stimulatory control of the hypothalamus.
T." has a stimulatory affect on '2L secretion. (estradiol increases '2L
production and levels of '2L rise during pregnancy and remain high during
lactation.
7hat can go wrong
'2L secreting tumours are a very common type of pituitary tumour. The high levels of
'2L lead to loss of reproductive function and inappropriate mil1 production
&galactorrhoea+ in males and females although male symptoms are often less obvious.
Treatment is with the dopamine agonist bromocriptine. ;ndersecretion of '2L is very
rare and does not have any clinical symptoms.
Adrenocorticotrophic hormone
%*T" is released in a pulsatile fashion from the pituitary following a circadian rhythm,
pea1ing in the morning and then declining. ,t is released under control of hypothalamic
*2".
The release of *2" can be affected by e/ternal influences such as stress. *2"
action is potentiated by petides such as vasopressin.
%*T" controls the production of glucocorticoids by the adrenal corte/,
stimulating the conversion of cholesterol to pregnenolone - a precursor of cortisol.
*ortisol feeds bac1 to inhibit both the hypothalamus and pituitary gland.
7hat can go wrong
(versecretion of %*T" leads to symptoms 1nown as *ushing syndrome. 7hen this is a
result of a feedbac1 abnormality it is *ushing disease and is caused by %*T" and *2"
secretion being suppressed at abnormally high levels of circulating cortisol. This results
in an %*T" secreting pituitary tumour due to overstimulation of the corticotrophs and
e/cess cortisol secretion secondary to this. 4/cess cortisol secretion may also be caused
by a *2" secreting tumour .ymptoms of e/cess cortisol include central obesity, thinning
of the s1in, bruising, glucose intolerance, susceptibility to infection, muscle wasting and
thin bones. "yperpigmentation of the s1in may occur due to the associoated secretion of
-)." with %*T". 7hen e/cess %*T" drives e/cess cortisol production adrenal
androgens are also oversecreted leading to symptoms of androgen e/cess. Treatment is
surgery to remove the tumour. ;ndersecretion of %*T" leads to problems of
glucocorticoid deficiency, such as hypoglycaemia, and androgen deficiency, such as lac1
of pubic hair and libido in females. This can be treated by administering hydrocortisone.
&%#!T&A/A'!+#T$TAR% A0( (TR$1T$RE AN2 2E3E/!#'ENT
The structure of the hypothalamo-pituitary a/is as a unit is of vital importance to its
ability to function.
,t has been shown, by e/periments where the pituitary gland is removed to a well-
vascularised site distant from the hypothalamus, that the pituitary gland must be near the
hypothalamus in order to function.
%natomy
The hypothalamus consists of nervous tissue lying inferior to the two lobes of the
thalamus. The pituitary )land, or hypophysis, is found at the base of the brain
below the hypothalamus and the two structures are connected via the
in-undibulum, or pituitary stal1, which carries both a/ons and blood vessels.
The pituitary gland is about #- #.< cm in diameter and weighs appro/imately =.<g
although it tends to weigh appro/imately 2=> more in women and may increase
by #=> during pregnancy. ,t sits in the sella turcica which is a depression of the
sphenoid bone at the base of the s1ull and lies behind the sphenoid sinus.
The top of the sella turcica is covered by a diaphragm, which has a foramen in the
centre through which the infundibulum passes.
.uperior to the diaphragm is the optic chiasm.
The pituitary gland can be divided into two functionally and embryologically
distinct parts. These are the anterior pituitary, or adenohypophysis, and the
posterior pituitary, or neurohypophysis.
The anterior pituitary ma1es up ?<> of the total weight of the pituitary. The pars
distalis forms the major part of the gland. The pars intermedia is rudimentary in
man. The pars tuberalis runs up the pituitary stal1.
The posterior pituitary is made up of neuronal processes and glia as an e/tension
of the hypothalamus and its major part is the pars distalis, which lies behind the
anterior pituiary in the sella turcica.
4$N1T!N( !4 T&E &%#!T&A/A'!+#T$TAR% A0(
The hypothalamo-pituitary a/is is the unit formed by the hypothalamus and pituitary
)land, which e/erts control over many parts of the endocrine system. This unit functions
by means of interaction of the nervous and endocrine systems whereby the nervous
system regulates the endocrine system and endocrine activity modulates the activity of
the *8..
The "ypothalamus
The hypothalamus has many functions and is one of the major regulators of homeostasis.
,t controls the autonomic nervous system, acts with the limbic system to regulate
emotional and behavioural patterns, regulates eating and drin1ing, controls body
temperature and regulates diurnal rhythms. ,t also controls pituitary gland
secretions.
