Summary: Hormones, brain and behavior
Task 1
What are hormones and their functions?
Endocrinology = study of hormones + their actions
Hormones = chemical messengers, released
into the blood, that act through receptors to
cause a change in the target cells
o The glands that release them are
ductless: synthesizing + releasing
hormones directly into the bloodstream
-> endocrine = internal secretion
Vascular endothelium, GI-tract
and skin -> diffuse endocrine system = scattered
endocrine cells in various tissues, that secrete
hormones but do not form a discrete endocrine gland.
Functions of hormones:
Control regulatory systems in the body (homeostasis, metabolism, reproduction)
o Homeostasis = regulation of any large physiological system in the body (blood
glucose levels, body temperature)
Make sure that blood levels of sodium/potassium/calcium/glucose stay within set limits.
The endocrine system is one of the two major regulatory systems in the body:
1. Neural system: designed to deliver its messenger directly to the surface of its target
cell -> neural regulation is very rapid
2. Endocrine system: puts the messengers into the blood and allows for diffusion from
blood to target cells -> slower and acts over a longer period but can deliver its
messengers to a wider range of targets throughout the body.
Both systems have some messengers that bind specifically to receptors, but
hormones have also some classes that can diffuse freely across the membrane
Some hormones are released from nerve endings (=neurohormones -> neuroendocrine regulation),
while other hormones, like adrenaline/dopamine, are perhaps better known as neurotransmitters.
Signaling:
Endocrine release = hormones travel from the (ductless) cells where
they are made, in the bloodstream, to reach the cells where they act
Exocrine release = secrete substances into a duct
o Pancreas has endocrine, but also exocrine functions
Paracrine effect = some hormones also act locally on different cell types
in the tissues where they are produced
Autocrine action = other hormones act directly on the same type of cell
that secretes them
Hormone antagonism and synergy:
Agonist = when the hormone has an effect
Antagonist of the first hormone = when another hormone has an
opposite effect
o Belt and braces approach = more than one hormone is used to
achieve control -> very often the hormones will act in opposition: one or more will tend to increase
the level of the substance, while one or more will act to decrease it
It allows considerable fine control and responsiveness to a changing environment
It can afford protection against a potentially devastating change in substance levels
, Example: insulin and insulin antagonists to regulate blood glucose levels
Synergy = hormones which exert the same effect have much greater action when the 2 act together than
either of them can have individually (is rare) -> synergy of CRH + AVP in stimulating ACTH secretion
Endocrine axis = many hormones function as part of a cascade, where the target tissue of one hormone is
another endocrine gland.
Example: TRH from the hypothalamus stimulates the release of pituitary TSH which in turn stimulates the
release of thyroxine from the thyroid = hypothalamo-pituitary-thyroid axis
The cascade allows amplifications of signal, flexibility of response to a variety of physiological stimuli and
fine regulation of levels of the hormonal end-product.
What are the different types of hormones?
1. Peptide hormones: made of chains of amino acids (e.g. TRH + TSH)
o Usually, pre-formed and stored in granules within the endocrine cell,
ready for release in response to the appropriate signal
o Many of them, especially larger ones, undergo modification of the
basic peptide sequence before being secreted (=post-translational
processing) in the Golgi apparatus and secretory granules.
E.g. the linking of peptide chains by disulphide bridges and the
addition of carbohydrate residues (=glycosylation)
o Peptide hormone-secreting cells are distinguished by the large amounts
of rough ER, the prominent Golgi apparatus and by the presence of
secretory granules that contain the finished hormone.
o Peptides require a specific secretory mechanism, exocytosis -> is
usually triggered by an increase in intracellular calcium levels or
depolarization of the cell.
2. Steroids: made of cholesterol and have a common core structure
o Are formed by metabolism of cholesterol by enzymes within the
steroid-secreting cell, located within either the mitochondria or smooth
ER
o Steroid hormone production cells have large amounts of smooth ER and
mitochondria. They also usually contain significant lipid droplets within which are cholesterol
esters, as steroid-secreting cells store the precursor to hormone synthesis, rather than the finished
product.
o Steroid hormones simply diffuse out of the cell -> do not require a specific secretory mechanism.
