Kelenjar Adrenal

Kelenjar Adrenal
dr M. Arman Nasution SpPD
ENDOCRINE SYSTEM
Brief Introduction
Hormones Regulations
Vertebrate hormones
regulate such diverse
activities as;
Growth
Development
Reproduction
Metabolic Rate
Fluid Balance
Blood Homeostasis
And Coping with stress
Hormones are Regulated by the

Glands
22
In this Presentation, Mainly we are

going to explain about the Classical
Human Endocrine glands
ENDOCRINE
GLANDS
1
Hypothalamus
Pituitary glands
Pineal gland
Thyroid gland
Parathyroid glands
Thymus gland
Adrenal gland
Pancreas
Testes
10
Ovary
Endocrine System
The classic members:
Hypothalamus and Pituitary Gland

Pineal Gland
Endocrine Pancreas
Thyroid
Parathyroids
Adrenals
Gonads
Endocrine System
The endocrine system is concerned
with internal secretions
endo- -crine
What makes up the endocrine

system?
(Actually quite a difficult question)
Endocrine System
Distance of Hormone Action
Autocrine
Paracrine
Endocrine
We typically leave out local
hormones
The grey area occurs because
no hormone is purely local.
Endocrine System
The classic members are useful for
learning
They are important

They provide order to learning
They introduce key concepts (hormonal axis)
Remember that it is an artificial system

Organ Hormones (GI, Cardiac, Pulmonary)
Cytokines (Immune Hormones)
Orphan Endocrine Cells
Endocrine Key Concepts

Key Concept One:
For each hormone, what is the target
cell
and its receptor?
Single or Multiple Target Cells
Single or Multiple Receptors

Key Concept Two:
What is the site of hormone release
and
its pathway to target tissue?
Focal: Hypothalamus Pituitary
Global: Thyroid Hormone Body

Key Concept Three:
What effects do secretion, excretion,
and degradation have on hormone
levels?
Steady State Disequilibrium

Key Concept Four:
What computational structures exist
to control and regulate hormonal
levels?
AXIS
Other Control Structures

Axis:
A linear control structure
consisting of a series
of cells each secreting
one hormone to
stimulate the
subsequent cell.

Examples of Axes:
Hypothalamic Pituitary Adrenal

Hypothalamic Pituitary Thyroid
Hypothalamic Fat axis
Renin Angiotensin Aldosterone

Key Concept Five:
What other hormones act on similar
targets
with similar effects?
Redundancy
Multiplicity

Key Concept Six:
How do these different hormones
affect
body metabolism?
Free Body Diagram

Its important to keep these ideas in
mind
when thinking about the endocrine
system
Endocrine Pancreas
The majority of the pancreas
is a secretory exocrine gland
A minority of the pancreas is

an secretory endocrine gland
These collections of endocrine cells

are called the Islets of Langerhans
Endocrine Pancreas
Endocrine Pancreas
Islets contain:
Alpha Cells - Glucagon

(15-20%)
Beta Cells - Insulin
(65-80%)
Delta Cells - Somatostatin
(3-10%)
PP Cells - Pancreatic Polypeptide (<
1%)
Epsilon Cells Ghrelin? (<0.5%)
Alpha Cells - Glucagon
Beta Cells - Insulin
Delta Cells - Somatostatin
Endocrine Pancreas
Hypothalamus
Anatomy and Microanatomy
Lives in the
Diencephalon
Inferomedial
to Thalamus
Hypothalamus
Hypothalamus
Hypothalamic Nuclei
Hypothalamus
Thyrotropin-releasing hormone (TRH)
Gonadotropin-releasing hormone
(GnRH)
Growth hormone-releasing hormone
(GHRH)
Corticotropin-releasing hormone
(CRH)
Somatostatin
Dopamine
Pitutary Gland
Lives in the
Skull Base
in its own
compartment
Sella Turcica
Pituitary Gland
Sella Turcica (Turkish Saddle)
Located in Sphenoid Bone
Pituitary Gland
Gross View
Posterior
Anterior
Pituitary Gland
The gland consists
of two grossly
identifiable parts
Anterior Pituitary
Posterior Pituitary
Pituitary Gland
Microscopically,
there are many
more parts
Posterior
The functional
division between
anterior and
posterior stays true.
Anterior
Pituitary Gland
Posterior Pituitary
Has Neurons
Cell Bodies are in
hypothalamus
Synapses with
Blood Vessels
Pituitary Gland
Anterior Pituitary
Has Endocrine Cells
Looks and Acts
like a Gland
Not Innervated
Pituitary Gland
The pituitary hangs off
the hypothalamus
Blood Supply is in three steps

Arterial supply arrives
at the hypothalamus
via the Circle of Willis
Pituitary Gland
Next, the venous drainage
from the Hypothalamus goes

to the Pituitary
This is called the

Portal System
Just like in the gut and liver
Pituitary Gland
After passing through the
Portal System and carrying
hypothalamic hormones to
the pituitary
The venous blood, carrying

pituitary hormones, returns
to the systemic veins
Pituitary Gland
Just like the portal system
of the gut gives the liver
first crack at gut absorbed stuff
This portal system gives the

pituitary first crack at secreted
hypothalamic hormones
Pituitary Gland
Hypothalamus and Pituitary

Gland
Together, they compare and contrast the
classic endocrine and neuroendocrine
systems
Neuroendocrine System:
Nerves release Neurotransmitters into
blood
Endocrine System:
Hormones from one part of the body go to
another
Posterior Pituitary
Cell Bodies in Hypothalamus
Supraoptic and Paraventricular Nuclei
Axons in the
Pars tuberalis
Synapse in the
Pars nervosa
Posterior Pituitary
Histologically, its not that interesting
(Looks like nerves)
Anterior Pituitary
Cell Bodies look like Glands
Anterior Pituitary
Depending on the stain
Some cells like stain:
Chromophils
Acidophils
Basophils
Neutrophils
Some cells dont:

Chromophobes
Anterior Pituitary
Why stain differently?
Each Cell
produces
one and
only one
hormone.
Different hormone
peptides have different

chemical properties
Pituitary Development
The two regions of pituitary have
separate origins
Anterior = Endoderm
Posterior = Neuroectoderm
Pituitary Gland
Pituitary Gland
Anterior lobe (adenohypophysis)
GH
Growth hormone
PRL
Prolactin
ACTH
Adrenocorticotropic
hormone
TSH
Thyroid-stimulating hormone
FSH
Follicle-stimulating hormone
LH
Luteinizing hormone
Pituitary Gland
Posterior lobe (neurohypophysis)
Oxytocin
Antidiuretic hormone (ADH)
Pineal Gland
Pineal gland
Early Chordates
histologically
resembles eye
Hypothesized to
regulate day-night
cycles
Pineal Gland
Located between
superior colliculi
In Humans
8 mm in size
Pineal Gland
Located inside
Meninges
Very Vascular
Pineal Gland
Secretes Melatonin
Thyroid Gland
Lives in
the Neck
Derived
from the
Branchial
Arches
Thyroid Gland
Consists of Lobes
Right and Left
Isthmus
Pyramidal
Thyroid Gland
Foramen Cecum inside the mouth
develops into a small diverticulum
This is dragged
towards the chest
during body folding
Thyroid Gland
Foramen Cecum lies medial to 1st
and 2nd arches
Thyroid Gland
Branchial Arches
Foramen Cecum
becomes Thyroid
Third and Fourth Arches

become Parathyroids
Third Arch
becomes Thymus
Thyroid Gland
Pyramidal Lobe
is the remnant
Right and Left