The hypothalamus receives input from the e/ternal and internal environment as
well as having its own receptors. ,t receives stimuli from the somatic and visceral
sense organs. These inputs travel via the medulla oblongata and reach the
hypothalamus through innervation by fibres producing dopamine, adrenaline,
noradrenaline, serotonin and acetylcholine as well as fibres releasing
neuropeptides such as en1ephalins, 8'@, neurotensin, dynorphins and endorphins.
The release of hormones from the pituitary is therefore subject to many different
stimuli from 3higher centres3 acting on the hypothalamus.
,n response to stimuli such as stress, pain and emotions, the hypothalamus can
e/ert effects on the anterior and posterior pituitary gland in order to respond
rapidly to environmental change as well as to feedbac1 from internal systems.
The hypothalamus is the least well understood area of the hypothalamo-pituitary a/is and
research into certain aspects of its function is ongoing. %n e/ample is current wor1
involving the recently discovered peptide hormone, Leptin, which has shed light on the
e/istance of an adipose tissue- brain endocrine a/is.
The hypothalmus e/erts its effects on the pituitary gland in two different ways5
'osterior pituitary
The hypothalamic paraventricular and supraoptic nuclei produce secretory droplets,
which are the first stage in formation of the neuropeptides vasopressin and o/ytocin. The
paraventricular nuclei produce mostly o/ytocin and the supraoptic mostly vasopressin
although both hormones may also be produced by the other type of nuclei. These
hormones are pac1aged with the protein neurophysin into granules which then move
down the a/on and are stored in the posterior pituitary. :ollowing stimulation of the
hypothalamus these hormones are then released into the bloodstream. .mall amounts of
the hormones also enter the portal blood supply.
%nterior pituitary
*ontrol of the anterior pituitary is not via a nervous lin1. ,t was discovered in the #$-=s
that the hypothalamus is lin1ed to the anterior pituitary by a networ1 of microcapillaries -
the hypophyseal portal vessels. *ontrol is maintained by release of hypothalamic
hormones, some of which stimulate release and others inhibit release
&ypothalamic hormone E--ect on anterior pituitary )land
Thyrotropin releasing hormone &T2"+ release of T." and '2L
onadotropin releasing hormone &n2"+ release of L" and :."
rowth hormone releasing hormone release of "
&"2"+
.omatostatin &..+ inhibition of "
*orticotrophn releasing hormone &*2"+ release of %*T"
9opamine &9%+ inhibition of '2L
These hormones are released by e/ocytosis from storage granules in the hypothalamic-
hypophyseotropic nuclei into the capillaries of the primary ple/us. :rom here the
hormones travel in the blood through the hypophyseal portal veins into the anterior
pituitary secondary ple/us. They then act on anterior pituitary cells giving a rapid
response. %nterior pituitary hormones are then released into the secondary ple/us and
anterior hypophyseal veins into the systemic circulation.
4eedback control
8egative feedbac1 is an important factor in controlling the hypothalamic-pituitary-target
organ a/is function. (nce hypothalamic hormones stimulate the release or inhibition of
the pituitary hormone, this may then acts at a target gland, such as the thyroid, causing
release of further hormones or causing metabolic effects. The action of hypothalamic
hormones may be inhibited by long feedbac1 loops from the target gland hormone or by
short feedbac1 loops from the pituitary hormone. There may also be direct feedbac1 from
the target gland hormone to the pituitary gland.
,nput is also received at the hypothalamus from higher brain centres, which can be due to
internal or e/ternal influences
'ositive feedbac1 also plays a part in certain systems. :or e/ample, in the situation where
high levels of oestradiol in the blood cause a surge in L" levels during the menstrual
cycle.
#!(TER!R #T$TAR% &!R'!NE(
The hormones produced by the posterior pituitary gland are o/ytocin and vasopressin,
which is also 1nown an arginine vasopressin &%A'+ or antidiuretic hormone &%9"+. These
are both peptides with similar structures and made up of $ amino acids. Their properties
are determined by the residue at position !.
!5ytocin
(/ytocin secretion occurs in response to nervous stimulation of the hypothalamus.
This hormone causes contraction of the smooth muscle of the uterus and also of
the myoepithelial cells lining the duct of the mammary gland. %lthough some
o/ytocin is found in males, its fuction is unclear.
2elease of o/ytocin is under positive feedbac1 control. .timulation of
mechanoreceptors in the uterus and vagina during parturition cause a rise in
o/ytocin levels up to a ma/imum until the stimulus is no longer present and the
action of the hormone is no longer needed. The nipple also sends nervous impulses
to the hypothalamus upon suc1ling, leading to contraction of the myoepithelial
cells and e/pulsion of mil1 under positive feedbac1 control.
(estradiol potentiates the uterus to o/ytocin and progesterone bloc1s it. (/ytocin
also acts with %A' to promote sodium e/cretion.
