Enrico Tiepolo
Corticosteroids
The adrenal gland is a gland with two components, which is located on top of the kidney, and
therefore is called “ad-renal”.
The two components are the cortex and the medulla.
1. The medulla is a modified sympathetic ganglion that receives preganglionic sympathetic
fibers from the CNS.
2. Around the medulla we have the cortex, which displays three layers:
o Zona glomerulosa, the most peripheral zone.
It has a granular, rough appearance because it
produces mineralocorticoids which act on
the kidney (the main one is aldosterone à
stimulates reabsorption of Na+ in the distal
convoluted tubules).
o Zona fasciculata is the thickest portion and
produces glucocorticoids (such as
corticosterone and cortisol). They are called
glucocorticoids because they mainly deal with
the metabolism of glucose. They are crucial in terms
of inflammation and immunity.
o Zona reticularis is the innermost layer in
charge of producing sex hormones and it is
particularly important before puberty.
Biochemical paths
• In the zona glomerulosa (where 21C compounds are found) we go through the production
of corticosterone, which is further metabolized, transformed into aldehyde which is aldosterone.
• In the zona fasciculata (where 21C compounds are found) we either have the same
production of corticosterone or the addition of a hydroxyl group to the ketone which leads to
the production of cortisol.
• In the zona reticularis (where 19C and 18C compounds are found) the sex steroids are
produced.
N.B. There are differences in terms of synthesis
depending on the location inside the cells,
specifically whether they are produced in the
mitochondrion or in the cytoplasm.
17 Body At Work II
, Enrico Tiepolo
Glucocorticoids are often referred to as stress hormones. The whole adrenal gland is actually
related to acute stress response: “fight or flight reactions” are connected to a diffuse sympathetic
stimulation which makes the medulla of the adrenal gland release adrenalin and noradrenalin.
The idea is that any kind of stress, either physical or psychological, will lead to an activation of the
hypothalamus, which will release Corticotropin Releasing Hormones/Factor (CRH/CRF)
which in turn stimulates the anterior pituitary which, releases ACTH, therefore stimulating the adrenal
cortex.
Through this pathway, the ACTH will stimulate mainly the zona fasciculata of the adrenal cortex.
In fact, aldosterone, produced in the zona glomerulosa is regulated in its secretion by other factors, such
as Na+ levels, K+ levels and angiotensin II (RAAS
system).
Under stimulation of the zona fasciculata, cortisol
is produced and will exert a negative feedback on
the anterior pituitary and the hypothalamus: this
double negative feedback is a standard mechanism in
endocrinology. For example, if the adrenal cortex is not
able to produce cortisol, we will observe high levels
of CRH and of ACTH. On the other hand, if we
have a pituitary tumor which secretes corticotropin
(ACTH), we will observe high levels of cortisol
(hypercortisolism/ Cushing’s syndrome) and of
ACTH, but low levels of CRH. If we have an excess
of cortisol, we may inject a similar substance and
check whether the endogenous levels decrease or not,
as due to the negative feedback the hypothalamus and hypophysis should decrease even more their
hormone production.
Glucocorticoids, as well as the other steroid hormones, have a strongly lipophilic structure which
means that these hormones are able to travel across membranes, and therefore they will have
intracellular receptors, which can be cytoplasmic or nuclear.
The most important thing is that these receptors are proteins and if they are cytoplasmic, they dimerize
when bound to the ligand, changing their conformation and becoming target for nuclear transport
(exposing nuclear translocation signal) in such a way that they will enter the nucleus and allow
transcription.
Glucocorticoids bind to cytoplasmic receptors which are usually bound to proteins of the Heat Shock
Protein family.
Glucocorticoids enter the cell and bind to the receptors
à the receptor detaches from the Heat Shock Protein
and dimerizes à travels into the nucleus binds to GRE
(glucocorticoids responsive element) and performs its
action.
By convention, these cytoplasmic receptors have three
domains:
1. Ligand binding domain
2. DNA binding domain
3. Transactivation domain.
These hormones through the binding of the receptor may end up having direct promotion or repression
as well as indirect promotion or repression, because they either affect DNA directly or affect other
factors which will then perform their actions.
They can affect non-transcriptional pathways as well, as other biochemical pathways may be activated
as a side effect.
