LECTURE 1.
1: INTRODUCTION TO
PHYSIOLOGY OF ADRENAL GLANDS
ADRENAL CORTEX
Adrenal cortex produces 3 classes of
CORTTICOSTEROID HORMONES:
a. Glucocorticoids- cortisol
b. Mineralocorticoids- aldosterone
c. Adrenal androgen precursors-
dehydroepiandrosterone (DHEA)
Glucocorticoids and
mineralocorticoids act thru specific
nuclear receptors:
a. Regulating aspects of the
physiologic stress response
b. Blood pressure and electrolyte
homeostasis
Adrenal androgen precursors:
a. Converted in the gonads and
peripheral target cells to sex
steroids
b. Act via nuclear androgen and
estrogen receptors
Disorders of the adrenal cortex are
characterized by DEFICIENCY or
EXCESS:
a. HORMONE DEFICIENCY caused
by inherited glandular or
enzymatic Disorder
b. HORMONE EXCESS- result of
neoplasia, adrenal nodules
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*ADRENAL NODULES- increasingly
identified incidentally during
abdominal imaging performed for
other reasons.
ADRENAL ANATOMY AND DEVELOPMENT
Normal weight- 6-11 gms. Each
Located above the kidneys
Arterial blood flows initially to the:
Subscapular region> outer cortical
zona glomerulosa> Intermediate zona
fasciculate> inner zona reticularis>
adrenal Medulla
RIGHT SUPRARENAL VEIN drains
directly into the vena cava
LEFT SUPRARENAL VEIN drains into
the left renal vein.
EMBRYONIC DEVELOPMENT
Adrenals originate from the
urogenital ridge
Separate from gonads and kidneys at
about 6th week of gestation
Together with the time of sexual
differentiation (7th-9th week)
a. Adrenal cortex produce cortisol
and adrenal sex steroid precursor
DHEA
Orphan Nuclear receptors SF1
(steroidogenic factor 1)
DAX1 (Dosage sensitive reversal gene
1)
REGULATORY CONTROL OF
STEROIDOGENESIS
1. HYPOTHALAMIC-PITUITARY-
ADRENAL (HPA) axis
- Controls the production of
glucocorticoids and adrenal
androgens
2. RENIN- ANGIOTENSIN-
ALDOSTERONE (RAA) system
- Regulates mineralocorticoids
GLUCOCORTICOID SYNTHESIS
a. Under inhibitory feedback control
by hypothalamus and pituitary
b. Hypothalamic release of
corticotropin- releasing hormone
(CRH) occurs in response to
endogenous or exogenous stress
c. CRH stimulates the cleavage of the
241- Amino acid polypeptide
proopiomelanocortin (POMC) by
pituitary-specific hormone
prohormone convertase 1 to 39-
Amino acid peptide ACTH
d. ACTH is released by the
corticotrope cells of the anterior
pituitary and acts as the pivotal
regulator of adrenal cortisol
synthesis
e. PULSATILE FASHION following
circadian rhythm is the release of
CRH and ACTH in the
hypothalamus specifically in the
SUPRACHIASMATIC NUCLEUS
f. Reflecting the pattern of ACTH
secretion, adrenal cortisol
secretion exhibits circadian
rhythm (peak levels MORNING,
low levels- EVENING)
g. Diagnostic tests assessing HPA
axis- negative feedback
GLUCOCORTICOID EXCESS is
diagnosed by employing a
DEXAMETHASONE SUPPRESSION
TEST:
a. DEXAMETHASONE
- Potent synthetic
glucocorticosteroid
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- Suppresses CRH/ ACTH by
binding in downregulation of
endogenous cortisol synthesis
b. If cortisol production is autonomous
(Adrenal nodule)
- ACTH is already suppressed
- Dexamethasone has little
additional effect
c. If cortisol production is driven by an
ACTH-producing pituitary adenoma:
- Dexamethasone suppression is
ineffective at low-doses but
usually induces suppression at
high-doses
d. If cortisol production is driven by
ectopic source of ACTH
- Tumors are resistant to the test
- Dexamethasone suppression test
is useful to establish the diagnosis
of CUSHINGs SYNDROME and
establish the diagnosis
differentially with cortisol excess.