Lobes are the
main gland
Thyroid Gland
Heavily Vascular
(Like most glands)
Arterial Supply
and Venous
Drainage from
Branchial Arches
Thyroid Gland
The gland consists
of Thyroid Follicles
Cuboidal Epithelium
Central Colloid
Supportive Stroma
Parafollicular Cells
Thyroid Gland
Thyroid Hormone
Thyroxine (T4)
Triiodothyronine (T3)
C-Cells
Calcitonin
Parathyroids
Aptly named glands that live around
thyroid:
Branchial Arches
Foramen Cecum
becomes Thyroid
Third and Fourth Arches

become Parathyroids
Third Arch
becomes Thymus
Parathyroid Gland
Parathyroid
Secretes
Parathyroid
hormone (PTH)
Adrenal Glands
These are paired
suprarenal glands
Embryologically:
Cortex forms first
Gonadal Ridge
Medulla forms second

Neural Crest Origin
Adrenal Glands
Histologically,
Its quite easy
to see the
difference
between
CORTEX and
MEDULLA
Adrenal Glands
Adrenal Cortex
This should remind you of the kidney
Adrenal Medulla
Adrenal Glands
Adrenal cortex
Glucocorticoids - cortisol
Mineralocorticoids - aldosterone
Androgens (including testosterone)
Adrenal medulla
Epinephrine
Norepinephrine
Gonads
Well save these for

Reproduction Endocrinology
Orphan Endocrine Cells

APUD Cells
Amine Precursor Uptake and
Decarboxylation
A
P
U
D
Generate tissue and organ levels of

Traditional Neurotransmitters
Orphan Endocrine Glands

Heart
Atrial-natriuretic peptide (ANP)
Stomach and intestines
Gastrin
Somatostatin
Secretin
Cholecystokinin (CCK)
Neuropeptide Y
Liver
Insulin-like growth factor

Angiotensinogen
Thrombopoietin
Orphan Endocrine Glands

Kidney
Renin
Erythropoietin (EPO)
Calcitriol
Skin
Calciferol (vitamin D3)
Adipose tissue
Leptin
Hypothalam
us
Controls an immense
amount of our bodily
functions.
Located in the middle of
the base of the brain and
encapsulates the
ventricle portion of the
third ventricle.
Your Logo
Pituitary
gland
Located in the center of the skull.
the size of the Pituitary gland is about the
size of a pea.
Important link between the nervous system
and the endocrine system and releases
many hormones which affect
Growth
sexual development
metabolism
system of reproduction
. The pituitary gland has two distinct parts,
the anterior and the posterior lobes.
This gland was once believed to be the main
controlling gland of the body.
The pituitary gland then makes hormones
of its own in answer to the body's needs.
Your Logo
Pineal gland
the "third eye" by ancient people.

The pineal does contain a complete map of the
visual field of the eyes, and it plays several
significant roles in human functioning.
center for the production of the hormone
melatonin.
regulates daily body rhythms, most notably the
day/night cycle, prevents jet lag, is implicated in
seasonal affective disorder, coordinates fertility,
and allows for deep restful sleep patterns
Connect to the brain and nerves system through
a complex network of bidirectionnel links.
Thyroid
gland
Shaped like a butterfly.
and usually weighs less than one

ounce.
The thyroid cartilage covers the

larynx and produces the prominence
on the neck known as the "Adam's
Apple".
Controls the rate at which the body
produces energy from nutrients.
If the body does not get enough
iodine, the thyroid gland cannot
produce a proper amount of
hormones
for
this
conversion
process.
Parathyroid
gland
small endocrine glands in the
neck that produce parathyroid
hormone.
Humans have four parathyroid

glands.
located in variable manner on the

posterior surface of the thyroid
gland, or, in rare cases, within the
thyroid gland itself or in the chest
(mediastinum)
or
even
the
thymus.
control the amount of calcium in
the blood and within the bones.
Thymus gland
Forms in a part of the immune system.
It is situated in the upper part of the

chest.
made up of two lobes that join in front of

function is to transform lymphocytes
(white blood cells developed in the bone
marrow) into T-cells (cells developed in
the thymus)
The thymus enlarges from about the
12th week of gestation until puberty.
transported to various lymph glands.
play an important part
infections and disease.
in
fighting
Adrenal gland
found on top of both
of the kidneys.
The center of the
adrenal consists of
the medulla which
produces
epinephrine and
norepinephrine.
Pancreas
pancreas has two main functions:

to produce pancreatic
endocrine hormones, which
help regulate many aspects of
our metabolism
to produce pancreatic
digestive enzymes
Ovary
o produce a female hormone

and it called as estrogen.
o store female sex cells, or
ova.
Testes
Testes is male gonads.

Suspended within a sac of skin called the
Scromtum.
It is composed of seminiferous tubles.
It have two main function:
Formation, Developmet and

excretion of sperm.
The secretion of testosteron.
Endocrine system is the

system of glands that
produce endocrine
secretions that help to
control bodily metabolic
activity
Growth
Development
Reproduction
Metabolic Rate
Fluid Balance
Blood Homeostasis
And Coping with stress
Hormones are
Regulated by the
Glands
Functions
The endocrine system influences almost every cell,
organ, and function of our bodies. The endocrine system
is instrumental in regulating mood, growth and
development, tissue function, metabolism, and sexual
function and reproductive processes.
In general, the endocrine system is in charge of body
processes that happen slowly, such as cell growth.
Faster processes like breathing and body movement are
controlled by the nervous system. But even though the
nervous system and endocrine system are separate
systems, they often work together to help the body
function properly.
Hormones
The foundations of the endocrine system are the
hormones and glands. As the body's chemical
messengers, hormones transfer information and
instructions from one set of cells to another. Many
different hormones move through the bloodstream,
but each type of hormone is designed to affect
only certain cells.There are three general classes
(groups) of hormones. These are classified into
three groups by chemical structure, not function.
1)Steroid hormones including
prostaglandins which function especially in

a variety of female functions (aspirin inhibits
synthesis of prostaglandins, some of which
cause cramps) and the sex hormones all of
which are lipids made from cholesterol,
2) Amino acid derivatives (like epinephrine)
which are derived from amino acids,
especially tyrosine, and
3) Peptide hormones (like insulin)

which is the most numerous/diverse
group of hormones.
A gland is a group of cells that
produces and secretes, or gives off,
chemicals. A gland selects and
removes materials from the blood,
processes them, and secretes the
finished chemical product for use
somewhere in the body.
Exocrine Glands
Some types of glands release their secretions in
specific areas. For instance, exocrine glands,
such as the sweat and salivary glands, release
secretions in the skin or inside the mouth.
Mammary glands, lacrimal glands, gastric glands,
sebaceous glands, mucous glands are also
exocrine glands. Endocrine glands, on the other
hand, release more than 20 major hormones
directly into the bloodstream where they can be
transported to cells in other parts of the body.
Endocrine Glands
The major glands that make up the human endocrine system
include the:
1. Hypothalamus
2. Pituitary gland (hypophysis)
3. Thyroid gland
4. Parathyroid glands
5. Thymus
6. Adrenal glands
7. Pancreas
8. Pineal gland (epiphysis)
9. Reproductive glands (which include the ovaries and
testes)
Hypothalamus
The hypothalamus, a collection of
specialized cells that is located in the
lower central part of the brain, is the
main link between the endocrine and
nervous systems. Nerve cells in the
hypothalamus control the pituitary gland
by producing chemicals that either
stimulate or suppress hormone
secretions from the pituitary.
The Pituitary Gland