18 Body At Work II
Corticosteroids
The adrenal gland is a gland with two components, which is located on top of the kidney, and
therefore is called “ad-renal”.
The two components are the cortex and the medulla.
1. The medulla is a modified sympathetic ganglion that receives preganglionic sympathetic
fibers from the CNS.
2. Around the medulla we have the cortex, which displays three layers:
o Zona glomerulosa, the most peripheral zone.
It has a granular, rough appearance because it
produces mineralocorticoids which act on
the kidney (the main one is aldosterone à
stimulates reabsorption of Na+ in the distal
convoluted tubules).
o Zona fasciculata is the thickest portion and
produces glucocorticoids (such as
corticosterone and cortisol). They are called
glucocorticoids because they mainly deal with
the metabolism of glucose. They are crucial in terms
of inflammation and immunity.
o Zona reticularis is the innermost layer in
charge of producing sex hormones and it is
particularly important before puberty.
Biochemical paths
• In the zona glomerulosa (where 21C compounds are found) we go through the production
of corticosterone, which is further metabolized, transformed into aldehyde which is aldosterone.
• In the zona fasciculata (where 21C compounds are found) we either have the same
production of corticosterone or the addition of a hydroxyl group to the ketone which leads to
the production of cortisol.
• In the zona reticularis (where 19C and 18C compounds are found) the sex steroids are
produced.
N.B. There are differences in terms of synthesis
depending on the location inside the cells,
specifically whether they are produced in the
mitochondrion or in the cytoplasm.
17 Body At Work II
, Enrico Tiepolo
Glucocorticoids are often referred to as stress hormones. The whole adrenal gland is actually
related to acute stress response: “fight or flight reactions” are connected to a diffuse sympathetic
stimulation which makes the medulla of the adrenal gland release adrenalin and noradrenalin.
The idea is that any kind of stress, either physical or psychological, will lead to an activation of the
hypothalamus, which will release Corticotropin Releasing Hormones/Factor (CRH/CRF)
which in turn stimulates the anterior pituitary which, releases ACTH, therefore stimulating the adrenal
cortex.
Through this pathway, the ACTH will stimulate mainly the zona fasciculata of the adrenal cortex.
In fact, aldosterone, produced in the zona glomerulosa is regulated in its secretion by other factors, such
as Na+ levels, K+ levels and angiotensin II (RAAS
system).
Under stimulation of the zona fasciculata, cortisol
is produced and will exert a negative feedback on
the anterior pituitary and the hypothalamus: this
double negative feedback is a standard mechanism in
endocrinology. For example, if the adrenal cortex is not
able to produce cortisol, we will observe high levels
of CRH and of ACTH. On the other hand, if we
have a pituitary tumor which secretes corticotropin
(ACTH), we will observe high levels of cortisol
(hypercortisolism/ Cushing’s syndrome) and of
ACTH, but low levels of CRH. If we have an excess
of cortisol, we may inject a similar substance and
check whether the endogenous levels decrease or not,
as due to the negative feedback the hypothalamus and hypophysis should decrease even more their
hormone production.
Glucocorticoids, as well as the other steroid hormones, have a strongly lipophilic structure which
means that these hormones are able to travel across membranes, and therefore they will have
intracellular receptors, which can be cytoplasmic or nuclear.
The most important thing is that these receptors are proteins and if they are cytoplasmic, they dimerize
when bound to the ligand, changing their conformation and becoming target for nuclear transport
(exposing nuclear translocation signal) in such a way that they will enter the nucleus and allow
transcription.
Glucocorticoids bind to cytoplasmic receptors which are usually bound to proteins of the Heat Shock
Protein family.
Glucocorticoids enter the cell and bind to the receptors
à the receptor detaches from the Heat Shock Protein
and dimerizes à travels into the nucleus binds to GRE
(glucocorticoids responsive element) and performs its
action.
By convention, these cytoplasmic receptors have three
domains:
1. Ligand binding domain
2. DNA binding domain
3. Transactivation domain.
These hormones through the binding of the receptor may end up having direct promotion or repression
as well as indirect promotion or repression, because they either affect DNA directly or affect other
factors which will then perform their actions.
They can affect non-transcriptional pathways as well, as other biochemical pathways may be activated
as a side effect.
18 Body At Work II