There are no 1nown disorders of o/ytocin secretion.
3asopressin
%A' acts primarily on the 1idneys at A2 receptors to aid reabsorption of water by
affecting the water permeability of the collecting duct of the 1idney.
%t high concentrations it also causes constriction of the arterioles through its
action at the A# receptors leading to an increase in blood pressure.
(smoreceptors in the hypothalamus detect an increase in osmotic pressure in the
blood. %s well as producing the sensation of thirst in order to cause increased
water inta1e, the hypothalamus causes the release of %A', which acts to retain
water and reduce plasma osmolality.
%A' is under negative feedbac1 control. % fall in blood volume stimulates release
of %A'. %lso, a fall in the arterial partial pressure of o/ygen and a rise in partial
pressure of carbon dio/ide stimulate %A' release. .ecretion is also affected by the
angiotensin ,,, adrenaline, cortisol and se/ steroids. %t the level of the
hypothalamus, pain, trauma, nausea and vomiting, and a rise in e/ternal
temperature increase %A' secretion, and psycological and emotional stimuli also
affect release.
7hat can go wrong
(verproduction of %A' can occur due to brain trauma. ,t leads to water retention, serum
hypo-osmolality, hyponatraemia and high urine osmolality.These effects cause symptoms
of headache, apathy, nausea and vomiting, impaired conciousness and can be fatal in
e/treme cases.
;nderproduction of %A' results in the condtion of diabetes insipidus, which is
neurogenic in origin &rather than due to failure of the 1idneys to respond to %A'+ and can
result from a pituitary tumour, head traumas or surgery which damages the pituitary gland
and hypothalamus..ometimes it is due to autoimmune destruction of the %A' neurons.
*linical signs are e/cretion of large volumes of urine leading to dehydration and thirst, as
well as increased plasma osmolality. The water deprivation test is often used as a
diagnostic aid - patients are unable to concentrate their urine and when deprived of water
will continue to pass dilute urine of low osmolality while plasma osmolality rises.
Treatment of this condition is with analogues of %A' such as desamino 9-arginine
administered subcutaneously or by nasal spray.
Antidiuretic Hormone (Vasopressin)
Roughly 60% of the mass of the body is water, and despite wide variation in the
amount of water taken in each day, body water content remains incredibly
stable. Such precise control of body water and solute concentrations is a
function of several hormones acting on both the kidneys and vascular system,
but there is no doubt that antidiuretic hormone is a key player in this process.
Antidiuretic hormone, also known commonly as arginine vasopressin, is a nine
amino acid peptide secreted from the posterior pituitary. ithin hypothalamic
neurons, the hormone is packaged in secretory vesicles with a carrier protein
called neurophysin, and both are released upon hormone secretion.
Physiologic Effects of Antidiuretic Hormone
Effects on the Kidney
!he single most important effect of antidiuretic hormone is to conserve body
water by reducing the loss of water in urine. A diuretic is an agent that increases
the rate of urine formation. "n#ection of small amounts of antidiuretic hormone
into a person or animal results in antidiuresis or decreased formation of urine,
and the hormone was named for this effect.
Antidiuretic hormone binds to receptors on cells in the collecting ducts of the
kidney and promotes reabsorption of water back into the circulation. "n the
absense of antidiuretic hormone, the collecting ducts are virtually impermiable to
water, and it flows out as urine.
Antidiuretic hormone stimulates water reabsorbtion by stimulating insertion of
$water channels$ or a%uaporins into the membranes of kidney tubules. !hese
channels transport solute&free water through tubular cells and back into blood,
leading to a decrease in plasma osmolarity and an increase osmolarity of urine.
Effects on the Vascular System
"n many species, high concentrations of antidiuretic hormone cause widespread
constriction of arterioles, which leads to increased arterial pressure. "t was for
this effect that the name vasopressin was coined. "n healthy humans,
antidiuretic hormone has minimal pressor effects.
Control of Antidiuretic Hormone Secretion
!he most important variable regulating antidiuretic hormone secretion is plasma
osmolarity, or the concentration of solutes in blood. 'smolarity is sensed in the
hypothalamus by neurons known as an osmoreceptors, and those neurons, in
turn, simulate secretion from the neurons that produce antidiuretic hormone.
hen plasma osmolarity is below a certain brink, the osmoreceptors are not
activated and antidiuretic hormone secretion is suppressed. hen osmolarity
increases above the threshold, the ever&alert osmoreceptors recogni(e this a
the cue to stimulate the neurons that secrete antidiuretic hormone. As seen the
the figure below, antidiuretic hormone
concentrations rise steeply and linearly with
increasing plasma osmolarity.