The pituitary gland is located at the base of the human
brain. It is suspended from the hypothalamus, to which it
is connected by a short stem. The gland consists of two
parts: the anterior lobe (adenohypophysis) and the
posterior lobe (neurohypophysis).
The anterior lobe secretes at least seven hormones. One
hormone, the human growth hormone (HGH), promotes
body growth by accelerating protein synthesis. This
hormone is also known assomatotropin. A deficiency of
the hormone results in dwarfism; an oversecretion results
in gigantism.
Another hormone of the anterior pituitary is

prolactin, also calledlactogenic hormone (LH).
This hormone promotes breast development
and milk secretion in females. A third hormone
is thyroid-stimulating hormone (TSH). The
function of TSH is to control secretions of
hormones from the thyroid gland. A fourth
hormone is adrenocorticotropic hormone
(ACTH). This hormone controls the secretion of
hormones from the adrenal glands.
There are three more hormones produced in the anterior

lobe of the pituitary gland. The first is follicle-stimulating
hormone (FSH). In females, FSH stimulates the
development of a follicle, which contains the egg cell; in
males, the hormone stimulates sperm production. The next
hormone is luteinizing hormone (LH). In females, LH
completes the maturation of the follicle and stimulates the
formation of the corpus luteum, which temporarily secretes
female hormones. In males, LH is interstitial cell-stimulating
hormone (ICSH), which stimulates the production of male
hormones in the testes. The final hormone is melanocytestimulating hormone (MSH), which stimulates production of
the pigment melanin.
The posterior pituitary gland manufactures two

hormones that are produced in the neurosecretory
cells in the hypothalamus, and pass into the
neurohypophysis through the axons of these cells.
When they are needed they are released. The first
hormone is antidiuretic hormone (ADH). This
hormone stimulates water reabsorption in the
kidneys. It is also calledvasopressin. The second
hormone is oxytocin, which stimulates
contractions in the muscles of the uterus during
birth.
The Thyroid Gland

The thyroid, located in the front part of the
lower neck, is shaped like a bow tie or butterfly
and produces the thyroid hormones thyroxine
and triiodothyronine. These hormones
control the rate at which cells burn fuels from
food to produce energy. Thyroid hormones
affect three fundamental physiologic
processes: cellular differentiation, growth, and
metabolism. Thyroxine production depends
on the availability of iodine.
The production and release of thyroid hormones is

controlled by thyrotropin, which is secreted by
the pituitary gland. The more thyroid hormone
there is in a person's bloodstream, the faster
chemical reactions occur in the body.
The thyroid gland also produces another hormone
called calcitonin, and the parathyroid glands
secrete parathyroid hormone. Parathyroid hormone
and calcitonin participate in control of calcium and
phosphorus homeostasis and have significant
effects on bone physiology.
The Parathyroid Glands

Theparathyroid glandsare
located on the posterior surfaces of
the thyroid gland. They are tiny
masses of glandular tissue that
produce parathyroid hormone, also
calledparathormone. Parathyroid
hormone regulates calcium
metabolism in the body by increasing
calcium reabsorption in the kidneys,
and by increasing the uptake of
The Thymus Gland

The thymus is a gland that forms part of the immune system. It is
situated in the upper part of the chest, behind the breastbone, and
is made up of two lobes that join in front of the trachea. Each lobe
is made of lymphoid tissue, consisting of tightly packed white blood
cells and fat. The thymus enlarges from about the 12th week of
gestation until puberty, when it begins to shrink. It
secretesthymosins, which influence the development of the Tlymphocytes of the immune system. Its function is to transform
lymphocytes (white blood cells developed in the bone marrow) into
T-cells (cells developed in the thymus). These cells are then
transported to various lymph glands, where they play an important
part in fighting infections and disease. Swelling of lymph glands and
fever are a signal that immune cells are multiplying to fight off
invaders of the body: bacteria, fungi, viruses or parasites.
The Adrenal (Suprarenal) Glands

Theadrenal glandsare two pyramid-shaped glands lying
atop the kidneys. The adrenal glands consist of an outer
portion, the cortex, and an inner portion, the medulla.
The adrenal cortex secretes a family of steroids
calledcorticosteroids.The two main types of steroid
hormones are mineralocorticoids and glucocorticoids.
Mineralocorticoids, such as aldosterone, control mineral
metabolism in the body. They accelerate mineral
reabsorption in the kidney. Mineralocorticoid secretion is
regulated by ACTH from the pituitary gland. Glucocorticoids,
such as cortisol and cortisone, control glucose metabolism
and protein synthesis in the body. Glucocorticoids are also
anti-inflammatory agents.
Adrenal Medulla
The adrenal medulla produces two
hormones:epinephrine(adrenaline) and
norepinephrine(noradrenaline). Epinephrine
increases heart rate, blood pressure, and the blood
supply to skeletal muscle. Epinephrine functions in
stressful situations to promote the fightflight
response. Norepinephrine intensifies the effects of
epinephrine. Both hormones prolong and intensify
the effects of the sympathetic nervous system.
Pancreas
The pancreas is located just behind the stomach. Its
endocrine portion consists of cell clusters called theislets
of Langerhans.
The pancreas produces two hormones: insulin and glucagon.
Insulin is a protein that promotes the passage of glucose
molecules into the body cells and regulates glucose
metabolism. In the absence of insulin, glucose is removed
from the blood and excreted in the kidney, a condition
calleddiabetes mellitus. Diabetes mellitus is characterized
by glucose in the urine, heavy urination, excessive thirst,
and a generally sluggish body metabolism.
The second pancreatic

hormone,glucagon, stimulates the
breakdown of glycogen to glucose in the
liver. It also releases fat from the adipose
tissue so the fat can be used for the
production of carbohydrates.
The pancreas is also associated with the
digestive system because it produces and
secretes digestive enzymes (Acinar cells).
Pineal Gland (epiphysis)

Thepineal glandis a tiny gland in
the midbrain. Its functions are largely
unknown, but it seems to regulate
mating behaviors and daynight
cycles.
The Reproductive Glands

The gonads are the main source of sex hormones.
Both men and women have gonads. In men the
male gonads, or testes, are located in the scrotum.
They secrete hormones called androgens, the most
important of which is testosterone. These
hormones tell a boy's body when it's time to make
the changes associated with puberty, like penis and
height growth, deepening voice, and growth in facial
and pubic hair. Working with hormones from the
pituitary gland, testosterone also tells a guy's body
when it's time to produce sperm in the testes.
A girl's gonads, the ovaries, are located in her

pelvis. They produce eggs and secrete the female
hormones estrogen and progesterone. Estrogen
is involved when a girl begins to go through puberty.
During puberty, a girl will experience breast growth,
will begin to accumulate body fat around the hips
and thighs, and will have a growth spurt. Estrogen
and progesterone are also involved in the regulation
of a girl's menstrual cycle. These hormones also
play a role in pregnancy.
Suprarenal Glands
Divided into two parts; each with
separate functions
Suprarenal Cortex
Suprarenal Medulla
Adrenal Cortex
Is divided into 3 zones in the adult
gland: Zona Glomerulosa, Zona
Fasciculata, Zona Rericularis.
Is divided onto 4 zones in the fetal

gland.
The three zones of the permanent

cortex constitutes only 20% of the fetal
glands size. The remaining zone (fetal
cortex) comprises up to 80% of glands
size during fetal life.
Adrenal Cortex
Synthesizes and releases steroid
hormones (corticosteroids)
Different corticosteroids are produced
in each of the three layers:
Zona glomerulosa mineralocorticoids
(mainly aldosterone)
Zona fasciculata glucocorticoids
+Androgens
(mainly cortisol and corticosterone)
Zona reticularis gonadocorticoids +

glucocorticoids
(mainly dehydroepiandrosterone DHEA)
Adrenal Cortex: Steroid

Hormone Production
Aldosterone, sex hormones, cortisol
Synthesized from cholesterolsteroid
ring
Adrenal Cortex: Steroid Hormone