3. Hormones derived from amino acids
o E.g.: tyrosine residues can be iodinated to give thyroid hormones or hydroxylated as the first step
on the biosynthetic pathway of catecholamines: dopamine, adrenaline and noradrenaline.
o Like peptide hormones, but usually smaller chains than peptide hormones + are hydrophilic.
4. Eicosanoids
Peptide hormones + catecholamines are quite water-soluble, dissolve readily in plasma, but cannot enter the
target cell; they interact with receptors on the cell surface. Lipophilic steroid + thyroid hormones dissolve poorly
in plasma, are mostly transported in blood bound to carrier proteins, but readily enter cells to interact with
cytoplasmic/nuclear receptors
When used therapeutically, steroid hormones and thyroid hormones are orally active, whereas most
peptide hormones must be injected to avoid being inactivated by digestive enzymes.
How does the transport and metabolism of hormones work?
Steroid + thyroid hormones need to be transported in blood bound to a carrier/binding protein -> 3 functions:
1. They increase the solubility of the hormone in blood, because the protein itself is polar (like blood).
2. They create a readily accessible reserve of the hormone in blood
, o Only the fraction of hormone that is not bound to the carrier protein is considered biologically
active = available to exert its physiological effects, but is also susceptible to metabolism/excretion
3. To increase the biological half-life of the hormone = the time taken for half the hormone present in
blood to be metabolized or excreted -> is done by protecting the hormone from metabolism and excretion
o Can be measured by injecting someone with a tagged hormone that can easily be distinguished
from the normal hormone, then seeing how quickly it disappears from the circulation by measuring
the amount present in samples taken at different times after the injection.
Different types of hormones are metabolized and excreted in different ways:
Peptide hormones are mainly metabolized following binding to a receptor in the target cell
o The hormone-receptor complex is internalized (taken up into the cell) and the hormone undergoes
degradation in a lysosome.
Steroids may be excreted by the kidney in unchanged form but mostly, they undergo metabolism in the
liver into more water-soluble forms which are then excreted in bile and in the urine
Catecholamines are metabolized rapidly by an enzyme catechol-O-methyltransferase (COMT), which
is found in most tissues (mostly in blood vessels) and by mono-amine oxidase (MAO) in neural tissues
Metabolism does not only result in the inactivation of hormones -> there is some principal secreted hormone being
inactive and requiring metabolism in the peripheral tissues to produce its active version:
Testosterone needs to be metabolized to 5-alpha dihydrotestosterone to have its effects in target tissues.
Metabolism of Vitamin D3 is essential to produce the active calcitriol
Thyroxine is metabolized by the removal of one of the iodine residues of the hormone -> depending on
which iodine residue is removed, this either increases the activity of the hormone by producing T3 or
decreases the activity by producing reverse T3.
What are patterns of hormone secretion?
Most hormones have diurnal patterns with episodic secretion on top of this underlying rhythm.
Episodic secretion Diurnal variation Set point
regulation
Regulation often involves maintenance The secretion of many hormones has a It is quite unusual for
of a set point by the correction of any predictable daily pattern = diurnal a hormone to be
deviation from this point. variation maintained at a set
Example: plasma calcium Example: growth hormone are usually level, but thyroxine
concentrations -> deviation very low during the day, but increase concentrations in
from set point triggers episodic during the early part of sleep, blood vary very little
secretion of regulatory whereas corticotropin concentration from day to day and
hormone to correct the calcium are at their lowest at midnight. are constant within a
levels The main regulator of the 24-h 24-h period.
Some hormones are always periodicity of hormone secretion is Changes in
secreted episodically or in the body clock principally the thyroxine
bursts (can be quite frequent) suprachiasmatic nucleus (SCN) in levels only
-> GnRH the hypothalamus. However, other occur over
The pattern of secretion for factors can influence the diurnal weeks of
hormones which are secreted pattern of secretion (cortisol -> food month -> has
episodically depends on other intake, melatonin -> darkness) very long
factors such as the half-life of o Some endocrine cells may half-life in
the hormone and the frequency have their own inbuilt 24-h blood
and amplitude of secretory clock
episodes.
