ANAT 322 Lecture 16: ANAT 322 - Lecture 16
7 Jun 2018
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ANAT 322 Winter 2017
Lectures
Lecture 16:
→ Regulatory Mechanisms of Adrenal and Corticotroph Tumors causing Cushig’s Sdoe
. Cushig’s sdoe epesets all of the causes of excess cortisol production in humans whereas
Cushig’s disease is limited to the most frequent cause which is pituitary corticotroph tumors which
produce excess ACTH and stimulate cortisol production abnormally.
2. From the hypothalamus, the production of CRH and vasopressin (AVP) regulate ACTH production from
the anterior pituitary that stimulates the adrenal gland to produce glucocorticoids that will negative
feedback at different levels to supress CRH, AVP and ACTH.
3. In the adrenal gland, ACTH will stimulate mostly the zona fasciculata production of cortisol whereas
there is a minor effect of ACTH on mineralocorticoid production and also on adrenal androgen
production.
4. Chronic cortisol excess will result in a very severe disease depending on the intensity and the
metabolic elevation of cortisol production and the duration of excess cortisol production.
There will be effects on every tissue almost because there are glucocorticoid receptors practically in
every tissue so it is a multi-system effect. There will be important effects in the brain such as with
personality, memory, irritability and concentration. There will be changes in fat distribution (central
obesity) and within the cardiovascular system with long-term complications. There is predisposition to
infections because of the suppression of the immune response. Abnormalities including catabolic effects
on the bone such as osteoporosis, bone fracture, among others.
5. Devastating disease that often requires 5-8 years for the appearance of the symptoms. After surgery
and the adrenal tumors are removed, there is a big difference and the daughter of the patient is shown
i hee so this shos a geeti fo of Cushig’s sdoe.
6. Etiologies are divided into those that are secondary to excess production of ACTH so these are ACTH
dependent and are the most feuet. The ost feuet of these is Cushig’s disease hih is a eig
corticotroph tumor in the pituitary gland where normal corticotroph cells expand and become a tumor
that secretes excess ACTH and this accounts for 70% of the cases of edogeous Cushig’s sdoe
and for unknown reasons it is predominant in women (3-5 women for 1 men). Sometimes ACTH does
not come from corticotroph tumors but from tumors outside of the pituitary which produces ectopic
ACTH for example gut tumors or tissues where ACTH is repressed.
The corticotropin-independent causes is when there is excess production primarily from an adrenal
tumor or hyperplasia, the excess cortisol production will supress endogenous ACTH. Despite the fact
that ACTH is completely supressed, you can have excess cortisol production either because of an
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ANAT 322 Winter 2017
Lectures
adenoma or carcinoma is producing excess cortisol and these bilateral adrenal gland diseases are most
common. Sometimes it comes from a primary disease from the adrenal glands called macronodular
hyperplasia. It can also occur from small nodule hyperplasia also called primary pigmented nodular
adrenal disease.
7. When we administer exogenous high amounts of a potent glucocorticoid like dexamethasone, you are
able to demonstrate that you supress endogenous CRH and AVP, ACTH will decrease and cortisol levels
will decrease tremendously as well by at least 90%.
I patiets ith Cushig’s disease, thee is a otiotoph tuo hih is peset i the pituita
gland and all the ACTH comes from the tumor which will stimulate excess cortisol production and that
will supress not only CRH from the PVN but also ACTH from the normal corticotroph cells that are
adjacent to the corticotroph tumor. Those tumors still have glucocorticoid receptors but the set point to
do the feedback is at a higher level so if you give only small amounts of dexamethasone you will not
supress sufficiently cortisol but if you give higher concentrations you will be able to partially supress
maybe by 50% cortisol levels. There is a shift in the dose response curve between the normal
corticotroph cells and the benign corticotroph tumor in the pituitary.
In contrast, if you look at ectopic sources of ACTH such as a malignant tumor that normally would not
produce ACTH, those tumors are very undifferentiated and all of the ACTH is coming from the tumor.
The excess cortisol will supress the normal system so the endogenous CRH and ACTH from the pituitary
will be supress but the tumors do not express receptors for CRH or AVP so even if you give large
amounts of CRH or dexamethasone, the cortisol levels will not change.
The complexity is that in some of the benign carcinoid tumors can behave like a corticotroph tumor
from the pituitary gland would. There can be receptors for CRH, AVP, glucocorticoids in those benign
tumors which are more differentiated and express the different genes that are normally expressed by
the normal corticotroph cells. There can be partial suppression by dexamethasone as is seen in patients
with pituitary origin sources of ACTH.
