There are two adrenal glands, one located above each kidney.
Each gland consists of two morphologically and functionally
distinct endocrine tissues – the outer cortex and the inner
medulla
The Adrenal Gland
The cortex, which is derived from mesodermal tissue, is
composed of three zones
1. The outermost zone, the Zona glomerulosa,
synthesizes the mineralocorticoid aldosterone
2. The middle zone, the Zona fasciculata, and the
innermost zone,
3. The Zona reticularis, synthesize the glucocorticoid
cortisol and the androgens dehydroepiandrosterone
(DHEA) and androstenedione
The medulla, which is derived from the neural crest, can be
considered a modified sympathetic ganglion that directly
releases catecholamines into the circulation
The reticularis is the one big in androgen production. Zones 1 &
2 & 3  all the hormones produced are steroids. The basic
backbone of cholesterol synthesis comes from diet or the liver.
They are cholesterol based. The conversion of the cholesterol to
its end product. Making the enzyme relies on Transcription and
translation. The androgens that are produced are DHEA and
androstenedione can be converted to testosterone, but they are
not the main sources of testosterone in the body.
Diet, liver
Adrenal Steroidogenesis
C3, 11, 17, 18, 21 are conversion sites
C11
C3
C21
Progesterones: 21 carbons
Androgens: 19 carbons
(Estrogens: 18 carbons)
C17
C18
The steroidogeneis pathway is messy!
1. The conversion of cholesterol in the
diet in the liver is canned out by
enzymes which is a rate limiitng step.
The pregnenolone – convereted to
andorogens. Most of the genetic
problems associated with 21 –
hydroxylase and the 11 B hydrolase.
The zones are unique because of the
complement of enzymes. The blue
arrows are to remind you that things
are occuring at different levels in the
cells. The CYP21 hydroxylase you will
see referred to as 21-alpha.
CYP11A1 - Side Chain Cleavage
CYP17 - 17-hydroxylase
*CYP21 - 21-hydroxylase (defect accounts
for 95% of genetic abnormalities)
*CYP11B1 - 11-hydroxylase(next most
common defect)
CYP11B2 - Aldosterone Synthase
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Becky Stepan
Rose-Hellekant – Adrenal Gland
Pregnenolone Synthesis
Rate
limiting
step;
ACTH
regulated!
(21 - carbons)
Aldosterone Synthesis in Z. glomerulosa only!
C3
C21
C11
C18
Cortisol is produced at the
highest level in the human body.
If the 11 B defect is in place, you
will not have cortisol,
corticosteroids, and androgens.
Glucocorticoids have
Zona glomerulosa cells:
-lack 17-hydroxylase but
-express Aldosterone Synthase
0.125 mg aldosterone secreted/d
Plasma concentration = 0.01 g/dL
Cortisol Synthesis in Z. fasciulata and z. reticularis
Cortisol is the negative feedback
to the pituitary and the anterior
pituitary –
11-Deoxgycortisol has a higher
mineralcorticoid properties and
actions. – too much of this will
increase BP because of volume
expansion.
10 mg/day secreted
Plasma concentration:
8 AM - 16 g/dL
4 PM - 4 g/dL
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Becky Stepan
Rose-Hellekant – Adrenal Gland
21-Hydroxylase Deficiency
↓Cortisol and Aldosterone
↑ACTH
↑Androgens
Symptoms: Virilization, Hypotension (due to reduced blood volume)
* With excess production – you can end up with a lot of testosterone. You are reducing aldosterone, and you are
reducing the mineralcorticoid effects.
11-hydoxylase Deficiency
↓Cortisol and Aldosterone
↑ACTH
↑Androgens
Virilization, Hypertension (due to excess 11-deoxycortisol which has mineralo-corticoid activity)
Mineralocorticoid System: Aldosterone is responsible for sodium absorption across epithelia
A. Aldosterone Synthesis
1. Synthesized by glomerulosa cells of adrenal cortex
2. Glomerulosa cells lack 17a -hydroxylase (CYP17) and uniquely express aldosterone synthase (CYP11B2)
B. Control of Aldosterone Synthesis
1. Regulated by the renin-angiotensin system and increased plasma potassium
2. Under tonic control of ACTH
3. Minimal binding to plasma proteins so metabolized and excreted quickly
C. Mineralocorticoid Receptor
1. Aldosterone binds to an intracellular receptor, mineralocorticoid receptor (MR), expressed, primarily, in
the kidney (distal tubule and collecting duct), distal colon, salivary glands, sweat glands, and hippocampus
2. MR is a member of the steroid-hormone receptor superfamily and is a ligand-activated transcription
factor that regulates gene expression.