Production
Cortisol and Chronic Stress
Prolonged exposure to high cortisol

levels can lead to break down of
muscle, excessive epinephrine
release, hyperglycemia, weakening
of bone, destruction of the immune
system, inhibition of reproductive
function, and other complications.
Cortisol Effects: Body Responses to

Stress
Permissive effect on glucagon

Memory, learning and mood
Gluconeogenesis
Skeletal muscle breakdown
Lipolysis, calcium balance
Immune depression
Circadian rhythms
Adrenal Gland
Anatomy was first described in 1563.
Is located above (or attached to) the
upper pole of the kidney.
Is pyramidal in structure and weighs ~ 4
g.
Consists of the adrenal cortex and adrenal
medulla
Activities are regulation of fluid volume
and stress response
The Adrenal Gland:

Anatomy
Adrenal Histology
The General Adaptation Syndrome
The General Adaptation Syndrome
The General Adaptation

Syndrome
Permissive Effects of Cortisol on

Development
Cortisol is required for normal
development:
- permissive role in final maturation of
many organs
- required for synthesis of digestive
enzymes, surfactant
- required for skeletal growth in children
Mechanisms of Cortisol Action

The actions of cortisol are mediated through
the glucocorticoid receptor.
Intracellular receptor in steroid receptor
superfamily.
Stimulates transcription of target genes by
interaction of bound receptor with GRE in 5
flanking region.
Inhibits transcription of some genes by
interaction of receptor with AP1 (jun/fos
dimer), decreasing
AP1-mediated
gene
AP1
expression.
cortisol
GR
transcription
AP1
site
Hormone Effects on Gene Activity

Cortisol
Cortisol Effects: Body Responses

to Stress to living
Control of Cortisol Secretion:

Feedback Loops
External stimuli
Hypothalamic
Anterior
Pituitary
Adrenal cortex
Tissues
Cortisol: Role in Diseases and

Medication
Use as immunosuppressant
Hyperimmune reactions (bee stings)
Serious side effects
Hypercortisolism (Cushing's syndrome)

Tumors (pituitary or adrenal)
Iatrogenic (physician caused)
Hypocortisolism (Addison's disease)
Aldosterone
Exclusively synthesized in Z.
Glomerulosa
Essential for life.

Promotes sodium retention and
Potassium elimination by the kidney.
Expands ECF volume
Regulation of Aldosterone Secretion
Aldosterone: Role in
Diseases
Complete failure to secrete
aldosterone leads to death
(dehydration, low blood volume).
Hyperalsdosterone states: Contribute

to hypertension associated with
increased blood volume.
Adrenal Medulla:
A Modified Sympathetic Ganglion
Sympathetic stimulation
Catecholamine release to blood
Epinephrine
Norepinephrine
Travel to:
Multiple targets
Distant targets
Adrenal Medulla:
A Modified Sympathetic Ganglion
Mechanism: Norepinephrine
Release and Recycling
Review of Efferent Pathways:

Motor and Autonomic
Catechalomines: Activity
Stimulates the fight or fight
reaction
Increased plasma glucose levels
Increased cardiovascular function
Increased metabolic function
Decreased gastrointestinal and
genitourinary function
Activity of Epinephrine
Adrenal glands
The adrenals are orange-colored
glands that sit on top of the kidneys
near the spine, just underneath the
last rib and extending down about an
inch. The right adrenal is shaped
something like a pyramid, whereas
the left is shaped more like a half
moon.
Each adrenal gland is composed of

two endocrine components: a medulla
(inner part) that constitutes 20% of
the gland and a cortex (outer part)
that constitutes the remaining 80%.
The cortex consists of three zones.
The medulla and each of the zones in
the cortex each produce different
hormones that serve a variety of
functions in your body.
Adrenal Glands
The Adrenal Cortex

The adrenal cortex is divided into
three zones which each secrete
different hormones that carry out
specific functions throughout your
body.
1. Zone of glomerulosa
Corte
x
2
3
Medull
Aldosterone is secreted from this zone which
a is the major hormone
controlling the sodium and potassium levels, and thus fluid balance,
within your bloodstream, cells and interstitial fluids. It is also called
mineralocorticoids.
The Adrenal Cortex

2. Zone of fasciculata
Coritsol (hydrocortisone) is produced,
affects glucose, amino acid and fat
metabolism, which is called glucocorticoids.
Cells of this zone are arranged into fascicles
separated by venous sinuses.
3. Zone of reticularis
Corte
x
Medull
Dehydroepiandrosterone (DHEA)-precursor foraandrogen is
synthesized. This zona manufactures an ancillary portion of sex
hormones for each sex and also produces male hormones in women
and female hormones in men to keep the effects of the dominant sex
hormones in balance .
Adrenals
CORTEX
Zona Glomerulosa
Mineralocorticoids
(Aldosterone)
Na+, K+
and
water
Zona
Fasciculata
homeostasis
Glucocorticoids (Cortisol)
Glucose homeostasis and
many others
Zona Reticularis
Sex steroids (androgens)
Medulla: Catecholamines
Epinephrine, Norepinephrine,
dopamine
Synthesis of adrenocorticosteroids
All steroid hormones have in common the 17-carbon cyclopentaoperhydrophenanthrene nucleus. Additional carbons can be added at
positions 10 and 13 or as a side chain attached to C17.
Steroid hormones and their precursors and metabolites differ in
1. number and type of substituted groups,
2. number and location of double bonds,
3. stereochemical configuration.
1
8 1
7
3
1
9
1
8
2
1
1. Uptake of cholesterol by the adrenal cortex is mediated by the LDL
receptor. With long-term stimulation of the adrenal cortex by ACTH, the
number of LDL receptors increases. Much of the cholesterol in the
adrenal is esterified and stored in cytoplasmic lipid droplets.
2. Upon stimulation of the adrenal by ACTH or cAMP, an esterase is
activated, and the free cholesterol formed is transported into the
mitochondria.
3. In the mitochondria, a cytochrome P450 side chain cleavage
enzyme (P450SCC) converts cholesterol to pregnenolone.
4. Pregnenolone may be converted by dehydrogenase/isomerase to
progesterone or else by P450c17 (17--hydroxylase) to 17hydroxypregnenolone. Progesterone can also be converted to 17hydroxyprogesterone by P450c17.
17-hydroxylase
dehydrogenase/isome
rase
17-hydroxylase
5. After the synthesis of progesterone and 17-hydroxyprogesterone,
P450c21(21-hydroxylase) can hydroxylate these steroids at the 21
position, resulting in 11-deoxycorticosterone and 11-deoxycortisol,
respectively.
21-hydroxylase
21-hydroxylase
6. The final step in the synthesis of adrenal mineralocorticoids and