8. If the tumor is a primary tumor of the adrenal gland, a benign or malignant tumor, the excess cortisol
coming from the tumor cells will supress CRH and ACTH. Because ACTH is fully supressed, even if give
large amounts of dexamethasone, there will be no further decrease in ACTH so cortisol levels are not
affected by the administration of dexamethasone.
9. Understanding the regulation between cortisol and ACTH is the basis for investigation to get to a
differential diagnosis in a patient that has excess of cortisol production as you are trying to identify the
origin of the excess cortisol.
Everything has to be based on the measurements of ACTH, if ACTH is supressed then this indicates
that there is a primary adrenal problem and thus imaging needs to be done to see what the tumor is
like.
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ANAT 322 Winter 2017
Lectures
If ACTH is inappropriately normal or elevated, this indicates it is an ACTH dependent cause so you will
look for the presence of a pituitary tumor or potentially an ectopic tumor. The problem is that many of
those tumors in the pituitary are very small (1-3mm) beyond the limit of detection and so it cannot be
detected by resonance imaging of the pituitary (MRI). We need to do other tests to confirm that it is
ACTH dependent such as measuring ACTH by other means. If the central source is not found, you can
start doing imagining elsewhere to find where the ectopic tumor is localized.
10. There has been a lot of progress in understanding the molecular mechanisms underlying the disease
and the causes. But the reason why there is ectopic expression of the gene in those tumor is still not
known so well.
11. Normally, ACTH receptor is a seven transmembrane receptor that through its interaction with the
Gsα stimulates adenylate cyclase (AC) which generates cAMP that will activate protein kinase A (PKA).
PKA is oposed of to suuits, a egulato suuit alled Rα ad the atalti suuit alled Cα.
cAMP stimulation of PKA will lead to phosphorylation of specific genes, including the ones implicated in
the enzyme steroidogenesis. Levels of cAMP are also regulated by phosphodiesterase which regulate so
the amounts of cAMP are maintain and stimulated adequately.
There are different causes of primary adrenal Cushing syndrome and there has been novel
identification of molecular mechanisms responsible for the syndrome.
12. In bilateral macronodular adrenal hyperplasia (BMAH), some genes are responsible for the
occurrence of the genetic forms of the disease. It has also being identified that in addition to the normal
ACTH receptor (and the downstream axis), there can be ectopic receptors which are expressed in the
adrenal gland and are responsible for this.
This can also be unilateral and it has been identified that a large proportion of patients who have
BMAH have in their adrenal tissue the expression of a diversity of receptors which are not normally
expressed in the zona fasciculata cells. Sometimes the receptors are expressed in low amounts in the
zona fasciculata cells but for some reason there is an increase expression or coupling of those receptors
to the machinery of steroidogenesis. So the adrenal gland is under the control of receptors which are
not normally expressed but for some of these receptors there are antagonists which open the possibility
to treat these patients by blocking the function of those receptors.
13. They designed an approach in vivo in which simple tests are performed in individuals such as posture
tests or eating tests that can stimulate the production of epinephrine, vasopressin, among others. You
can then see if there is a response that is not supposed to be there. If cortisol is modulated by an
aberrant receptor, those tests which are conducted in sequence over three days will allow the physician
to identify the receptors.
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Document Summary
Regulatory mechanisms of adrenal and corticotroph tumors causing cushi(cid:374)g"s s(cid:455)(cid:374)d(cid:396)o(cid:373)e (cid:1005). Cushi(cid:374)g"s s(cid:455)(cid:374)d(cid:396)o(cid:373)e (cid:396)ep(cid:396)ese(cid:374)ts all of the causes of excess cortisol production in humans whereas. There will be effects on every tissue almost because there are glucocorticoid receptors practically in every tissue so it is a multi-system effect. There will be important effects in the brain such as with personality, memory, irritability and concentration. There will be changes in fat distribution (central obesity) and within the cardiovascular system with long-term complications. There is predisposition to infections because of the suppression of the immune response. Abnormalities including catabolic effects on the bone such as osteoporosis, bone fracture, among others: devastating disease that often requires 5-8 years for the appearance of the symptoms. Sometimes acth does not come from corticotroph tumors but from tumors outside of the pituitary which produces ectopic. Acth for example gut tumors or tissues where acth is repressed.