'smotic control of antidiuretic hormone
secretion makes perfect sense. "magine
walking across a desert) the sun is beating
down and you begin to lose a considerable
amount of body water through sweating.
*oss of water results in concentration of
blood solutes & plasma osmolarity increases.
Should you increase urine production in
such a situation? Clearly not. Rather,
antidiuretic hormone is secreted, allowing
almost all the water that would be lost in urine to be reabsorbed and conserved.
!here is an interesting parallel between antidiuretic hormone secretion and
thirst. +oth phenomena appear to be stimulated by hypothalamic
osmoreceptors, although probably not the same ones. !he osmotic threshold for
antidiuretic hormone secretion is considerably lower than for thirst, as if the
hypothalamus is saying $*et,s not bother him by invoking thirst unless the
situation is bad enough that antidiuretic hormone cannot handle it alone.$
Secretion of antidiuretic hormone is also simulated by decreases in blood
pressure and volume, conditions sensed by stretch receptors in the heart and
large arteries. -hanges in blood pressure and volume are not nearly as
sensitive a stimulator as increased osmolarity, but are nonetheless potent in
severe conditions. .or e/ample, *oss of 01 or 20% of blood volume by
hemorrhage results in massive secretion of antidiuretic hormone.
Another potent stimulus of antidiuretic hormone is nausea and vomiting, both of
which are controlled by regions in the brain with links to the hypothalamus.
Disease States
!he most common disease of man and animals related to antidiuretic hormone
is diabetes insipidus. !his condition
can arise from either of two situations)
Hypothalamic ("central")
diabetes insipidus results from a
deficiency in secretion of
antidiuretic hormone from the
posterior pituitary. -auses of this
disease include head trauma,
and infections or tumors
involving the hypothalamus.
Nephrogenic diabetes insipidus
occurs when the kidney is unable
to respond to antidiuretic
hormone. 3ost commonly, this
results from some type of renal
disease, but mutations in the
A45 receptor gene or in the
gene encoding a%uaporin&2 have
also been demonstrated in
affected humans.
!he ma#or sign of either type of
diabetes insipidus is e/cessive urine
production. Some human patients
produce as much as 06 liters of urine
per day6 "f ade%uate water is available
for consumption, the disease is rarely
life&threatening, but withholding water
can be very dangerous. 5ypothalamic
diabetes insipidus can be treated with
e/ogenous antidiuretic hormone.
Vasopressin
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Ar)inine 6asopressin &A3#+, also 1nown as
ar)ipressin or antidiuretic hormone
&A2&+, is a human hormone that is mainly
released when the body is low on waterC it causes the 1idneys to conserve water by
.pace-filling model of arginine
vasopressin
arginine vasopressin &antidiuretic
hormone+
denti-iers
.ymbol %A' A', %9"
";( !$0
4ntrez <<#
(),) #$2-0=
2ef.eD 8)E===0$=
;ni'rot '=##!<
!ther data
Locus *hr. 2= p13
concentrating the urine and reducing urine volume. ,t also has various functions in the
brain and blood vessels.
% very similar substance, lysine 6asopressin &/3#+ or lypressin, has the same function
in pigs and is often used in human therapy.
Aasopressin is a peptide hormone liberated from a preprohormone precursor that is
synthesized in the hypothalamus as it is transported to the posterior pituitary. )ost of it is
stored in the posterior part of the pituitary gland to be released into the blood streamC
some of it is also released directly into the brain.
1ontents
FhideG
# 'hysiology
o #.# *ontrol
o #.2 .ources
o #.- 'eripheral actions
o #.0 %ctions within the brain
2 .tructure and relation to o/ytocin
- 2ole in disease
0 'harmacology
o 0.# Aasopressin analogues
o 0.2 Aasopressin receptor inhibition
< 2eferences
6 :urther 2eading
? 4/ternal lin1s
7edit8 #hysiolo)y
7edit8 1ontrol
Aasopressin is secreted from the posterior pituitary gland in response to reductions in
plasma volume and in response to increases in the plasma osmolality5
.ecretion in response to reduced plasma volume is activated by pressure receptors
in the veins, atria, and carotids.
.ecretion in response to increases in plasma osmotic pressure is mediated by
osmoreceptors in the hypothalamus.
The neurons that ma1e vasopressin, in the supraoptic nucleus and paraventricular
nucleus, are themselves osmoreceptors, but they also receive synaptic input from other
osmoreceptors located in regions adjacent to the anterior wall of the third ventricle. These
regions include the organum vasculosum of the lamina terminalis and the subfornical
organ.