3. MR shares significant homology with GR. Cortisol binds with equal affinity to MR as aldosterone.
D. Effects of Aldosterone
1. Aldosterone stimulates sodium reabsorption and potassium and H+ excretion in target organs such as the kidney,
colon, and salivary glands.
Mineralocorticoids
Mineralcorticoids
Aldosterone Effects:
• Causes retention of Na+ and excretion of K+
and results in ECF and blood volume
expansion.
 Increasing reabsorption of Na+ from
urine, sweat, saliva and colon.
 Increases in sodium in kidneys
results in increase exchange for K+
and H+ in renal tubules producing
K+ diuresis and increased urine
acidity and alkalosis.
 Renin suppression is a result
 A decrease in plasma volume
promotes angiotensin II conversioncauses vasoconstriction in adrenals causes aldosterone production.
• Regulated by Renin-Angiotensin, K+, ACTH
 Induced by sodium depletion or
blood volume decrease
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Becky Stepan
Rose-Hellekant – Adrenal Gland
Hypothalamic-Pituitary-Adrenal Axis
ACTh is stimulatory – the primary
hormone responsible for the negative
feedback will be cortisol.
Physical and psychological STRESS
+
Low dose dexamethasone test
HYPOTHALAMUS
+
CRF
+
ANTERIOR PITUITARY
-
ACTH
ADRENAL CORTEX
CYTOKINES
IL-1
IL-6
TNF-
Corticotropin Releasing Hormone
• 41 AA polypeptide
• Synthesized in hypothalamus
• Proinflammatory cytokines
augment release of CRF
Inflammation
-
CORTISOL
CRF/H: corticotropin releasing factor/hormone
ACTH: adrenocorticotropic hormone
Adreno Cortico Tropic Hormone
• Synthesized in the A. pituitary as part of a larger 241 aa precursor, propriomelanocortin.
• ACTH binds to Melanocortin-2-receptor (a Gαs coupled protein so elevation of cAMP initiates signal
transduction cascade)
• 39 AA polypeptide
• Rapidly stimulates side-chain cleavage enzyme (CYP11A). THIS IS A RATE-LIMITING STEP. Therefore
ACTH promotes conversion of cholesterol to pregnenolone.
• Has little effect on aldosterone by glomerulosa cells except at high levels. The glucocorticoids, 11
deoxycortocosterone and cortisol have weak mineralocorticoid activity (compared to aldosterone).
• Ectopic production possible in cancer and is not responsive to neg feedback by cortisol.
•
These hormones can easily traverse across cell membranes. Higher in the non-golmerulus. Those hormones
can easily get to the glomerulosa.
Glucocorticoids
• Cortisol is the principal glucocorticoid secreted
− 10% circulates free
− 90% circulates bound
• 60% to CBG (corticotropin binding globulin=transcortin)
• 30% to albumin
− T 1/2= 70-90 min
− Cortisol, cirrhosis, nephrosis, hyperthyroidism ↓CBG
• Estrogens, pregnancy and hypothyroidism ↑CBG
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Becky Stepan
Rose-Hellekant – Adrenal Gland
Glucocorticoid Metabolism
• Cortisol is quickly converted to cortisone. Cortisone can be easily converted to cortisol.
• But most of metabolism occurs in the liver where cortisone is rapidly conjugated to form tetrahydrocortisone
glucuronide or sulfated. These derivatives are soluble in serum and are excreted by kidneys.
• These 17-hydroxycorticosteroid metabolites are used to assess adrenal steroid production in 24h urine collections
• Other conversion enzymes found in kidney, colon and salivary glands.
Glucocorticoid Receptor
• GR - Intracellular Steroid Hormone Receptor
• Transcription factor regulating gene expression
• Found in virtually all cells where it regulates a variety
of processes including development, metabolism and
immune response.
• Two isoforms - GR and GR
− GR mediates physiological effects
− GR dominant negative regulator
• They are promiscusis and may dimerize with an
alpha-lapha or a beta-beta. The binding and storage
of these hormones in the cytoplasms are done by
heat-shock proteins; these are drug target productions
in development. HSP = important for the oncology field.
