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LECTURE 1.

1: INTRODUCTION TO *ADRENAL NODULES- increasingly


PHYSIOLOGY OF ADRENAL GLANDS identified incidentally during
abdominal imaging performed for
ADRENAL CORTEX other reasons.
Adrenal cortex produces 3 classes of ADRENAL ANATOMY AND DEVELOPMENT
CORTTICOSTEROID HORMONES:
a. Glucocorticoids- cortisol Normal weight- 6-11 gms. Each
b. Mineralocorticoids- aldosterone Located above the kidneys
c. Adrenal androgen precursors- Arterial blood flows initially to the:
dehydroepiandrosterone (DHEA) 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
Glucocorticoids and
Adrenals originate from the
mineralocorticoids act thru specific
urogenital ridge
nuclear receptors:
Separate from gonads and kidneys at
a. Regulating aspects of the
about 6th week of gestation
physiologic stress response
Together with the time of sexual
b. Blood pressure and electrolyte
differentiation (7th-9th week)
homeostasis
a. Adrenal cortex produce cortisol
Adrenal androgen precursors:
and adrenal sex steroid precursor
a. Converted in the gonads and
DHEA
peripheral target cells to sex
Orphan Nuclear receptors SF1
steroids
(steroidogenic factor 1)
b. Act via nuclear androgen and
DAX1 (Dosage sensitive reversal gene
estrogen receptors
1)
Disorders of the adrenal cortex are
characterized by DEFICIENCY or REGULATORY CONTROL OF
EXCESS: STEROIDOGENESIS
a. HORMONE DEFICIENCY caused
by inherited glandular or 1. HYPOTHALAMIC-PITUITARY-
enzymatic Disorder ADRENAL (HPA) axis
b. HORMONE EXCESS- result of - Controls the production of
neoplasia, adrenal nodules glucocorticoids and adrenal
androgens

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2. RENIN- ANGIOTENSIN- - Suppresses CRH/ ACTH by
ALDOSTERONE (RAA) system binding in downregulation of
- Regulates mineralocorticoids endogenous cortisol synthesis
GLUCOCORTICOID SYNTHESIS b. If cortisol production is autonomous
a. Under inhibitory feedback control (Adrenal nodule)
by hypothalamus and pituitary - ACTH is already suppressed
b. Hypothalamic release of - Dexamethasone has little
corticotropin- releasing hormone additional effect
(CRH) occurs in response to c. If cortisol production is driven by an
endogenous or exogenous stress ACTH-producing pituitary adenoma:
c. CRH stimulates the cleavage of the - Dexamethasone suppression is
241- Amino acid polypeptide ineffective at low-doses but
proopiomelanocortin (POMC) by usually induces suppression at
pituitary-specific hormone high-doses
prohormone convertase 1 to 39- d. If cortisol production is driven by
Amino acid peptide ACTH ectopic source of ACTH
d. ACTH is released by the - Tumors are resistant to the test
corticotrope cells of the anterior - Dexamethasone suppression test
pituitary and acts as the pivotal is useful to establish the diagnosis
regulator of adrenal cortisol of CUSHINGs SYNDROME and
synthesis establish the diagnosis
e. PULSATILE FASHION following differentially with cortisol excess.
circadian rhythm is the release of To assess GLUCOCORTICOID
CRH and ACTH in the DEFICIENCY, ACTH STIMULATION of
hypothalamus specifically in the cortisol production is used:
SUPRACHIASMATIC NUCLEUS a. ACTH peptide contains 39- Amino
f. Reflecting the pattern of ACTH Acid, first 24 are sufficient to elicit
secretion, adrenal cortisol a physiologic response
secretion exhibits circadian b. The standard ACTH stimulation
rhythm (peak levels MORNING, test involves administration of:
low levels- EVENING) 1. Cosyntropin (ACTH 1-24),
g. Diagnostic tests assessing HPA 0.25mg IM or IV
axis- negative feedback 2. Collection of blood samples @
GLUCOCORTICOID EXCESS is 0, 30, and 60 minutes for
diagnosed by employing a cortisol.
DEXAMETHASONE SUPPRESSION c. Normal response is defined as a
TEST: cortisol level of >20g/dl
a. DEXAMETHASONE (> 550 nmol/L) 30-60
- Potent synthetic minutes after cosyntropin
glucocorticosteroid administered.

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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
a. Initiated by release of renin from
1. Regular insulin 0.1 u/kg IV the juxtaglomerular cells in the
(dose should be lowered if kidney
Hypopituitarism is suspected) b. Resulting in cleavage of
2. Collection of blood samples @ angiotensinogen to angiotensin I
0, 30, 60 and 120 minutes of in the liver
glucose, cortisol and growth c. Angiotensin- converting enzyme
hormone (if also assessing the (ACE) cleaves Angiotensin I to
GH axis) Angiotensin II
3. Oral or IV glucose is d. Then binds and activates the
administered after the patient angiotensin II receptor type 1
has achieved symptomatic (AT1 Receptor [AT1R])
hypoglycemia (<40 mg/dl) Resulting in increased adrenal
c. Normal response is defined as: aldosterone production and
Cortisol > 20g / dl vasoconstriction
GH > 5.1 g/ L Aldosterone enhances sodium
d. ITT requires careful clinical retention and potassium excretion
monitoring and sequential a. Increases the arterial perfusion
measurements of glucose pressure that regulates renin
e. CONTRAINDICATED: coronary release
disease, cerebrovascular disease, b. Because mineralocorticoid
seizure disorders (Which has synthesis is primarily under the
made the short cosyntropin test control of RAA system
the commonly accepted 1st line c. Hypothalamic- pituitary damage
test) does not significantly impact the
Mineralocorticoid production is capacity of the adrenal to
controlled by RAA regulatory cycle. synthesize aldosterone
Similar to the HPA axis:

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a. The assessment of the RAA b. Inactive PKA is a tetramer of two
system can be used for diagnostic regulatory and 2 catalytic
purposes subunits bound to cAMP and 2
b. If mineralocorticoid is present, free and active catalytic subunits.
there is a counter-regulatory c. PKA activation impacts
downregulation of plasma renin steroidogenesis in 3 ways:
c. If mineralocorticoid deficiency is 1. Increases the import of
present, plasma renin is increased 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
Physiologically, oral or IV sodium that enhances transcription of
loading results in suppression of CYP11A1 and other enzymes
aldosterone required for glucocorticoid
A response that is attenuated or synthesis.
absent in patients with autonomous Adrenal steroidogenesis occurs in a
mineralocorticoid excess. zone specific fashion:
a. With mineralocorticoid synthesis
STEROID HORMONE SYNTHESIS, occurring in the zona glomerulosa
METABOLISM and ACTION b. Glucocorticoid synthesis in the
zona fasciculate
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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c. Adrenal androgen synthesis in the Mineralocorticoid synthesis also
inner zona reticularis requires PROGESTERONE
a. First to convert to
All steroidogenic pathways require deoxycorticosterone by CYP21A2
cholesterol import into the b. Then converted to corticosterone
mitochondrion and 18-hydroxycorticosterone to
a. A process initiated by the action aldosterone in three steps
of the steroidogenic acute catalyzed by CYP11B2
regulatory (stAR) protein For adrenal androgen
b. stAR protein- shuttles cholesterol synthesis
from the outer to the inner a. Pregnenolone undergoes
mitochondrial membrane conversion by CYP17A1
Majority of the steroidogenic enzymes that catalyzes two
are cytochrome P450 enzymes enzymatic reactions
a. Located in the mitochondrion b. 17-hydroxylase
1. side chain enzyme- CYP11A1 activityCYP17A1
2. 11-hydroxylase -CYP11B1 converts pregnenolone to
3. Aldosterone synthase-CYP19B 17-hydroxypregnenolone
b. Located in the Endoplasmic c. Followed by generation of
Reticulum membrane the generation of the
1. 17- Hydroxylase- CYP17A1 universal sex steroid
2. 21-hydroxylase- CYP21A2 precursor DHEA via CYP
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 17A1,17,20 lyase activity
Further hydroxylation at C-21 by The majority of DHEA is
CYP1A2 secreted by the adrenal in the
Eventually 11-hydroxylation by form of its sulfate ester
CYP11B1 to generate active cortisol

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(DHEAS), generated by DHEA a. Cortisol binds and activates the
sulfotransferase (SULT2A1). glucocorticoid receptor (GR)
Following its release from the b. Resulting in dissociation of heat
adrenal 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
a. Cortisol circulates in the Important to note that the
bloodstream mainly corticosterone also exerts
bound to cortisol-binding glucocorticoid activity
globulin (CBG) a. Albeit much weaker than cortisol
b. Lesser extent to albumin, itself
with only a minor fraction
Cortisol is inactivated by cortisone by
circulating as free,
the microsomal enzyme 11
unbound hormone
hydroxysteroid dehydrogenase type 2
Free cortisol is thought to enter the (11-HSD2)
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
Cortisol and aldosterone bind the
glucocorticoid action.
mineralocorticoid receptor (MR) with
For the conversion of inactive equal affinity
cortisone to active cortisol
Deoxycortisone (DOC) also exerts
a. 11-HSD1 requires nicotinamide
mineralocorticoid activity
adenine dinucleotide phosphate
a. DOC accumulation due to 11
(NADPH reduced form)
Hydroxycortisone deficiency
In the cytosol of target cells

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b. Or due to tumor-related excess a. Allowing homodimerization of the
production can result in MR
mineralocorticoid excess b. Translocation of the hormone-
Aldosterone synthesis in the adrenal bound MR dimer to the nucleus
zona glomerulosa cells is driven by c. Activated MR enhances
the enzyme aldosterone synthase transcription of the epithelial
The binding of Angiotensin II to the sodium channel (ENaC) and
Angiotensin I Receptor causes serum glucocorticoid-inducible
glomerulosa cell membrane kinase 1 (SGK-1)
depolarization by increasing In the cytosolinteraction of ENaC
intracellular sodium thru inhibition of with Nedd4 prevents cell surface
Sodium potassium ATPase enzymes expression of ENaC
as well as potassium channels. a. SGK-1 phosphorylates serine
a. This drives an increase in residues within the Nedd-4
intracellular Calcium channel or protein
inhibition of Calcium ATPase b. Reduces the interaction between
enzymes Nedd4 and ENaC
b. The calcium signaling pathway is c. Enhances trafficking of ENaC to
triggered the cell surface that mediates
c. Resulting in upregulation of sodium retention.
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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