)any factors influence the secretion of vasopressin5
4thanol and caffeine reduce vasopressin secretion. The resulting decrease in water
reabsorption by the 1idneys leads to a higher urine output. *offee is an e/ample
of a food product that supresses the body3s release of antidiuretic hormones, due
to its level of caffeine. This inta1e of caffeine causes the body to lose more water
and may lead to dehydration if consumed e/cessively.
%ngiotensin ,, stimulates the secretion of vasopressin.
F#G

7edit8 (ources
The vasopressin that is measured in peripheral blood is almost all derived from secretion
from the posterior pituitary gland &e/cept in cases of vasopressin-secreting tumours+.
"owever there are two other sources of vasopressin with important local effects5
Aasopressin is secreted from parvocellular neurons of the paraventricular nucleus
at the median eminence into the short portal vessels of the pituitary stal1. These
vessels carry the peptide directly to the anterior pituitary gland, where it is an
important releasing factor for %*T", acting in conjunction with *2".
Aasopressin is also released into the brain by several different populations of
neurons &see below+.
7edit8 #eripheral actions
Aasopressin acts on three different vasopressin receptors. The receptors are differently
e/pressed in different tissues, and e/ert different actions5
Type (econd messen)er system /ocations Actions
%A'2#% phosphatidylinositolHcalcium
liver, 1idney,
peripheral
vasculature, FFbrain
vasoconstriction,
gluconeogenesis, platelet
aggregation, and release of
factor A,,, and von
7illebrand factorC social
recognition
F2G
, circadian tau
F-G
%A'2#6 phosphatidylinositolHcalcium
pituitary gland,
brain
adrenocorticotropic hormone
secretion in response to
stress
F0G
C social interpretation
to olfactory cues
F<G
%A'22 adenylate cyclaseHc%)' apical membrane of insertion of aDuaporin-2
the cells lining the
collecting ducts of
the 1idneys
&especially the
cortical and outer
medullary
collecting ducts+
&%I'2+ channels &water
channels+. This allows water
to be reabsorbed down an
osmotic gradient, and so the
urine is more concentrated.
7edit8 Actions .ithin the brain
Aasopressin released within the brain has many actions5
,t has been implicated in memory formation, including delayed refle/es, image,
short- and long-term memory, though the mechanism remains un1nown, and these
findings are controversial. "owever, the synthetic vasopressin analogue
desmopressin has come to interest as a li1ely nootropic.
Aasopressin is released into the brain in a circadian rhythm by neurons of the
suprachiasmatic nucleus of the hypothalamus.
Aasopressin released from centrally-projecting hypothalamic neurons is involved
in aggression, blood pressure regulation and temperature regulation.
,n recent years there has been particular interest in the role of vasopressin in social
behavior. ,t is thought that vasopressin, released into the brain during se/ual activity,
initiates and sustains patterns of activity that support the pair-bond between the se/ual
partnersC in particular, vasopressin seems to induce the male to become aggressive
towards other males.
4vidence for this comes from e/perimental studies, in several species, which indicate that
the precise distribution of vasopressin and vasopressin receptors in the brain is associated
with species-typical patterns of social behavior. ,n particular, there are consistent
differences between monogamous species and promiscuous species in the distribution of
vasopressin receptors, and sometimes in the distribution of vasopressin-containing a/ons,
even when closely-related species are compared. )oreover, studies involving either
injecting vasopressin agonists into the brain, or bloc1ing the actions of vasopressin,
support the hypothesis that vasopressin is involved in aggression towards other males.
There is also evidence that differences in the vasopressin receptor gene between
individual members of a species might be predictive of differences in social behavior.
7edit8 (tructure and relation to o5ytocin
The vasopressins are peptides consisting of nine amino acids &nonapeptides+. &865 the
value in the table above of #60 amino acids is that obtained before the hormone is
activated by cleavage+. The amino acid seDuence of arginine vasopressin is *ys-Tyr-'he-
ln-%sn-*ys-'ro-%rg-ly, with the cysteine residues forming a sulfur bridge. Lysine
vasopressin has a lysine in place of the arginine.
The structure of o/ytocin is very similar to that of the vasopressins5 it is also a
nonapeptide with a sulfur bridge and its amino acid seDuence differs at only two positions
&see table below+. The two genes are located on the same chromosome separated by a
relatively small distance of less than #<,=== bases in various species. The magnocellular
neurons that ma1e vasopressin are adjacent to magnocellular neurons that ma1e o/ytocin,
and are similar in many respects. The similarity of the two peptides can cause some cross-
reactions5 o/ytocin has a slight antidiuretic function, and high levels of vasopressin can
cause uterine contractions.