Glucocorticoid promotes mobilization of serum
energy substrates
Glucocorticoids: Actions at Excess Levels
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Becky Stepan
Rose-Hellekant – Adrenal Gland
Hyperadrenocorticism/hyperadrenalism/Cushing Syndrome
If due to excess ACTH secretion, blood profiles are:
↑ACTH
↑Cortisol
If due to excess Cortisol production blood profiles are:
↑ Cortisol
↓ ACTH
Most common cause is iatrogenic w/long term glucocorticoid use.
Hypoadrenalism
1o -Addison’s Disease (usually due to immune
mediated destruction of adrenal cortex)
↓Cortisol
↓Aldosterone
↑ACTH
o
2 - Iatragenic by sudden withdrawal of
exogenous glucocorticoid
↓Cortisol
↓ACTH
Hyperpigmentation may be seen in primary
adrenal insufficiency due to ACTH
overproduction by the pituitary. The ACTH
molecule contains the sequence for alphamelanocyte-stimulating hormone (MSH),
which stimulates melanocytes. (See CRH slide).
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Becky Stepan
Rose-Hellekant – Adrenal Gland
Here is an example of endocrine imbalance which occurs with the
administration of exogenous hormone, in this case cortisol. High levels
of circulating cortisol reduces the levels of hypothalamic releasing
hormone (corticotrophic releasing hormone) and anterior pituitary
hormone (adrenocorticotrophic hormone) due to long loop negative
feedback. Cortisol is typically produced by the adrenal cortex. Target
cells/tissues respond to cortisol (whether it is endogenous or
exogenously provided). Usually excess cortisol is provided
exogenously due to need to reduce immune reaction Once the reaction
subsides, exogenous cortisol is withdrawn. Slow withdrawal from
exogenous cortisol is necessary to allow a smooth transition back to
endogenous regulation of cortisol. Too rapid of exogenous cortisol
withdrawal would lead to cortisol crash because the hypothalamopituitary-adrenal axis is temporarily shut down. The adrenal glands
are incapable of producing cortisol without a transition period to
normal production levels. FYI: Look to specific lecture on adrenal gland
physiology.
* Too little glucocorticoid causes symptoms of adrenal insufficiency,
such as anorexia, nausea, vomiting, abdominal pain, asthenia, poor
weight gain, and weight loss.
* Too much glucocorticoid causes excessive weight gain, cushingoid
features, hypertension, hyperglycemia, cataracts, and growth failure.
* In children, growth failure is a sensitive indicator of exposure to
excessive glucocorticoids.
If the endocrine imbalance,
in this case hypersecretion,
is due to problems at the
level of the peripheral
endocrine gland, then it is
called “primary
hypersecretion” If the
problem is at the level of
the hypothalamus it is
known as secondary. Some
references suggest that
problems at the level of the
pituitary is referred to as
“tertiary” but others lump
this into “secondary
hypersecretion” along with
the hypothalamus. One
can distinguish the
problem endocrine gland
by measuring hormone
levels in the peripheral
blood.
Expected circulating levels of
hormone:
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Becky Stepan
Rose-Hellekant – Adrenal Gland
Secondary Hyposecretion
Primary Hyposecretion
What relative levels of CRH,
ACTH and cortisol would you
expect in each of these
scenarios?
Circadian and Pulsatile Rhythm
Cortisol concentration follows a circadian rhythm, peaking in the early morning and reaching a nadir in the
evening. Superimposed on this rhythm is the pulsatile secretion of ACTH. The circadian rhythm reflects, in part, the
influence of the hypothalamic pacemaker, suprachiasmatic nucleus, on CRF secretion.
When blood is drawn is important to interpretation of results?
Key Concepts
• Glucocorticoid production and release are under ACTH regulation. Glucocorticoid supports homeostasis of
blood glucose regulation; growth; thyroid system, reproduction
• Mineralocortiocid (aldosterone) is under antiotensen II and K+ regulation, as well as tonic ACTH. High
levels in ACTH will cause high levels of aldosterone production.
• Aldosterone regulates body sodium balance.
• Two genetic anomalies of adrenal cortex:
 11b hydroxylase defect: low cortisol and corticosterone levels and mineralocorticoids.
Hypertension due to 11 deoxycortisol which has mineralocortioid effects even though aldosterone
is low.
 21 - hydroxylase defect: low glucocortiocids and low mineralocorticoids: Hypotension due to low
mineralocorticoid production as well as low 11-deoxycortisolproduction.
Hyperpigmentation due to excess MSH co-production with ACTH
ACTH is produced as a preprohormone, pro-opiomelanocortin.
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Becky Stepan
Rose-Hellekant – Adrenal Gland