glucocorticoids is mediated by P450c11 (11--hydroxylase), which
also mediates the final steps in the synthesis of aldosterone from
deoxycorticosterone.
1
1
11--hydroxylase
11--hydroxylase
7. P450c17 has two activities, that of a 17-hydroxylase and that of a C17,20 lyase capable of breaking up the C-17,20 carbon bond of 17hydroxypregnenolone or 17-hydroxyprogesterone, yielding
dehydroepiandrosterone (DHEA) or androstenedione, respectively.
8. 17-hydroxysteroid dehydrogenase
convert androstenedione to
testosterone. P450aro mediates the
aromatisation of androgens to
estrogens in the gonads. In peripheral
target tissues, testosterone can further
be converted to 5dihydrotestosterone by 5-reductase.
Biosynthesi
s
Of human
steroid
Hormones
Some autosomal recessive mutations in biosynthetic enzymes

responsible for converting cholesterol to androgens generally lead to
partial male-to-female sex reversal.
CAH (congenital adrenal hyperplasia): For P450c21 is deficiency,
cortisol synthesis decreases, leading to overproduction of ACTH. When
this occurs adrenal steroid synthesis is stimulated and 17hydroxyprogesterone is converted to androstenedione and further to
testosterone, leading to severe virilization of the female fetus. This
disorder is known as CAH which disrupts the synthesis of all adrenal
and gonadal steroids. Affected genetic males are born with normal
female external genitalia.
Biochemical actions of adrenocorticosteroids

A. Mineralocorticoids: aldosterone
It promotes Na+ reabsorption at the distal
convoluted tubules of kidney. Na+ retention
is accompanied by corresponding excretion
of K+,H+ and NH4+ ions.

B. Glucocorticoids: Cortisol

B. Glucocorticoids: Cortisol
1. Effects on glucose metabolism: They promote gluconeogenesis.
They work in tandem with insulin from the pancreas to maintain blood
glucose levels in the proper balance.
2. Effects on lipid metabolism: They increase lipolysis in adipose
tissue and reduce synthesis of TAG.
3. Effects on protein and nucleic acid metabolism: They promote
transcription and protein synthesis in liver. They also cause catabolic
effects in extrahepatic tissues results in enhanced degradation of protein.
4. Effects on water and electrolyte metabolism: Deficiency of them

cause increased production of ADH which can decrease glomerular
filtration rate causing water retention in the body.
5. Effects on immune system: Cortisol suppress the immune response
directly and indirectly by affecting most cells that participate in immune
reactions and inflammatory reactions. It is powerful anti-inflammatory
even when secreted at normal levels. It also reduces the rate at which
lymphocytes multiply and accelerates their programmed cell death to
further protect the body from this overreaction. This is one of the
reasons why strong corticosteroids (prednisone, prednisolone, etc.) are
used with all diseases involving inflammatory processes, including
auto-immune diseases.
6. Effects on cardiovascular system: Cortisol could control the

contraction of the walls of the mid-sized arteries in increasing blood
pressure, but this hypertensive effect is moderated by calcium and
magnesium. It also directly affects the heart by regulating sodium and
potassium in the heart cells and increasing the strength of contraction of
the heart muscle.
7. Effects on central nervous system: The changes of behavior, mood,
excitability and even the electrical activity of neurons in the brain
frequently occur in cases of excess and deficient cortisol levels. Many
signs and symptoms of adrenal fatigue involve moodiness, decreased
tolerance, decreased clarity of thought and decreased memory. These
occur because the brain is affected by both too little and too much
cortisol.
Stress
Adrenal glands are the anti-stress glands of the body.
There are four major categories of stress:
1. Physical stress: such as overwork, lack of sleep, athletic
overtraining. 2.Chemical stress: environmental pollutants, allergies to
foods, diets high in refined carbohydrates, endocrine gland imbalances.
3. Thermal stress: over-heating or over-chilling of the body
4. Emotional and mental stress
Stress: During stress cortisol must

simultaneously provide more blood glucose,
mobilize fats and proteins for a back-up
supply of glucose, modify immune reactions,
heartbeat, blood pressure, brain alertness and
nervous system responsiveness. If cortisol
level cannot rise in response to these needs,
maintaining your body under stress is nearly
impossible.
Hypothalamopituitary adrenal (HPA) axis

Immune
system:
altered
Stress
Circadian
rhythm
Hypothalamus
CRH
(-)
Anterior
Pituitary Gland
Posterior
Pituitary Gland
ACTH
Glucocorticoids,
Adrenals Catecholamines,
etc..
Kidney
Muscle:
Net loss of amino
Acids (glucose)
Liver:
Deamination of
proteins into amino
acids,
gluconeogenesis
(glucose)
Fat Cells:
Free fatty
acid
mobilization
Heart rate:
Increased
(Figure 9-40)
Fasting
People have considerable difficulty when on a prolonged fasting.
They will always rationalize the problems encountered on a fasting
as being due to the body detoxifying.
During a fasting, the body will call on the adrenals to produce
glucocorticoids to maintain blood glucose level which is adequate for
normal level of activity. The glucocorticoids can elevate blood
glucose by breaking down protein into carbohydrates through the
process of gluconeogenesis.
Regulation of glucocorticoids
The Secretion of glucocorticoids from the adrenal cortex is regulated
by negative feedback involving the CRH secretion by the
hypothalamus. CRH then acts on the anterior pituitary to stimulate
ACTH secretion, which then stimulates the adrenal cortex into cortisol
secretion. About 70% of blood cortisol is bound to a carrier protein
called corticosteroid-binding globulin. Another 15% is bound to
albumin, the remaining 15% exists free in solution.
The Hypothalamus/Pituitary/Adrenal (HPA) Axis

The HPA axis or HPA system, a negative
feedback system, is one of the most
important elements of homeostasis, the
process that maintains a steady internal
biochemical and physiological balance in
your body. The HPA Axis adjusts cortisol
level according to the needs of the body,
under normal and stressed conditions, via
ACTH. ACTH is secreted from the pituitary
gland in response to orders form the
hypothalamus and travels in the
bloodstream to the adrenal cortex.
Addison's Disease: Primary Chronic Adrenocortical

Insufficiency
People who suffer from adrenal fatigue almost always have some
form of irregular blood sugar pattern, of which hypoglycemia is the
most common.
When your adrenals are fatigued, their cortisol output is diminished
and you have lower levels of circulating blood cortisol, your liver has
a more difficult time converting glycogen into glucose.
Cushing's syndrome (hyperadrenocorticism or hypercorticism) is a

endocrine disorder caused by high levels of cortisol (hypercortisolism)
in the blood. This can be caused by taking glucocorticoid drugs, or by
tumors that produce cortisol or ACTH.
The Adrenal Medulla

The functional unit of the adrenal
medulla is the chromaffin cell, which
functions as a neuroendocrine cell. In
response to stimulation, chromaffin cells
secrete the hormones epinephrine
(adrenaline) and norepinephrine
(noradrenalin) directly into the blood.
Corte
x
2
3
Medull
a
The medulla is involved in extreme stress and, within this context,
epinephrine and norepinephrine both work with cortisol from the
adrenal cortex. Epinephrine and norepinephrine are important mainly in
crisis situations.
Catecholamines Biosynthesis
1. Tyrosine is precursor for the synthesis of
catecholamines.
2. The catecholamine are produced in response to fight,
fright and flight (3F). These include emergencies like
shock, cold, fatigue, emotional condition like anger.
Biochemical function of catecholamine