"ere is a table showing the superfamily of vasopressin and o/ytocin neuropeptides5
3ertebrate 3asopressin 4amily
*ys-Tyr-'he-ln-%sn-*ys-'ro-%rg-ly-8"2 %rgipressin &%A', %9"+
)ost
mammals
*ys-Tyr-'he-ln-%sn-*ys-'ro-Lys-ly-8"2 Lypressin &LA'+
'igs,
hippos,
warthogs,
some
marsupials
*ys-'he-'he-ln-%sn-*ys-'ro-%rg-ly-8"2 'henypressin
.ome
marsupials
*ys-Tyr-,le-ln-%sn-*ys-'ro-%rg-ly-8"2 AasotocinJ
8on-
mammals
3ertebrate !5ytocin 4amily
*ys-Tyr-,le-ln-%sn-*ys-'ro-Leu-ly-8"2 (/ytocin &(KT+
)ost
mammals,
ratfish
*ys-Tyr-,le-ln-%sn-*ys-'ro-,le-ly-8"2 )esotocin
)ost
marsupials,
all birds,
reptiles,
amphibians,
lungfishes
*ys-Tyr-,le-.er-%sn-*ys-'ro-,le-ly-8"2 ,sotocin 6ony fishes
*ys-Tyr-,le-%snHln-%sn-*ys-'ro-LeuHAal-ly-8"2 Aarious tocins .har1s
n6ertebrate 3#/!T (uper-amily
*ys-Leu-,le-Thr-%sn-*ys-'ro-%rg-ly-8"2 9iuretic "ormone Locust
*ys-'he-Aal-%rg-%sn-*ys-'ro-Thr-ly-8"2 %nnetocin 4arthworm
*ys-'he-,le-%rg-%sn-*ys-'ro-Lys-ly-8"2 Lys-*onnopressin eography
L imperial
cone snail,
pond snail,
sea hare,
leech
*ys-,le-,le-%rg-%sn-*ys-'ro-%rg-ly-8"2 %rg-*onnopressin
.triped cone
snail
*ys-Tyr-'he-%rg-%sn-*ys-'ro-,le-ly-8"2 *ephalotocin (ctopus
*ys-'he-Trp-Thr-.er-*ys-'ro-,le-ly-8"2 (ctopressin (ctopus
JAasotocin is the evolutionary progenitor of all the vertebrate neurohypophysial hormones. (nly vasotocin
found in hagfish L lampreys &%gnatha appeared <== million years ago+
7edit8 Role in disease
9ecreased vasopressin release or decreased renal sensitivity to vasopressin leads to
diabetes insipidus, a condition featuring hypernatremia &increased blood sodium content+,
polyuria &e/cess urine production+, and polydipsia &thirst+.
"igh levels of vasopressin secretion &syndrome of inappropriate antidiuretic hormone,
.,%9"+ and resultant hyponatremia &low blood sodium levels+ occurs in brain diseases
and conditions of the lungs. ,n the perioperative period, the effects of surgical stress and
some commonly used medications &e.g., opiates, syntocinon, anti-emetics+ lead to a
similar state of e/cess vasopressin secretion. This may cause mild hyponatraemia for
several days.
7edit8 #harmacolo)y
7edit8 3asopressin analo)ues
Aasopressin agonists are used therapeutically in various conditions, and its long-acting
synthetic analogue desmopressin is used in conditions featuring low vasopressin
secretion, as well as for control of bleeding &in some forms of von 7illebrand disease+
and in e/treme cases of bedwetting by children. Terlipressin and related analogues are
used as vasocontrictors in certain conditions. ;se of vasopressin analogues for
esophageal varices commenced in #$?=.
F6G
Aasopressin infusion has been used as a second line of management in septic shoc1
patients not responding to high dose of inotropes &e.g., dopamine or epinephrine+. ,t had
been shown to be more effective than epinephrine in asystolic cardiac arrest.
F?G
7hile not
all studies are in agreement, a 2==6 study of out-of hospital cardiac arrests has added to
the evidence for the superiority of vasopressin in this situation.
F!G
7edit8 3asopressin receptor inhibition
9emeclocycline, a tetracycline antibiotic, is sometimes used to bloc1 the action of
vasopressin in the 1idney in hyponatremia due to inappropriately high secretion of
vasopressin &.,%9", see above+, when fluid restriction has failed. % new class of
medication &conivaptan, tolvaptan, relcovaptan, li/ivaptan+ acts by inhibiting the action
of vasopressin on its receptors &A# and A2+, with tolvaptan acting on A#a and A2 and the
remainder mainly on A#a receptors. The same class of drugs is also being studied in
congestive heart failure.
7edit8 Re-erences
#. 9 Aander, %.B., 2enal 'hysiology, )craw-"ill, #$$#.
