Block Endocrine System, Metabolism, and Disorders

ADRENAL GLANDS
AND HORMONES
Dr. Made Ratna Saraswati, SpPD-KMED, FINASIM

Faculty of Medicine, Udayana University

Further reading

 David G Gardner, Dolores Shoback.

Greenspan’s Basic and Clinical Endrocrinology
8th ed. Lange. McGraw Hill 2007.
 Harrison’s Principles of Internal Medicine 17th

ed. McGraw Hill 2008.

(Part 15 Endocrinology and Metabolism)
Adrenal gland

The ADRENAL GLANDS

(supra-renal glands):
are triangular, flattened glands
embedded in fatty tissue
overlying the kidneys.

There are 2 adrenal glands, one

at the cranial (superior) pole of
each kidney.
Gross structure of adrenal gland
3 major structural components:

1. CONNECTIVE TISSUE CAPSULE,

which surrounds the gland

2. CORTEX of the gland,

constitutes about 90% of gland by
weight

3. MEDULLA of gland,
which lies deep to the cortex and
forms the center of the gland
Histology
Adrenal cortex divided into 3 zones:
Biochemistry
 The adrenal cortex produces three major classes of
steroid:
 Glucocorticoids (cortisol)
Modulating intermediary metabolism and immune
system
 Mineralocorticoids (aldosterone)
Blood pressure, vascular volume, electrolytes
 Adrenal androgens (dehydroepiandrosterone/DHEA
and its sulphuric ester/DHEAS)
Secondary sexual characterisitics in female
 Fig. Hormones of
adrenal gland

ADRENAL CORTEX:
• Cells of Z. glomerulosa secrete
mineralocorticoids (aldosterone)
• Cells of Z. fasciculata secrete
glucocorticoids (cortisol, corticosterone)
and weak androgens
• Cells of Z. reticularis secrete
glucocorticoids and weak androgens

ADRENAL MEDULLA:
• Chromaffin cells secrete either
epinephrine (adrenalin) or
norepinephrine (noradrenalin), in
response to neural stimuli from
preganglionic sympathetic nerve ending
Biosynthesis of steroid

 Substrate for steroidogenesis: cholesterol (derived

from the diet and from endogenous synthesis)
 Uptake of cholesterol by the adrenal cortex is
mediated by the LDL receptor.
 Long term stimulation of the adrenal cortex by
adrenocorticotropic hormone (ACTH) will increase
the number of LDL receptors.
Fig. Basic steroid structure and nomenclature

Adrenal steroid contain either 19 or 21

carbon atoms.

The C19 have methyl groups at C-18

and C-19 . C19 with a ketone group at
C17 are termed 17-ketosteroids
(predominantly have androgenic
activity).

The C21 steroid have a 2-carbon side

chan (C-20 and C-21 attached at
position 17 and methyl groups at C-18
and C-19. C21 with a hydroxyl group at
position 17 are termed 17-
hydroxycorticosteroids (have either
glucocorticoid or mineralocorticoid
properties).

Harrison’s Principles of Internal Medicine, 17th ed. p. 2248

Hypothalamic - Pituitary - Adrenal axis

 The primary controller of synthesis and release of

cortisol from the adrenal zona fasciculata is ACTH
(adrenocorticotropic hormone), including:
acute control (plasma cortisol increase within
minutes of an elevation of ACTH level), and
long term trophic effect on the adrenal cortex
(prolonged stimulation leads to adrenal hypertrophy
as in bilateral adrenal hypertrophy, and prolonged
decreased in ACTH level leads to adrenal atrophy, as
in so-called secondary adrenal insufficiency)
 Hypothalamus

CRH

Pituitary

ACTH

Adrenal Cortex
Cortisol

Normal State
 Fig.
The hypothalamic –
pituitary – adrenal axis

Β-LPT = β-lipoprotein
POMC = proopiomelanocortin
LC=locus coeruleus
NE = norepinephrine.

Harrison’s Principles of Internal Medicine, 17th ed. p. 2250

 Synthesis of ACTH

 ACTH is synthesized as part of large precursor

molecule called proopiomelanocortin (POMC).
ACTH is released from POMC by posttranslational
processing within the pituitary corticotroph cells.
 Non pituitary tumor which has undergone abnormal
differentiation, can synthesized POMC and some or
all of its translational products.
This explain ectopic ACTH syndrome
 Release of ACTH

controlled by:
 CRH (corticotropin releasing hormone)

synthesized in parvocellular nerve of paraventricular nucleus

of hypothalamus
 AVP (arginine vasopressin)
synthesized in parvocellular nerve of paraventricular nucleus
of hypothalamus, distinct from AVP released from
magnocellular nerve terminal of posterior pituitary which
control free water clearance in the kidney
 Glucocorticoid negative feedback
(physiologic basic of dexamethasone supression test)
 Release of CRH (and AVP)

from parvocellular nerve of paraventricular nucleus

of hypothalamus into the portal vein controlled by:
variety of humoral and hormonal inputs, such as:
 Respon to stress,
i.e. hypoglycemia is sensed by hypothalamic glucose
sensor
 Neural input from suprachiasmatic nuclei of the
hypothalamus (this explain the circadian rhythm)
 Glucocorticoid negative feedback
Steroid receptors

Glucocorticoid diffuse pasively through the cell

membrane and bind to intracellular receptor:
Glucocorticoid receptor

Mineralocorticoid receptor

Glucocorticoid and mineralocorticoid bind with nearly

equal affinity to MR, however only glucocorticoid
bind to GR receptor.
 Glucocorticoid physiology