1. Effect on carbohydrate metabolism: Both of them can increase
glycogenolysis and gluconeogenesis and decrease glycogenesis.
Catecholamine promote the release of glucose from liver and decrees
its utilization by muscle; Epinepherine inhibits insulin secretion
but promote glucagon secretion.
2. Effect on lipid metabolism: Both of them enhance the breakdown of
TAG in adipose tissue. This cause increase in the free fatty acid in
the circulation which are effectively utilized by the heart and muscle
as fuel source.
3. Effect on physiological function: Cateccholamines increase cardiac
output, blood pressure and oxygen consumption. They cause smooth
muscle relaxation in bronchi, GIT and blood vessels supplying
skeletal muscle.
phaeochromocytoma (PCC) or
pheochromocytoma:
a neuroendocrine tumor of the medulla of the
adrenal glands (originating in the chromaffin cells),
or extra-adrenal chromaffin tissue that failed to
involute after birth and secretes excessive
amounts of catecholamines, usually adrenaline
(epinephrine) if in the adrenal gland and not extraadrenal, and noradrenaline (norepinephrine).
17% of adrenal cases are bilateral (suggesting hereditary

disease)
18.4% in children (also suggesting hereditary disease)

5% are extra-adrenal (located in any orthosympathetic
tissue): of these 9% are in the abdomen and 1% are
located elsewhere. Some extra-adrenal
phaeochromocytomas are probably actually
paragangliomas, but the distinction is only possible after
surgical resection.
11.1% malignant, but this rises to 30% for extraadrenal cases
26% are hereditary
3% recur after being resected
14% of affected individuals do not have arterial
Here's a look at the extra-adrenal sites of pheochromocytomas
1. Within the sympathetic nerve chain along the spinal cord (orange spots)
2. Overlying the distal aorta (the main artery from the heart) (green spots)
3. Within the ureter (collecting system from the kidney (yellow spot)
4. Within the urinary bladder (blue spot)
5. Remember, 90% are in the adrenal glands (red spots on the kidneys)
The Adrenal Glands
Adrenal medulla
Adrenal cortex
Three specific zones and each produces a specific
class of steroid hormone
Zona glomerulosa mineralocorticoids
(Aldosterone)
Zona fasciculata glucocorticoids ( Cortisole )
Zona reticularis - androgens
Hormones of the Adrenal Cortex

Sex hormones
Produced in the inner layer of the adrenal
cortex
Androgens (male) and some estrogen
(female)
Copyright2003PearsonEducation,Inc.publishingasBenjaminCummings
Slide 9.29b
Functions of
mineralocorticoids
Aldosterone exerts the 90% of the
mineralocorticoid activity. Cortisol also have
mineralocorticoid activity, but only 1/400th
that of aldosterone
Aldosterone increases renal tubular (principal

cells) reabsorption of sodium & secretion of
potassium
Excess aldosterone ECF volume & arterial

pressure, but has only a small effect on
Functions of
mineralocorticoids
Excess aldosterone causes hypokalemia
& muscle weakness, & too little
aldosterone causes hyperkalemia &
cardiac toxicity
Excess aldosterone increases tubular

(intercalated cells) hydrogen ion
secretion, with resultant mild alkalosis
Aldosterone stimulates sodium &

potassium transport in sweat glands,
Functions of
glucocorticoids
Effect of cortisol on protein
metabolism
Reduction of protein storage in all cells

except those of liver protein
catabolism & protein synthesis
Cortisol increases liver & plasma

proteins
Mobilizes aminoacids from non hepatic

cells, thus increase blood amino acid
level.
Figure 21.15
Hormones of the Adrenal Cortex
Figure 9.10
Slide 9.28b
Renin-angiotensin-aldosterone
axis
Principal factor
controlling Ang II
levels is renin
release.
Decreased
circulating volume
stimulates renin
release via:
Decreased BP
(symp effects on
JGA).
Decreased [NaCl]
at macula densa
(NaCl sensor)
Decreased renal
perfusion pressure
(renal
baroreceptor)
REGULATION OF CORTISOL
SECRETION
HYPOTHALAMUS
STRESS
+
CRH
DIURNAL
RHYTHM
ANTERIOR PITUITARY
INCREASED
BLOOD GLUCOSE
BLOOD AA
BLOOD FATTY ACIDS
ACTH
ADRENAL CORTEX
CORTISOL
TARGET ORGANS
Pathway of RAAS
Figure 6.12b
Atrial natriuretic peptide
Decreased blood
pressure stimulates renin
secretion
Renin-Angiotensin System:
renal blood flow &/or
Na+
++ Juxtaglomerular apparatus of
kidneys
(considered volume receptors)
Renin
Angiotensinog
en
Angiotensi
nI
(Lungs)
Angiotensin III
(powerful
vasoconstrictor)
Converting
enzymes
Angiotensin II
(powerful
vasoconstrictor)
Adrenal
cortex
Aldosteron
e
N.B. Aldosterone is the main regulator of Na+ retention.
Corticostero
ne
Renin-Angiotension-Aldosterone
System
Na+ Reabsorption
Angiotensisn II can
raise blood pressure
by:
vasoconstrictor
effects.
stimulating
aldosterone
secretion.
Insert fig. 17.26
Ooooooh!
Zymogen!
Blood Osmolarity
ADH
increased
water
reabsorption
pituitary
nephron
high
blood osmolarity
blood pressure
adrenal
gland
increase
thirst
increased
water & salt
reabsorption
low
JuxtaGlomerular
Apparatus (JGA)
nephron
renin
aldosterone
angiotensin
angiotensinogen
Hormones of the Adrenal Medulla

Produces two similar hormones
(catecholamines)
Epinephrine
Norepinephrine
These hormones prepare the body to

deal with short-term stress
Slide 9.30
Effects of Epinephrine
Gets you ready to fight or run
Heightens your senses, tenses your
muscles, openings breathing
passages, etc.
In response to stress
Take less than 30 seconds to kick in
and last several minutes
Disorders of the Adrenal Gland

1. Hypoaldosteronism
loss of water/Na+
Addisons disease low aldosterone & cortisol
2. Hyperaldosteronism
3. Cushings syndrome
hypersecretion of cortisol,androgens,aldosterone
15.4 Adrenal glands
Adrenal glands can malfunction

Cushing syndrome hypersecretion of
glucocorticoids by the adrenal cortex

characterized by weight gain in the trunk
of the body but not arms and legs
Cushings Disease
Proximal muscle
wasting & weakness

Osteoporosis
Glucose intolerance
HTN, hypokalemia
Thromboembolism
Depression, Psyc
Infection
Glaucoma
15.4 Adrenal glands
Adrenal glands can malfunction

Addisons disease hyposecretion of
glucocorticoids by the adrenal cortex
characterized by bronzing of the skin
Primary Adrenal Disease
Objectives
Normal adrenal physiology
Common causes of primary adrenal
insufficiency
Evaluation of suspected adrenal
insufficiency
Acute and chronic management
issues
Normal Adrenals
Adrenal Cortex
Zona Glomerulosa:
Mineralocorticoids
Zona Fasiculata: Glucocorticoids
Zona Reticularis: Androgens
Medulla
Adrenal Histology
Reticularis
Glomerulosa
Capsul
e
Medulla
Fasiculata
Adrenal physiology 1:
HPA axis
Adrenal physiology 2:
Renin-angiotensin system
Endocrine Glands
Agenda
Anatomy and physiology of adrenal