2. 9 6iels1y ,:, "u .6, .zegda ML, 7estphal ", @oung LB. 'rofound impairment in
social recognition and reduction in an/iety-li1e behavior in vasopressin A#a
receptor 1noc1out mice.8europsychopharmacology. 2==0C 2$50!--$-. '),9
#060?0!0
-. 9 7ersinger .2, *aldwell "M, )artinez L, old ', "u .6, @oung 7. -rd.
Aasopressin #a receptor 1noc1out mice have a subtle olfactory deficit but normal
aggression. enes 6rain 6ehav. 2==6 8ov -C F4pub ahead of printG '),9
#?=!---#
0. 9 Lolait .B, .tewart LI, Bessop 9., @oung 7. -rd, (3*arroll %). The
hypothalamic-pituitary-adrenal a/is response to stress in mice lac1ing functional
vasopressin A#b receptors. 4ndocrinology. 2==?C#0!5!0$-<6. '),9 #?#22=!#
<. 9 7ersinger .2, Melliher M2, Nufall :, Lolait .B, (3*arroll %), @oung 7. -rd.
.ocial motivation is reduced in vasopressin #b receptor null mice despite normal
performance in an olfactory discrimination tas1. "orm 6ehav. 2==0C0656-!-0<.
'),9 #<<<<<=6
6. 9 6aum ., 8usbaum ), Tumen "B. The control of gastrointestinal hemorrhage by
selective mesenteric infusion of pitressin. Gastroenterology #$?=C<!5$26.
?. 9 7enzel A, Mrismer %*, %rntz "2, .itter ", .tadlbauer M", Lindner M"C
4uropean 2esuscitation *ouncil Aasopressor during *ardiopulmonary
2esuscitation .tudy roup. % comparison of vasopressin and epinephrine for out-
of-hospital cardiopulmonary resuscitation. N Engl J Med 2==0C-<=5#=<-#-. '),9
#0?##$=$.
!. 9 rmec ., )ally .. Aasopressin improves outcome in out-of-hospital
cardiopulmonary resuscitation of ventricular fibrillation and pulseless ventricular
tachycardia5 an observational cohort study. *rit *are. 2==6 :ebC#=&#+52#-. '),9
#602=66=.
7edit8 4urther Readin)
6renner L 2ector3s The Midney, ?th ed., .aunders, 2==0. :ull Te/t with
)9*onsult subscription
*aldwell, ".M. and @oung, 7..., ,,,. (/ytocin and Aasopressin5 enetics and
6ehavioral ,mplications in Lim, 2. &ed.+ "andboo1 of 8eurochemistry and
)olecular 8eurobiology, -rd edition, .pringer, 8ew @or1, pp. <?--6=?, 2==6.
-2=1b '9:
Thirst and sodium appetite
The sensations caused by dehydration, the continuing loss of fluid through the s1in and
lungs and in the urine and feces while there is no water inta1e into the body. Thirst
becomes more and more insistent as dehydration worsens. 7ater and electrolytes are
needed to replace losses, and an adeDuate inta1e of sodium as well as water is important
for maintaining blood volume. 8ormally, the amounts of water drun1 and ta1en in food
are more than enough to maintain hydration of the body, and the usual mi/ed diet
provides all the electrolytes reDuired.
9eficit-induced drin1ing occurs when a deficit of fluid in one or both of the major fluid
compartments of the body serves as a signal to increase drin1ing. *ellular dehydration,
detected by osmoreceptors, causes thirst and vasopressin release. "ypovolemia &low
blood volume+, detected by volume receptors in the heart and large veins and the arterial
baroreceptors, causes immediate thirst, a delayed increase in sodium appetite, activation
of the renin-angiotensin system, and increased mineralocorticoid and vasopressin
secretion. ,ncreases or decreases in amounts drun1 in disease may result from normal or
abnormal functioning of mechanisms of thirst or sodium appetite.
1ellular dehydration
(bservations using a variety of osmotic challenges have established that hyperosmotic
solutions of solutes that are e/cluded from cells cause more drin1ing than eDuiosmolar
amounts of solutes that penetrate cells. Thus, the osmotic shift of water out of the cells
caused by the e/cluded solutes provides the critical stimulus to drin1ing. *ontinuing
water loss in the absence of inta1e is perhaps a more significant cause of cellular
dehydration than administration of an osmotic load, but the same mechanisms apply. See
also (smosis.
.haring in the overall cellular dehydration are osmoreceptors which initiate the responses
of thirst and renal conservation of water. (smoreceptors are mainly located in the
hypothalamus. The nervous tissue in the hypothalamus surrounding the anterior third
cerebral ventricle and, in particular, the vascular organ of the lamina terminalis also
respond to osmotic stimuli. (smoreceptors initiating thirst wor1 in conjunction with
osmoreceptors initiating antidiuretic hormone &%9"+ release to restore the cellular water
to its prehydration level. ,n addition to reducing urine loss, %9" may lower the threshold
to the onset of drin1ing in response to cellular dehydration and other thirst stimuli. The
cellular dehydration system is very sensitive, responding to changes in effective
osmolality of #O2>.