Hormone A = diurnal variation
Hormone B = very little diurnal variation
Hormone C = episodic secretion
Taking a single-point blood measurement of the hormone is of little
value in diagnosing endocrine disorder because there is so much
variation during the day.
Negative feedback
The simplest form of negative feedback is where the final product of an
endocrine cascade acts to inhibit the release of hormones higher up in the
cascade -> thyroxine acts on both the hypothalamus and anterior pituitary to
decrease TRH + TSH production
, Delayed feedback: most negative feedback operates through a genomic mechanism resulting in a
decrease in the production of hormones higher up in the endocrine axis -> takes place over a relatively
long period (hours-days)
o Is determined by both the amplitude of the original increase in hormone secretion and its duration
o E.g. CRH gene expression is inhibited by e.g. methylation, so translation and CRH-protein
production is inhibited
Fast feedback: not mediated by a genomic mechanism as it can take place within 10 min. and is
determined by the gradient of increase -> when hormone levels rise rapidly.
o HPA-axis where cortisol is the hormonal end-product, and where rapid cortisol increases trigger a
fast feedback mechanism, which reduces activity of the axis at higher levels.
Some systems also have short feedback loops which allow intermediate products of an endocrine axis to
exert negative feedback at higher levels
o ACTH, which stimulates cortisol secretion, also inhibits CRH
In summary, the CRH-ACTH-cortisol cascade is regulated both by classical negative feedback from
cortisol (end-product) and by short-loop feedback from ACTH (intermediate product)
Negative feedback does not mean that hormone production is switched on and off like in neurotransmitters, but
there is a basal/residual rate of hormone secretion which can be increased by a variety of stimuli and decreased
by negative feedback -> all endocrine systems are dynamic/responsive to change and tend to return to the
basal/residual state of activity.
What is the HPA-axis?
HPA-axis = the hypothalamo-pituitary-adrenal axis: hypothalamus secretes corticotropin releasing
hormone (CRH) and arginine vasopressin (AVP), which both act on the corticotroph cells of the
anterior pituitary which in turn releases adrenocorticotropic hormone (ACTH). ACTH signals the
adrenal cortex which releases cortisol into the bloodstream.
Cortisol has negative feedback effects both at the level of the hypothalamus, inhibiting CRH
and AVP secretion, and the pituitary, inhibiting ACTH secretion.
o Cortisol is produced by cells of the zona fasciculata and reticularis
The actions of CRH and AVP together is greater than the sum of their individual effects -> they
activate different intracellular pathways and act through G-protein coupled receptors on the
corticotroph cells
o CRH receptors are linked to cAMP generation -> via blood vessel
o AVP receptors are linked to intracellular calcium signaling -> via neuron and synapses
The HPA axis is stimulated by stress: physiological stressors (cold exposure, infection, hypoglycemia,
exercise) + psychological stressors
Several brain regions are involved in the regulation of the HPA axis, including the hypothalamic sub-regions
and the thalamus which connects to the PVN
o Other regions indirectly mediate HPA axis activity, including the limbic system = hippocampus,
amygdala and PFC -> amygdala hypes hypothalamus up, PFC and hippocampus slow it down.
There is diurnal variation in ACTH production and secretion and therefore serum
cortisol concentration vary with a peak at 6-9h -> serum cortisol is usually
sampled at 9h.
What is the cortisol awakening response?
Circadian rhythm
The SCN communicates with other neurons in the hypothalamus to start the
activation of the HPA axis, thereby being responsible for the overall coordination
of the HPA-axis. In addition, the SCN regulates circadian rhythms -> cortisol
secretion fluctuates according to a marked circadian pattern.
Circadian rhythms = physical, mental, and behavioral changes that follow a 24-hour cycle. These natural
processes respond primarily to light and dark e.g. sleeping at night and being awake during the day.
Links between the SCN and paraventricular nucleus (PVN) of the hypothalamus synchronize the time of
day with neuroendocrine output.
CAR definition
Cortisol awakening response (CAR) = sharp increase in cortisol levels immediately following awakening.