To assess GLUCOCORTICOID
DEFICIENCY, ACTH STIMULATION of
cortisol production is used:
a. ACTH peptide contains 39- Amino
Acid, first 24 are sufficient to elicit
a physiologic response
b. The standard ACTH stimulation
test involves administration of:
1. Cosyntropin (ACTH 1-24),
0.25mg IM or IV
2. Collection of blood samples @
0, 30, and 60 minutes for
cortisol.
c. Normal response is defined as a
cortisol level of >20g/dl
(> 550 nmol/L) 30-60
minutes after cosyntropin
administered.
 d. Low-level dose (1 g cosyntropin
IV) version of this test has been
advocated.
INSULIN TOLERANCE TEST (ITT)
a. Can be used to assess adrenal
function
b. Involves injection of insulin to
induce hypoglycemia which
triggers hypothalamic CRH
release which leads to activation
of the entre HPA axis
1. Regular insulin 0.1 u/kg IV
(dose should be lowered if
Hypopituitarism is suspected)
2. Collection of blood samples @
0, 30, 60 and 120 minutes of
glucose, cortisol and growth
hormone (if also assessing the
GH axis)
3. Oral or IV glucose is
administered after the patient
has achieved symptomatic
hypoglycemia (<40 mg/dl)
c. Normal response is defined as:
Cortisol > 20g / dl
GH > 5.1 g/ L
d. ITT requires careful clinical
monitoring and sequential
measurements of glucose
e. CONTRAINDICATED: coronary
disease, cerebrovascular disease,
seizure disorders (Which has
made the short cosyntropin test
the commonly accepted 1st line
test)
Mineralocorticoid production is
controlled by RAA regulatory cycle.
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a. Initiated by release of renin from
the juxtaglomerular cells in the
kidney
b. Resulting in cleavage of
angiotensinogen to angiotensin I
in the liver
c. Angiotensin- converting enzyme
(ACE) cleaves Angiotensin I to
Angiotensin II
d. Then binds and activates the
angiotensin II receptor type 1
(AT1 Receptor [AT1R])
Resulting in increased adrenal
aldosterone production and
vasoconstriction
Aldosterone enhances sodium
retention and potassium excretion
a. Increases the arterial perfusion
pressure that regulates renin
release
b. Because mineralocorticoid
synthesis is primarily under the
control of RAA system
c. Hypothalamic- pituitary damage
does not significantly impact the
capacity of the adrenal to
synthesize aldosterone
Similar to the HPA axis:
 a. The assessment of the RAA
system can be used for diagnostic
purposes
b. If mineralocorticoid is present,
there is a counter-regulatory
downregulation of plasma renin
c. If mineralocorticoid deficiency is
present, plasma renin is increased
Physiologically, oral or IV sodium
loading results in suppression of
aldosterone
A response that is attenuated or
absent in patients with autonomous
mineralocorticoid excess.
STEROID HORMONE SYNTHESIS,
METABOLISM and ACTION
ACTH stimulation is required for the
initiation of steroidogenesis.
ACTH receptor MC2R
(melanocortin 2 receptor)
a. Interacts with the MC2R-accessory
protein MRAP and transported to the
adrenocortical cell membrane, that
binds to ACTH
ACTH stimulation activates cyclic
AMP (cAMP)
a. Upregulates the protein kinase A
(PKA) signaling pathway
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b. Inactive PKA is a tetramer of two
regulatory and 2 catalytic
subunits bound to cAMP and 2
free and active catalytic subunits.
c. PKA activation impacts
steroidogenesis in 3 ways:
1. Increases the import of
cholesterol esters
2. Increases the activity of
hormone-sensitive lipase that
cleaves cholesterol esters to
cholesterol for import into the
mitochondrion
3. Increases the availability and
phosphorylation of CREB
(cAMP response element
binding)
CREB (cAMP response
binding)- transcription factor
that enhances transcription of
CYP11A1 and other enzymes
required for glucocorticoid
synthesis.