 The division of adrenal steroid into glucocorticoid

and mineralocorticoid is arbitrary (most glucocorticoids
have some mineralocorticoid-like properties).
 The descriptive term for glucocorticoid is used for
adrenal steroid whose dominant action is on
intermediary metabolism: directed to enhancing the
production of the high energy fuel, glucose, and
reducing all other metabolic effect.
 Glucocortioids have antiinflamatory properties.
 Fig. The immune – adrenal axis

CRH – secreting Thermoregulatory Immune stimulus

neurons centers
+ + Macrophages
-
CRH Fever -
Inflammatory
Pituitary cytokines (IL-1α,
- IL-1β, IL-6, TNF)
ACTH

Adrenal Cortisol
-
Mediators of inflammation (eicosanoids, Harrison’s Principles of
serotonin, PAF, bradykinin) Internal Medicine, 17th ed.
p. 2250
Mineralocorticoid physiology
 Major regulators of ECFV and the major
determinants of potassium metabolism.
 These effect mediated by binding of aldosteron to
MR in epithelial cells, primarily the principal cells
in the renal cortical collecting duct.
Adrenal Androgens
 The principal adrenal androgens are
 DHEA
 androstenedione
 11-hydroxyandrostenedione.
 DHEA and androstenedione are weak androgens
and exert their effects via conversion to the potent
androgen testosterone in extraglandular tissues.
 DHEA also has poorly understood effects on the
immune and cardiovascular systems.
 Adrenal androgen formation is regulated by ACTH,
not by gonadotropins.
 Adrenal androgens are suppressed by exogenous
glucocorticoid administration
Renin – Angiotensin physiology
 Renin is a proteolytic enzyme that is produced and stored
in the granules of the juxtaglomerular cells surrounding
the afferent arterioles of glomeruli in the kidney.
 Renin acts on the basic substrate angiotensinogen (a
circulating α2-globulin made in the liver) to form the
decapeptide angiotensin I.
 Angiotensin I is then enzymatically transformed by
angiotensin-converting enzyme (ACE), which is present in
many tissues (particularly the pulmonary vascular
endothelium), to angiotensin II.
Lab test of adrenal disfunction
 Blood level
 Urine level
 Stimulation test
 Suppression test
 Test of pituitary – adrenal responsiveness
1. Blood level
 Plasma level of ACTH
 Angiotensin II
 Steroid level
 Cortisol level
 Aldosterone level
 DHEA
2. Urine level
 Elevated levels of urinary free cortisol correlate
with states of hypercortisolism, reflecting changes
in the levels of unbound, physiologically active
circulating cortisol
 Normally, the rate of excretion is higher in the
daytime (7 A.M.–7 P.M.) than at night (7 P.M.–7
A.M.).
 Urinary creatinine should be measured
simultaneously to determine the accuracy and
adequacy of the collection procedure.
3. Stimulation test
Stimulation tests are useful in the diagnosis
of hormone deficiency states.

 Tests of Glucocorticoid Reserve

 Tests of Mineralocorticoid Reserve and
Stimulation of the Renin-Angiotensin
System
 A screening test (rapid ACTH stimulation test) involves
the administration of 25 units (0.25 mg) of
cosyntropin IV or IM and measurement of plasma
cortisol levels before administration and 30 and 60
min after administration
 the test can be performed at any time of the day.
 The most clear-cut criterion for a normal response is a
stimulated cortisol level of >500 nmol/L (>18 μg/dL),
and the minimal stimulated normal increment of
cortisol is >200 nmol/L (>7 μg/dL) above baseline.
4. Suppression test
Suppression tests to document
hypersecretion of adrenal hormones involve
measurement of the target hormone
response after standardized suppression of
its tropic hormone.

 Tests of Pituitary-Adrenal Suppressibility

 Tests of Mineralocorticoid Suppressibility
 Overnight dexamethasone suppression test

 This involves the measurement of plasma cortisol

levels at 8 A.M. following the oral administration of 1
mg dexamethasone the previous midnight.
 The 8 A.M. value for plasma cortisol in normal
individuals should be <140 nmol/L (5 μg/dL).
 The definitive test of adrenal suppressibility involves
administering 0.5 mg dexamethasone every 6 h for
two successive days while collecting urine over a 24-
h period for determination of creatinine and free
cortisol and/or measuring plasma cortisol levels.
 In a patient with a normal hypothalamic-pituitary ACTH
release mechanism, a fall in the urine free cortisol to <25
nmol/d (10 μg/d) or of plasma cortisol to <140 nmol/L (5
μg/dL) is seen on the second day of administration.
5. Test of pituitary – adrenal responsiveness

 Stimuli such as insulin-induced hypoglycemia, AVP,

and pyrogens induce the release of ACTH from the
pituitary by an action on higher neural centers or
on the pituitary itself.
 Insulin-induced hypoglycemia is particularly useful,
because it stimulates the release of both growth
hormone and ACTH.
 Insulin-induced hypoglycemia
 stimulates the release of GH and ACTH.
 In this test, regular insulin (0.05–0.1 U/kg body
weight) is given intravenously as a bolus to reduce the
fasting glucose level to at least 50% below basal.
 The normal cortisol response is a rise to >500 nmol/L
(18 μg/dL). Glucose levels must be monitored during
insulin-induced hypoglycemia, and it should be
terminated if subjects develop symptoms of
hypoglycemia.