Task 1
What are hormones and their functions?
Endocrinology = study of hormones + their actions
Hormones = chemical messengers, released
into the blood, that act through receptors to
cause a change in the target cells
o The glands that release them are
ductless: synthesizing + releasing
hormones directly into the bloodstream
-> endocrine = internal secretion
Vascular endothelium, GI-tract
and skin -> diffuse endocrine system = scattered
endocrine cells in various tissues, that secrete
hormones but do not form a discrete endocrine gland.
Functions of hormones:
Control regulatory systems in the body (homeostasis, metabolism, reproduction)
o Homeostasis = regulation of any large physiological system in the body (blood
glucose levels, body temperature)
Make sure that blood levels of sodium/potassium/calcium/glucose stay within set limits.
The endocrine system is one of the two major regulatory systems in the body:
1. Neural system: designed to deliver its messenger directly to the surface of its target
cell -> neural regulation is very rapid
2. Endocrine system: puts the messengers into the blood and allows for diffusion from
blood to target cells -> slower and acts over a longer period but can deliver its
messengers to a wider range of targets throughout the body.
Both systems have some messengers that bind specifically to receptors, but
hormones have also some classes that can diffuse freely across the membrane
Some hormones are released from nerve endings (=neurohormones -> neuroendocrine regulation),
while other hormones, like adrenaline/dopamine, are perhaps better known as neurotransmitters.
Signaling:
Endocrine release = hormones travel from the (ductless) cells where
they are made, in the bloodstream, to reach the cells where they act
Exocrine release = secrete substances into a duct
o Pancreas has endocrine, but also exocrine functions
Paracrine effect = some hormones also act locally on different cell types
in the tissues where they are produced
Autocrine action = other hormones act directly on the same type of cell
that secretes them
Hormone antagonism and synergy:
Agonist = when the hormone has an effect
Antagonist of the first hormone = when another hormone has an
opposite effect
o Belt and braces approach = more than one hormone is used to
achieve control -> very often the hormones will act in opposition: one or more will tend to increase
the level of the substance, while one or more will act to decrease it
It allows considerable fine control and responsiveness to a changing environment
It can afford protection against a potentially devastating change in substance levels
, Example: insulin and insulin antagonists to regulate blood glucose levels
Synergy = hormones which exert the same effect have much greater action when the 2 act together than
either of them can have individually (is rare) -> synergy of CRH + AVP in stimulating ACTH secretion
Endocrine axis = many hormones function as part of a cascade, where the target tissue of one hormone is
another endocrine gland.
Example: TRH from the hypothalamus stimulates the release of pituitary TSH which in turn stimulates the
release of thyroxine from the thyroid = hypothalamo-pituitary-thyroid axis
The cascade allows amplifications of signal, flexibility of response to a variety of physiological stimuli and
fine regulation of levels of the hormonal end-product.
What are the different types of hormones?
1. Peptide hormones: made of chains of amino acids (e.g. TRH + TSH)
o Usually, pre-formed and stored in granules within the endocrine cell,
ready for release in response to the appropriate signal
o Many of them, especially larger ones, undergo modification of the
basic peptide sequence before being secreted (=post-translational
processing) in the Golgi apparatus and secretory granules.
E.g. the linking of peptide chains by disulphide bridges and the
addition of carbohydrate residues (=glycosylation)
o Peptide hormone-secreting cells are distinguished by the large amounts
of rough ER, the prominent Golgi apparatus and by the presence of
secretory granules that contain the finished hormone.
o Peptides require a specific secretory mechanism, exocytosis -> is
usually triggered by an increase in intracellular calcium levels or
depolarization of the cell.
2. Steroids: made of cholesterol and have a common core structure
o Are formed by metabolism of cholesterol by enzymes within the
steroid-secreting cell, located within either the mitochondria or smooth
ER
o Steroid hormone production cells have large amounts of smooth ER and
mitochondria. They also usually contain significant lipid droplets within which are cholesterol
esters, as steroid-secreting cells store the precursor to hormone synthesis, rather than the finished
product.
o Steroid hormones simply diffuse out of the cell -> do not require a specific secretory mechanism.