Adrenal steroidogenesis occurs in a
zone specific fashion:
a. With mineralocorticoid synthesis
occurring in the zona glomerulosa
b. Glucocorticoid synthesis in the
zona fasciculate
 c. Adrenal androgen synthesis in the
inner zona reticularis
All steroidogenic pathways require
cholesterol import into the
mitochondrion
a. A process initiated by the action
of the steroidogenic acute
regulatory (stAR) protein
b. stAR protein- shuttles cholesterol
from the outer to the inner
mitochondrial membrane
Majority of the steroidogenic enzymes
are cytochrome P450 enzymes
a. Located in the mitochondrion
1. side chain enzyme- CYP11A1
2. 11-hydroxylase -CYP11B1
3. Aldosterone synthase-CYP19B
b. Located in the Endoplasmic
Reticulum membrane
1. 17- Hydroxylase- CYP17A1
2. 21-hydroxylase- CYP21A2
3. Aromatase-CYP19A1
These enzymes require electron
donation via specific redox cofactor
enzymes
1. P450 oxidoreductase (POR)
2. Adrenodoxin/adrenodoxin
reductase( ADX/ADR)
The cholesterol side-chain cleavage
enzyme CYP11A1 generate
pregnenolone
Glucocorticoid synthesis requires
conversion of pregnenolone to
progesterone by 3-HSD2
Followed by conversion to 17-
hydroxyprogesterone by CYP17A1
Further hydroxylation at C-21 by
CYP1A2
Eventually 11-hydroxylation by
CYP11B1 to generate active cortisol
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Mineralocorticoid synthesis also
requires PROGESTERONE
a. First to convert to
deoxycorticosterone by CYP21A2
b. Then converted to corticosterone
and 18-hydroxycorticosterone to
aldosterone in three steps
catalyzed by CYP11B2
For adrenal androgen
synthesis
a. Pregnenolone undergoes
conversion by CYP17A1
that catalyzes two
enzymatic reactions
b. 17-hydroxylase
activityCYP17A1
converts pregnenolone to
17-hydroxypregnenolone
c. Followed by generation of
the generation of the
universal sex steroid
precursor DHEA via CYP
17A1,17,20 lyase activity
The majority of DHEA is
secreted by the adrenal in the
form of its sulfate ester
 (DHEAS), generated by DHEA
sulfotransferase (SULT2A1).
Following its release from the
adrenal
a. Cortisol circulates in the
bloodstream mainly
bound to cortisol-binding
globulin (CBG)
b. Lesser extent to albumin,
with only a minor fraction
circulating as free,
unbound hormone
Free cortisol is thought to enter the
cells directly, not requiring active
transport
Cortisol is generated from inactive
cortisone with the cell by enzyme 11
hydroxysteroid dehydrogenase type 1
(11-HSD1)
11-HSD1
a. Functions as a tissue-specific
prereceptor regulator of
glucocorticoid action.
For the conversion of inactive
cortisone to active cortisol
a. 11-HSD1 requires nicotinamide
adenine dinucleotide phosphate
(NADPH reduced form)
In the cytosol of target cells
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a. Cortisol binds and activates the
glucocorticoid receptor (GR)
b. Resulting in dissociation of heat
shock proteins from the receptor
and subsequent dimerization
Cortisol- bound GR dimers translocate
to the nucleus and activate
glucocorticoid response elements
(GRE) in the DNA-sequence
a. Enhancing transcription factors
such as AP-1 or nF-
b. Resulting in transrepression of
proinflammatory genes
Important to note that the
corticosterone also exerts
glucocorticoid activity
a. Albeit much weaker than cortisol
itself
Cortisol is inactivated by cortisone by
the microsomal enzyme 11
hydroxysteroid dehydrogenase type 2
(11-HSD2)
Cortisol and aldosterone bind the
mineralocorticoid receptor (MR) with
equal affinity
Deoxycortisone (DOC) also exerts
mineralocorticoid activity
a. DOC accumulation due to 11
Hydroxycortisone deficiency
 b. Or due to tumor-related excess
production can result in
mineralocorticoid excess
Aldosterone synthesis in the adrenal
zona glomerulosa cells is driven by
the enzyme aldosterone synthase
The binding of Angiotensin II to the
Angiotensin I Receptor causes
glomerulosa cell membrane
depolarization by increasing
intracellular sodium thru inhibition of
Sodium potassium ATPase enzymes
as well as potassium channels.
a. This drives an increase in
intracellular Calcium channel or
inhibition of Calcium ATPase
enzymes
b. The calcium signaling pathway is
triggered
c. Resulting in upregulation of
CYP11B2 transcription
Analogous to cortisol action via the
GR, aldosterone (or cortisol) binding
to MR in kidney tubule cell dissociates
the HSP-
receptor
complex
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a. Allowing homodimerization of the
MR
b. Translocation of the hormone-
bound MR dimer to the nucleus
c. Activated MR enhances
transcription of the epithelial
sodium channel (ENaC) and
serum glucocorticoid-inducible
kinase 1 (SGK-1)
In the cytosolinteraction of ENaC
with Nedd4 prevents cell surface
expression of ENaC
a. SGK-1 phosphorylates serine
residues within the Nedd-4
protein
b. Reduces the interaction between
Nedd4 and ENaC
c. Enhances trafficking of ENaC to
the cell surface that mediates
sodium retention.