&ypo6olemia
The cells of the body are bathed by sodium-rich e/tracellular fluid that corresponds to the
aDuatic environment of the unicellular organism. Loss of sodium from the e/tracellular
fluid is inevitably accompanied by loss of water, resulting in hypovolemia with thirst
followed by a delayed increase in sodium appetite. ,f not corrected, continuing severe
sodium loss eventually leads to circulatory collapse.
.tretch receptors in the walls of blood vessels entering and leaving the heart and in the
heart itself are thought to initiate hypovolemic drin1ing. Aolume receptors in the
venoatrial junctions and receptors that register atrial and ventricular pressure respond to
the underfilling of the circulation with a reduction in inhibitory nerve impulses to the
thirst centers, which results in increased drin1ing. %ngiotensin ,, and other hormones
&such as aldosterone and %9"+ are also involved in this response. %rterial baroreceptors
function in much the same way as the volume receptors on the low-pressure side of the
circulation, e/erting continuous inhibitory tone on thirst neurons. % fall in blood pressure
causes increased drin1ing, whereas an acute rise in blood pressure inhibits drin1ing. The
anterior third cerebral ventricle region, which is implicated in angiotensin-induced
drin1ing, plays a crucial role in hypovolemic drin1ing, body fluid homeostasis, and blood
pressure control.
Renin+an)iotensin systems
,t is believed that drin1ing caused by hypovolemic stimuli partly depends on the 1idneys.
The renal thirst factor is the proteolytic enzyme renin, which is secreted into the
circulation by the 1idney in response to hypovolemia. 2enin cleaves an inactive
decapeptide, angiotensin ,, from angiotensinogen, an P2-globulin that is synthesized in the
liver and released into the circulation. %ngiotensin , is converted to the physiologically
active octapeptide angiotensin ,, during the passage of blood through the lungs.
%ngiotensin ,, is an e/ceptionally powerful stimulus of drin1ing behavior in many
animals when administered systemically or into the brain. ,ncreased activation of the
renin-angiotensin system may sometimes account for pathologically increased thirst in
humans. %ngiotensin ,, also produces &#+ a rise in arterial blood pressure, release of
norepinephrine from sympathetic nerve endings, and secretion of adrenomedullary
hormonesC and &2+ water and sodium retention by causing release of %9" from the
posterior pituitary and stimulation of renal tubular transport of sodium through direct
action on the 1idney and indirectly through increased aldosterone secretion from the
adrenal corte/. See also %ldosteroneC Midney.
Neuropharmacolo)y
)any substances released by neurons, and in some cases by neuroglial cells, affect
drin1ing behavior when injected into the brain and may interact with the brain and
modify angiotensin-induced drin1ing. .ubstances may stimulate or inhibit drin1ing, or
both, depending on the species and the conditions of the e/periment. %cetylcholine is a
particularly powerful stimulus to drin1ing in rats, and no inhibitory effects on drin1ing
have been described. "istamine also seems to be mainly stimulatory. "owever, a
lengthening list of neuroactive substances, including norepinephrine, serotonin, nitric
o/ide, opioids, bombesin-li1e peptides, tachy1inins, and neuropeptide @, may either
stimulate or inhibit drin1ing with varying degrees of effectiveness, depending on the
species or the site of injection in the brain. 8atriuretic peptides, prostaglandins, and
gamma-amino butyric acid seem to be e/clusively inhibitory. See also %cetylcholineC
8eurobiologyC .ynaptic transmission.
)any hormones also affect water or sodium inta1e. 2ela/in stimulates water inta1e, and
%9" &or vasopressin+ lowers the threshold to thirst in some species. Aasopressin injected
into the third cerebral ventricle may stimulate water inta1e, suggesting a possible role for
vasopressinergic neurons. ,ncreased sodium appetite in pregnancy and lactation depends
partly on the conjoint action of progesterone, estrogen, adrenocorticotrophic hormone
&%*T"+, cortisol, corticosterone, prolactin, and o/ytocin. %ldosterone and other
mineralocorticoids, the stress hormones of the hypothalamo-pituitary-adrenocortical a/is,
corticotrophin, %*T", and the glucocorticoids also stimulate sodium inta1e. See also
8eurohypophysis hormone.
The effect of many of these substances on drin1ing behavior shows both species and
anatomical diversity. The multiplicity of effects of many of these substances ma1es it
impossible to generalize on their role in natural thirst, but none of these substances seems
to be as consistent and as universal a stimulus of increased thirst and sodium appetite as
angiotensin.