HORMONES OF THE
ADRENAL CORTEX
INTRODUCTION
The adrenal cortex synthesizes
glucocorticoids, mineralocorticoids, and
androgens
It initiates its action by combining with
specific intracellular receptors
The hormone-receptor complex then binds
to specific DNA regions to regulate gene
expression
IMPORTANCE
Glucocorticoids are essential for
adapatation to stress
Mineralocorticoids regulate sodium and
potassium balance
LAYERS OF THE ADRENAL CORTEX
Zona glomerulosa
produces
mineralocorticoids
Zona Fasciculata and
zona reticularis
produce
glucocorticoids and
androgens
All glucocorticoids have mineralocorticoid
activity and vice-versa
GLUCOCORTICOIDS
21-carbon steroids that regulate
gluconeogenesis
Cortisol produced by the zona fasciculata
predominates in humans
Corticosterone produced by the zona
fasciculata and glomerulosa is less
dominant in humans
MINERALOCORTICOIDS
21-carbon steroids that promote sodium
retention and excretion of potassium and
hydrogen ions
The most potent, aldosterone, is produced
by the zona glomerulosa
The zona fasciculata and reticularis
produce dehydroepinandrosterone and
the weak precursor androstenedione,
which are converted to more potent
androgens in extra-adrenal tissues
Estrogens are not made in the normal
adrenal gland in significant amounts
NOMENCLATURE
All steroids have
cyclopentanoperhydrophenanthrene ring
Steroid hormones and their precursors
and metabolites differ in number and type
of substituted groups, number and type of
double bonds, and stereochemical
configuration
Asymmetric carbons allow for
stereoisomerism
Most adrenal cholesterol is esterified and
stored in the cytoplasm
Upon stimulation by ACTH or cAMP, an
esterase is activated and free cholesterol
is transported to mitochondria where
CytP450 side chain cleavage enzyme
converts cholesterol to pregnenolone
An ACTH-dependent steroidogenic
acute regulatory (StAR) protein is
essential for the transport of cholesterol to
P450scc in the inner mitochondrial
membrane
Aminoglutethimide inhibits P450scc
3β -OHSD and
∆ 5,4-
isomerase are
found in the
SER
They convert
pregnenolone to
progesterone
17-Hydroxylase and 21-
hydroxylase are SER
enzymes
11β hydroxylase is in
the mitochondria
Progesterone is
hydroxylated at C21 to form
11-DOC which is a sodium-
retaining mineralocorticoid
Hydroxylation at C11
forms corticosterone,
which has glucocorticoid
activity but is only 5% as
potent as aldosterone in
man
C21 hydroxylation is
necessary for both
glucocorticoid and
mineralocorticoid activity
Found only in glomerulosa cells, so
aldosterone can only be synthesized
in the zona glomerulosa
Glucocorticoid synthesis requires 3 hydroxylases
acting on C17, C21, and C11 (C11 is the slowest
reaction)
DHEA
DHEA is the major
androgen produced by the
adrenal gland
Adrenal androgen
production increases if
glucocorticoid biosynthesis
is impeded
DHEA
Most DHEA is rapidly
modified by adding sulfate
in the adrenal gland and
liver
DHEA sulfate is inactive;
sulfate removal reactivates
DHEA
DHEA
Reduction of
androstenedione at C17
forms testosterone, the
most potent adrenal
androgen
SECRETION OF STEROID
HORMONES
There is little storage of steroids in the
adrenal gland; most are released in
plasma after synthesis
Cortisol levels are highest in AM after
awakening and lowest in late afternoon
(diurnal rhythm)
HORMONE TRANSPORT IN
PLASMA
The main carrier is transcortin or
corticosteroid-binding globulin (CBG)
produced by the liver, whose synthesis is
increased by estrogen
Small amounts of cortisol are bound to
albumin
CBG-bound cortisol has a half-life of 1.5-2
hours while corticosterone, which binds
less tightly, has a half-life of less than 1
hour
Deoxycorticosterone and progesterone
compete with cortisol for binding with
CBG
Aldosterone does not have a specific