3. Hormones derived from amino acids
o E.g.: tyrosine residues can be iodinated to give thyroid hormones or hydroxylated as the first step
on the biosynthetic pathway of catecholamines: dopamine, adrenaline and noradrenaline.
o Like peptide hormones, but usually smaller chains than peptide hormones + are hydrophilic.
4. Eicosanoids
Peptide hormones + catecholamines are quite water-soluble, dissolve readily in plasma, but cannot enter the
target cell; they interact with receptors on the cell surface. Lipophilic steroid + thyroid hormones dissolve poorly
in plasma, are mostly transported in blood bound to carrier proteins, but readily enter cells to interact with
cytoplasmic/nuclear receptors
When used therapeutically, steroid hormones and thyroid hormones are orally active, whereas most
peptide hormones must be injected to avoid being inactivated by digestive enzymes.
How does the transport and metabolism of hormones work?
Steroid + thyroid hormones need to be transported in blood bound to a carrier/binding protein -> 3 functions:
1. They increase the solubility of the hormone in blood, because the protein itself is polar (like blood).
2. They create a readily accessible reserve of the hormone in blood
, o Only the fraction of hormone that is not bound to the carrier protein is considered biologically
active = available to exert its physiological effects, but is also susceptible to metabolism/excretion
3. To increase the biological half-life of the hormone = the time taken for half the hormone present in
blood to be metabolized or excreted -> is done by protecting the hormone from metabolism and excretion
o Can be measured by injecting someone with a tagged hormone that can easily be distinguished
from the normal hormone, then seeing how quickly it disappears from the circulation by measuring
the amount present in samples taken at different times after the injection.
Different types of hormones are metabolized and excreted in different ways:
Peptide hormones are mainly metabolized following binding to a receptor in the target cell
o The hormone-receptor complex is internalized (taken up into the cell) and the hormone undergoes
degradation in a lysosome.
Steroids may be excreted by the kidney in unchanged form but mostly, they undergo metabolism in the
liver into more water-soluble forms which are then excreted in bile and in the urine
Catecholamines are metabolized rapidly by an enzyme catechol-O-methyltransferase (COMT), which
is found in most tissues (mostly in blood vessels) and by mono-amine oxidase (MAO) in neural tissues
Metabolism does not only result in the inactivation of hormones -> there is some principal secreted hormone being
inactive and requiring metabolism in the peripheral tissues to produce its active version:
Testosterone needs to be metabolized to 5-alpha dihydrotestosterone to have its effects in target tissues.
Metabolism of Vitamin D3 is essential to produce the active calcitriol
Thyroxine is metabolized by the removal of one of the iodine residues of the hormone -> depending on
which iodine residue is removed, this either increases the activity of the hormone by producing T3 or
decreases the activity by producing reverse T3.
What are patterns of hormone secretion?
Most hormones have diurnal patterns with episodic secretion on top of this underlying rhythm.
Episodic secretion Diurnal variation Set point
regulation
Regulation often involves maintenance The secretion of many hormones has a It is quite unusual for
of a set point by the correction of any predictable daily pattern = diurnal a hormone to be
deviation from this point. variation maintained at a set
Example: plasma calcium Example: growth hormone are usually level, but thyroxine
concentrations -> deviation very low during the day, but increase concentrations in
from set point triggers episodic during the early part of sleep, blood vary very little
secretion of regulatory whereas corticotropin concentration from day to day and
hormone to correct the calcium are at their lowest at midnight. are constant within a
levels The main regulator of the 24-h 24-h period.
Some hormones are always periodicity of hormone secretion is Changes in
secreted episodically or in the body clock principally the thyroxine
bursts (can be quite frequent) suprachiasmatic nucleus (SCN) in levels only
-> GnRH the hypothalamus. However, other occur over
The pattern of secretion for factors can influence the diurnal weeks of
hormones which are secreted pattern of secretion (cortisol -> food month -> has
episodically depends on other intake, melatonin -> darkness) very long
factors such as the half-life of o Some endocrine cells may half-life in
the hormone and the frequency have their own inbuilt 24-h blood
and amplitude of secretory clock
episodes.