Causes of adrenal insufficiency
Addison Disease
Adrenal crisis
Congenital adrenal hyperplasia
Cushing Syndrome
ADRENAL MEDULLA:
The principal cells of the medulla are the

chromaffin cells. They secretes
adrenaline & noradrenaline.
.
ADRENAL GLAND
Adrenal Cortex, Function :
MINERALOCORTICOIDS regulate sodium
retention and potassium loss and body fluid
GLUCOCORTICOIDS act as anti-inflammatory
agents; affect metabolism.
ANDROGENS regulates growth and development
of genetalia and puberty
Adrenal Medulla, Function :
ADRENALINE (EPINEPHRINE) increases heart
rate and blood pressure.
NORADRENALINE (NOREPINEPHRINE) constricts
arterioles.
Pattern of cortisole level during

the day
C. The Adrenal Glands
Adrenal medulla
Adrenal cortex
Three specific zones and each produces a specific class of steroid
hormone
Zona glomerulosa mineralocorticoids (Aldosterone)
Zona fasciculata glucocorticoids ( Cortisole )
Zona reticularis - androgens
Renin-Angiotensin System:
renal blood flow &/or
Na+
++ Juxtaglomerular apparatus of
kidneys
(considered volume receptors)
Renin
Angiotensinog
en
Angiotensi
nI
(Lungs)
Angiotensin III
(powerful
vasoconstrictor)
Converting
enzymes
Angiotensin II
(powerful
vasoconstrictor)
Adrenal
cortex
Corticostero
Aldosteron
ne
e
.B. Aldosterone is the main regulator of Na+ retention.
Renin-Angiotension-Aldosterone
System
Na+ Reabsorption
Angiotensisn II can
raise blood pressure
by:
vasoconstrictor
effects.
stimulating
aldosterone
secretion.
Insert fig. 17.26
Hormones of the Adrenal Medulla

Produces two similar hormones
(catecholamines)
Epinephrine
Norepinephrine
These hormones prepare the body to

deal with short-term stress
Slide 9.30
Effects of Epinephrine
Gets you ready to fight or run
Heightens your senses, tenses your
muscles, openings breathing
passages, etc.
In response to stress
Take less than 30 seconds to kick in
and last several minutes
Hormones secreted by
cortex
CORTICOSTEROIDS
GlucocorticoidsMineralocorticoids
CORTISOL
ALDOSTERON
immune
system
glucose
stress
blood pressure
water and salt balance
Cushing's syndrome
Cushing's syndrome
CORTISOL
Pituitary adenomas
Ectopic ACTH sy
Adrenal tumors
Familial Cushings
Drug related
Cushings disease
24-hour urinary free cortisol level
Cushing's syndrome
TREATMENT
SURGERY
RADIATION
CHEMOTHERAPY
CORTISOL-INHIBITING DRUGS
Conn's syndrome
ALDOSTERONE
HYPERTENSION
BLOOD POTASSIUM
TIREDNESS
MUSCLE
WEAKNESS
POLYURIA
ADRENAL ADENOMA
Conn's syndrome
TREATMENT
SURGICAL REMOVAL
(UNILATERAL ADRENALECTOMY)
SPIRINOLACTONE
Addisons disease
WEIGHT LOSS
MUSCLE WEAKNESS
FATIGUE
LOW BLOOD PRESSURE
DARKENING OF SKIN
Addisons disease
PRIMARY
destruction of
adrenal cortex
- autoimmune
disorders
- tuberculosis
- chronic infection
CORTISOL
ALDOSTERONE
SECONDARY
Lack of ACTH
- drugs
- tumors and
infections of
pituitary gland
CORTISOL
Addisons disease
DIAGNOSIS
ACTH STIMULATION TEST

TREATMENT
REPLACEMENT THERAPY
CORTISOL
ALDOSTERONE
HYDROCORTISONE
FLUDROCORTISONE
Addisons disease
ADDISONIAN CRISIS
ACUTE ADRENAL INSUFFICIENCY
- SUDDEN PENETRATING PAIN IN LOWER BACK, ABDOMEN OR LEGS
- SEVERE VOMITING AND DIARRHEA, FOLLOWED BY DEHYDRATION

- LOW BLOOD PRESSURE
- LOSS OF CONSCIOUSNESS
- HYDROCORTISONE i.v.
- 0,9 % NaCl i.v.

- DEXTROSE
Aldosterone
Mineralocorticoid
Regulates concentration of Na+ and
K+.
Kidney conserves Na+.

Kidney excretes K+.
Responds to changes in composition

of plasma.
Regulated by renin-angiotensin
Regulation
of adrenal
gland
secretion
ACTH
Cortisol
Cortisol
Adrenal Dysfunction
Decrease function
Increase function
Cushing syndrome
Adrenal insufficiency
Low cortisol, aldestrone
Eg Addison disease
.
High Cortisol
Hyperaldosteronism
High aldestrone
Pheochromocytoma
High catecholamine
Causes of Adrenal
insufficiency
Congenital adrenal hyperplasia

Addison disease
Infection (TB, sepsis)
Adrenoleukodystrophy
Addison disease
Autoimmune
Isolated or associated with other
autoimmune disease
Presents with tiredness, weight loss,
skin pigmentation
Aldestrone & cortisol low, high ACTH,
high renin
Low sodium , high potasium
.
ACTH stimulation
test
Hyperpigmentation
A Color Atlas of Endocrinology p97
Primary Adrenal Insufficiency
Hyperpigmentation
Dehydration
Hypotension
Hyperkalemia
Hyponatremia
Hypoglycemia
Addisonian crisis
Life threatening complication

Severe vomiting and diarrhoea followed
by dehydration
Low blood pressure and shock
Hypoglycemia
Loss of consciousness
Treatment: IV fliuds+IV hydrocortisone
Trivia Question: Which famous

President had Addisons
Disease???
Congenital Adrenal
Hyperplasia
The first case was described in 1865
Family of inherited disorders of adrenal
steroidogenesis
Each disorder results from a deficiency of
one of several enzymes necessary for
steroid synthesis
Autosomal Recessive (M=F)
21-hydroxylase is the commonest form
Congenital Adrenal
Hyperplasia (CAH)
1) Example of genetic heterogeneity.

2) Natural quasi-experiment on the effects
of prenatal androgens on behavior.
Cholesterol
Ambiguous,no
androgens,saltwasting
desmolase
Pregnenolone
Ambiguous,low
androgens,hypertension
17hydroxylase
17Hydroxy
pregnenalone
3OH
dehydrogenase
Androgens
Virilized,high
androgens,lethal
17Hydroxy
progesterone
Virilized,high
androgens,saltwasting
21hydroxylase
11Deoxycortisol
Virilized,high
androgens,hypertension
11hydroxylase
Cortisol
HGSS:Carey:Figure5.2
Key:Genitalia, androgen level, medical symptom
21-Hydroxylase Deficiency: 21-OHD-CAH

Classic: No or very little enzyme activity (1/15,000 births)
Nonclassic: Low enzyme activity (1/100 births)
Feature:
Classical:
Non-classical:
Prenatal virilization:
Present in Females
Absent
Postnatal virilization:
Males & Females
Variable
Salt-wasting:
> 75% of cases
Absent
Cortisol Deficiency:
100%
Rare
Enzymatic Pathway for Cortisol and Aldosterone