transport protein, but it forms a weak
association with albumin
METABOLISM AND EXCRETION
Glucocorticoids are reduced and
conjugated at C3 by glucuronide, or to a
lesser extent with sulfate, making it water-
soluble
70% of conjugated steroids are urinated,
20% are defecated, and 10% exit the skin
Aldosterone is cleared by the liver and
excreted through urine again via
glucuronidation
Androgens are excreted as 17-keto
compounds
Testosterone is converted by the liver to
less active metabolites
THE BIOLOGIC ACTIVITY OF A
STEROID DEPENDS ON:
1. Its ability to bind to a receptor
2. Concentration of free hormone in the
plasma
Cortisol, corticosterone, and aldosterone
all bind with high affinity to the
glucocorticoid receptor
However, cortisol is dominant because of
its high plasma concentration
Cortisol synthesis is regulated by ACTH,
which is regulated via negative feedback
by CRH
THE RENIN-ANGIOTENSIN
SYSTEM (RAS)
Also called renin-angiotensin-
aldosterone system (RAAS)
Regulates electrolytes and blood pressure
Primary hormone is angiotensin II
(produced by the juxtaglomerular cells
of the renal afferent arteriole)
- low blood
pressure
- blood loss
Formation of angiotensin peptides. The solid arrows show the classic pathways, and the
dashed arrows indicate minor alternative pathways
Juxtaglomerular cells are sensitive to
sodium and chloride levels in the blood
Renin release is stimulated by low water,
sodium, and chloride levels
FACTORS THAT INFLUENCE
RENIN RELEASE
STIMULATORS INHIBITORS
Decreased BP High BP
Supine Erect Erect Supine
Low salt levels High salt levels
β -adrenergic antagonists
β -adrenergics
PG inhibitors
Prostaglandins
K+, ADH, angiotensin II
EFFECTS OF GLUCOCORTICOIDS
Increase glucose production by increasing
delivery of amino acids from peripheral
tissues and increasing gluconeogenesis
Increase hepatic glycogen deposition by
stimulating glycogen synthase
Increase lipolysis in extremities
Increase lipogenesis in face and trunk
EFFECTS OF GLUCOCORTICOIDS
Increase protein and RNA metabolism
Suppress immune response (lysis of
lymphocytes)
Suppress inflammation by :
- Decreased leukocyte activity
- Decreased fibroblast
- Increased lipocortins which inhibit phospholipase
A2
OTHER EFFECTS OF
GLUCOCORTICOIDS
Maintain normal BP and cardiac output
Maintain water and electrolyte equilibrium
Mediate response to stress
EFFECTS OF
MINERALOCORTICOIDS
Stimulate sodium transport by the distal convoluted
and collecting tubules
Promote potassium, hydrogen, and ammonium ion
secretion by the kidney
In terms of mineralocorticoid effect, cortisol is less
potent than aldosterone, but because of its high
serum concentration, it also has significant
mineralocorticoid activity
ADDISON’S DISEASE
Primary adrenal insufficiency
Hypoglycemia, extreme sensitivity to
insulin, stress intolerance, anorexia, wt
loss, nausea, weakness
Low BP, low GFR, Low ability to excrete
excess water
Salt craving
ADDISON’S DISEASE
Low sodium, high potassium in serum
Increased skin pigmentation because of
increased POMC activation
CUSHING’S SYNDROME
Glucocorticoid excess
May also be due to increased pharmacologic
use or pituitary adenoma
Diurnal pattern of ACTH secretion is lost
Thinning of skin, muscle wasting, osteoporosis
Truncal obesity, buffalo hump
Impaired resistance to infection
CONN’S SYNDROME
Primary aldosteronism due to adenomas in
the zona glomerulosa
Hypertension, hypokalemia,
hypernatremia, alkalosis
Renal artery stenosis can lead to JG cell
hyperactivity and elevate renin and
angiotensin II, resulting in secondary
aldosteronism
CONGENITAL ADRENAL
HYPERPLASIA
Included in newborn screening
Decreased cortisol, increased ACTH
Increased adrenal androgens causing
virilization and ambiguous genitalia
(Adrenogenital syndrome)
