EAST 501 Lecture Notes - Lecture 14: Proprotein Convertase, Congenital Adrenal Hyperplasia, Corticotropic Cell
21 Jun 2018
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L14 – Bernard 03/28
Adrenal Disorders
1
OUTLINE
1. Overview of HPA axis (feedback regulation)
2. Adrenal insufficiency
a. Congenital adrenal hyperplasia (CAH)
b. Addison’s disease – autoimmune
3. Cushing’s syndrome/disease (Cushing disease is a type of Cushing’s syndrome)
4. Challenges of corticosteroid therapy
HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS
- CRH binds to receptors (CRH receptor) on the anterior pituitary gland (corticotrope cells)
- The corticotrope will synthesis and secrete ACTH which goes through the systemic circulation and will find
receptor MC2R on the adrenal cortical cells and stimulate the production of corticosteroids (particularly cortisol
in humans an corticosterone in rodents)
- Difference between cortisol and corticosterone
o In humans – cortisol
o In rodent – corticosterone
§ rodents lack a particular enzyme
that does not enable them to make
cortisol
- Cortisol feedsback to the brain (negative feedback) to
inhibit CRH synthesis and secretion and to the
pituitary to impair ACTH production and the
responsiveness of the cells to CRH
REGULATION OF HPA AXIS
- there is circadian regulation (natural daily regulation in cortisol
production and release throughout the day)
o Change is cortisol release through
the day
o Released in pulsatile fashion
o We are diurnal creatures
o The cortisol increases at the end of the night
around the time of awakening – this is an important
awakening signal (while sleeping you are in a fasted
state)
o cortisol = glucocorticoid
o cortisol stimulates glucose production
by the liver à providing glucose to the brain and coming
out of the fasted state
- in rodents, cortisol increases from the light to dark
(because they are nocturnal), but they still have circadian
corticosterone changes
- the other regulator is stress (physical or psychological)
o stress suppressed reproduction
o stress increased cortisol/corticosterone (they go up very rapidly)
this is part of the fight or flight response
o there are other stressors – cold, hypoglycemic stress
L14 – Bernard 03/28
Adrenal Disorders
2
CRH SIGNALS TO PITUITARY CORTICOTROPE CELLS
- PVN synthesized CRH à released through the
median eminence and goes through the pituitary portal system
and binds to its receptor on corticotrope cells
- This is one of the lesser cells types in the pituitary
- in response to CRH, the anterior pituitary will secrete ACTH
MECHANISMS OF CRH STIMULATED POMC EXPRESSION
- CRH binds to its GPRC which is mainly coupled to Gs à activation of AC à PKA production
- PKA enables Ca to enter the cell à important for exocytosis à need Ca to come in for vesicles with the ACTH to
be released à downstream regulation of gene expression
o we are mainly interested in POMC
- A product of the POMC gene is ACTH
ADRENOCORTICOTROPIC HORMONE (ACTH)
- depending on the pro-hormone convertases that are expressed in particular cell types this precursor (POMC) will
be chopped up into different biologically active peptides
- in the case of corticotrope cells à pro-hormone convertase 1 is expressed à get ACTH
- Produced in pituitary corticotropes
- 39 aa peptide derived from the pro-opmelanocortin (POMC) precursor (cleaved by prohorme convertase 1)
- ACTH can be then cleaved into alpha-MSH and CLIP
o alpha-MSH is important in the brain in terms of regulating appetite
L14 – Bernard 03/28
Adrenal Disorders
3
- Alpha MSH and beta MSH bind to the MC3R and MC4R
o AgRP is the endogenous inverse agonist that acts on both of these receptors (can also function as an
antagonist)
- ACTH binds to the MC2R à this is expressed mainly in adrenal cortical cells
- In Addison’s disease there is hyperpigmentation (look tan) because they are hyper-synthesizing POMC
o some ACTH is cleaved into alpha-MSH à binds to MC2R on the skin and changes the pigmentation
o Can use this pigmentation as a method of diagnosis of Addison’s
ACTH SIGNALS TO THE ADRENAL CORTEX
- ACTH binds to the M2CR on the adrenal gland
- ACTH goes through systemic circulation
ADRENAL CORTICAL ARCHITECTURE
- adrenals sit above the kidney (both sides)
- the adrenal has a nervous system component – the medulla (where epinephrine is released)
- the steroidogenic cells are in the cortex
- There are different layers in the cortex that produce different steroids
- Corticosteroids = all the steroids that are made in the adrenal cortex
- Glucocorticoids = steroids that are all made in different layers
- Mineralocorticoids are made in a different layer from glucocorticoids
- Androgens are also made in the adrenal (testosterone, androstenedione)
- Post-menopausal women are more likely to get estrogen dependent breast cancer than pre-menopausal
women, but if they are menopausal the ovaries are not making estrogen anymore – the estrogen is coming from
the adrenal
o Androgen from the adrenal glands is produced after menopause and converted in fat into estrogen by
aromatase (local conversion)
- Epinephrine comes from the medulla
- there is a stem cell population in the cortex and they migrate to the medulla
o new cells generated in the zona glomerulosa and start by making mineralocorticoids à then make
glucocorticoids à then make androgens
o as the cells change their microenvironment they change the complement of steroidogenic enzymes that
they make
- Zona glomerulosa à produces aldosterone à regulation of fluid and therefore blood pressure
- The mineralocorticoid production is not dependent on ACTH and is mainly driven by angiotensin II
- ACTH acts through the MC2R à acts through the zonae fasiculata and reticularis
o CYP11B1 is essential for cortisol production (more expression in the zona fasiculata and reticularis)
o CYP17 à critical for androgen biosynthesis
Document Summary
Outline: overview of hpa axis (feedback regulation, adrenal insufficiency, congenital adrenal hyperplasia (cah, addison"s disease autoimmune, cushing"s syndrome/disease (cushing disease is a type of cushing"s syndrome, challenges of corticosteroid therapy. Crh binds to receptors (crh receptor) on the anterior pituitary gland (corticotrope cells) The corticotrope will synthesis and secrete acth which goes through the systemic circulation and will find receptor mc2r on the adrenal cortical cells and stimulate the production of corticosteroids (particularly cortisol in humans an corticosterone in rodents) In rodent corticosterone rodents lack a particular enzyme that does not enable them to make cortisol. Cortisol feedsback to the brain (negative feedback) to inhibit crh synthesis and secretion and to the pituitary to impair acth production and the responsiveness of the cells to crh. Pvn synthesized crh released through the median eminence and goes through the pituitary portal system and binds to its receptor on corticotrope cells.