Hormone A = diurnal variation
Hormone B = very little diurnal variation
Hormone C = episodic secretion
Taking a single-point blood measurement of the hormone is of little
value in diagnosing endocrine disorder because there is so much
variation during the day.
Negative feedback
The simplest form of negative feedback is where the final product of an
endocrine cascade acts to inhibit the release of hormones higher up in the
cascade -> thyroxine acts on both the hypothalamus and anterior pituitary to
decrease TRH + TSH production
, Delayed feedback: most negative feedback operates through a genomic mechanism resulting in a
decrease in the production of hormones higher up in the endocrine axis -> takes place over a relatively
long period (hours-days)
o Is determined by both the amplitude of the original increase in hormone secretion and its duration
o E.g. CRH gene expression is inhibited by e.g. methylation, so translation and CRH-protein
production is inhibited
Fast feedback: not mediated by a genomic mechanism as it can take place within 10 min. and is
determined by the gradient of increase -> when hormone levels rise rapidly.
o HPA-axis where cortisol is the hormonal end-product, and where rapid cortisol increases trigger a
fast feedback mechanism, which reduces activity of the axis at higher levels.
Some systems also have short feedback loops which allow intermediate products of an endocrine axis to
exert negative feedback at higher levels
o ACTH, which stimulates cortisol secretion, also inhibits CRH
In summary, the CRH-ACTH-cortisol cascade is regulated both by classical negative feedback from
cortisol (end-product) and by short-loop feedback from ACTH (intermediate product)
Negative feedback does not mean that hormone production is switched on and off like in neurotransmitters, but
there is a basal/residual rate of hormone secretion which can be increased by a variety of stimuli and decreased
by negative feedback -> all endocrine systems are dynamic/responsive to change and tend to return to the
basal/residual state of activity.
What is the HPA-axis?
HPA-axis = the hypothalamo-pituitary-adrenal axis: hypothalamus secretes corticotropin releasing
hormone (CRH) and arginine vasopressin (AVP), which both act on the corticotroph cells of the
anterior pituitary which in turn releases adrenocorticotropic hormone (ACTH). ACTH signals the
adrenal cortex which releases cortisol into the bloodstream.
Cortisol has negative feedback effects both at the level of the hypothalamus, inhibiting CRH
and AVP secretion, and the pituitary, inhibiting ACTH secretion.
o Cortisol is produced by cells of the zona fasciculata and reticularis
The actions of CRH and AVP together is greater than the sum of their individual effects -> they
activate different intracellular pathways and act through G-protein coupled receptors on the
corticotroph cells
o CRH receptors are linked to cAMP generation -> via blood vessel
o AVP receptors are linked to intracellular calcium signaling -> via neuron and synapses
The HPA axis is stimulated by stress: physiological stressors (cold exposure, infection, hypoglycemia,
exercise) + psychological stressors
Several brain regions are involved in the regulation of the HPA axis, including the hypothalamic sub-regions
and the thalamus which connects to the PVN
o Other regions indirectly mediate HPA axis activity, including the limbic system = hippocampus,
amygdala and PFC -> amygdala hypes hypothalamus up, PFC and hippocampus slow it down.
There is diurnal variation in ACTH production and secretion and therefore serum
cortisol concentration vary with a peak at 6-9h -> serum cortisol is usually
sampled at 9h.
What is the cortisol awakening response?
Circadian rhythm
The SCN communicates with other neurons in the hypothalamus to start the
activation of the HPA axis, thereby being responsible for the overall coordination
of the HPA-axis. In addition, the SCN regulates circadian rhythms -> cortisol
secretion fluctuates according to a marked circadian pattern.
Circadian rhythms = physical, mental, and behavioral changes that follow a 24-hour cycle. These natural
processes respond primarily to light and dark e.g. sleeping at night and being awake during the day.
Links between the SCN and paraventricular nucleus (PVN) of the hypothalamus synchronize the time of
day with neuroendocrine output.
CAR definition
Cortisol awakening response (CAR) = sharp increase in cortisol levels immediately following awakening.