(
: results of 21-ODH-CAH)
Virilized
Females:
Adult Virilized emale:
http://psych.unn.ac.uk/users/nick/hormonespp03/sld023.htm
Masculine
Feminine
Toy Preference
CAH
Girls
Control
Boys
CAH
B
o
y
s
Control
Girls
Based on Berenbaum & Hines (1992) for children and Berenbaum (1999) for
adolescents
Other Findings:
(1) No difference between CAH boys and control boys on
interest
patterns, personality, cognition, and sex orientation.
(2) CAH girls are more masculine in interest patterns than
control girls.
(3) CAH girls have more masculine personality traits: more
aggressive, less interested in infants, less maternal, and
less empathetic than control girls.
(4) CAH girls have higher spatial-visualization and spatial
orientation than control girls.
(5) Most CAH girls are heterosexual (c. 70%), but have a
higher rate of same-sex orientation than their sisters.
(6) Biggest difference between CAH and control girls is on
interest patterns.
Steroid biosynthetic
enzymes
1) Cholesterol side chain cleavage=scc
(20,22 desmolase)
2) 3-Hydoxysteroid dehydrogenase
3) 17 hydroxylase and 17,20 lyase
4) 21-Hydroxylase
5) 11-Hydroxylase
6) Aldosterone synthetase (11,18
hydroxylase & 18 oxidase
Congenital Adrenal
Hyperplasia
Congenital Adrenal
Hyperplasia
CAH due to 21-Hydroxylase

Deficiency
9095% of CAH cases are caused by 21OHD
Females affected with severe, classic 21OHD are exposed to excess androgens
prenatally and are born with virilized
external genitalia
Presentations of 21 HCAH
Ambiguous genitalia in girls

Dehydration
Shock
Salt-loss presentations with electrolytes
imbalance
Hyponatremia
Hyperkalaemia
Hypoglycemia
Hyperpigementations
AMBIGUOUS GENETALIA
BOYS WITH CAH

Are unrecognized at birth because their genitalia are normal.
Present early with salt wasting

crisis resulting in dehydration,
hypotension, hyponatremia and
hyperkalemia
Or present later in childhood with
early pubic hair, precocious
puberty and accelerated growth
Nonclassical CAH
Residual enzyme activity.
Non salt losing CAH
present late in childhood with
precocious pubic hair and/or
clitoromegaly and accelerated
growth.
Present in adolescence or
adulthood with varying virilizing

symptoms ranging from
oligomenorrhea to hirsutism and
Non classical
CAH
Diagnosis
Serum electrolytes & glucose
Low Na & high K

Fasting hypoglycemia
Elevated serum urea due to associated dehydration
Elevated plasma Renin & ACTH levels

Low Cortisol
High 17 OHP
High androgens especially testosterone level
Low Aldosterone
Urinary steroid profile
Chromosomes
Pelvic US
Management
Hydrocortisone
Fludrocortisone 0.05 - 0.2 mg/day
Triple hydrocortisone duiring stress.
During adrenal crisis intravenous
hydrocortisone and IV fliud
Surgey for female external genetalia
Newborn screening for

CAH
Neonatal screening by filter paper on
3rd day of life
17 Hydroxyprogestrone blood level
(17 OHP)
Causes, incidence, and risk factors

Congenital adrenal hyperplasiacan affect both boys and girls. People
with congenital adrenal hyperplasialack of an enzyme needed by the
adrenal gland to make the hormones cortisol and aldosterone.
Without these hormones, the body produces more androgen, a type of
male sex hormones. This causes early (or inappropriate) appearance of
male characteristics.
Newborn girls with this disorder have a swollen clitoris with the urethral
opening at the base (ambiguous genitalia, often appearing more male
than female). The internal structures of the female reproductive tract
(ovaries, uterus, and fallopian tubes) are normal. As the female grows
older, some features start to appear male, such as deepening of the
voice, facial hair, and failure to menstruate at puberty.
No obviousproblems are seen in newborn males, butchanges can be
seenlong before puberty normally occurs. The child becomes
increasingly muscular, the penis enlarges, pubic hair appears, and the
voice deepens. Boys may appear to enter puberty as early as 2-3 years
of age. At puberty, the testes are small.
Some forms of congenital adrenal hyperplasia are more severe and
cause adrenal crisis in the newborn due to salt wasting. In this salt-losing
form of congenital adrenal hyperplasia, newborns develop severe
symptoms shortly after birth, including vomiting, dehydration,
electrolyte changes, and cardiac arrhythmias. Untreated, this condition
Symptoms
In girls:
Ambiguous genitalia
Early appearance of pubic and armpit hair
Excessive hair growth
Deep voice
Abnormal menstrual periods
Failure to menstruate
In boys:
Early development of masculine characteristics
Well-developed musculature
Enlarged penis
Small testes
Early appearance of pubic and armpit hair
Both boys and girls will be tall as children but significantly
shorter than normal as adults
Complications
Adrenal crisis, including hyponatremia and shock (especially in
newborns)
Abnormal female external genitalia (internal organs are normal)
Early development of male sexual characteristics
Short adult stature despite early, rapid childhood growth
Tumors of the testes in adult men
High blood pressure
Low blood sugar
Side effects of corticosteroids used as treatment
Prevention
Genetic counseling is indicated for parents with a family history of
congenital adrenal hyperplasia (of any type) or a family with a child
who has the condition.
Prenatal diagnosis is available for some forms of congenital adrenal
hyperplasia. Diagnosis is made in the first trimester by chorionic
villus sampling and in the second trimester by measuring hormones
such as 17-hydroxyprogesterone in the amniotic fluid.
A newborn screening test is available for the most common form of
congenital adrenal hyperplasia and can be done on heelstick blood
(as part of the routine screenings done on newborns). This test is
not yet widely available.
Incidence and Clinical Presentation

CAH due to 21-hydroxylase deficiency is seen in roughly 1 of every
15,000 live births worldwide; it is a relatively common disorder in
humans. Clinically, it is seen in three primary manifestations:
Simple virilizing form: Excessive prenatal production of androgens in
affected females results in masculinization of the reproductive tract to
a point that the sex of the newborn is not clear ("ambiguous genitalia")
or appears male-like. Affected males are usually normal at birth. In
both sexes, linear growth in childhood is accelerated, but the
epiphyses fuse early, leading to short stature. The simple virilizing
form of CAH is seen in approximately 25% of those with 21hydroxylase deficiency.
Salt-wasting form: Roughly 75% patients are unable to synthesize
adequate amounts of aldosterone, which is essential for sodium
homeostasis. Such individuals lose large amounts of sodium in urine,
which leads to potentially fatal electrolyte and water imbalance.
Individuals with severe deficiency usually present with "adrenal crisis"
between 1 and 4 weeks of age; signs are often non-specific, but can
include poor appetite, vomiting and failure to grow. Replacement
therapy is mandatory in such patients.
Non-classical form: This form of the disease is mild and usually
manifest as some type of androgen excess later in life. Aldosterone
Genetics
The 21-hydroxylase enzyme is encoded by the CYP21 gene. More than
50 different mutations of CYP21 have been identified, of which about 15
account for a large majority of 21-hydroxylase cases. Most mutations
appear to be the result of a recombination between CYP21 and a
pseudogene (CYP21P). One consequence of this multitude of mutations
is that there is considerable variability in the clinical presentation of
disease, ranging from severe salt-wasting or virilizing disease to milder
syndromes. This disorder is seen as a simple autosomal recessive trait.
Diagnosis and Prenatal Screening
Most commonly, 21-hydroxylase deficiency is first suspected in a
newborn infant with "ambiguous genitalia". Finding elevated blood
levels of 17-hydroxyprogesterone, in conjuction with ultrasound
examination of the abdomen and genital tract usually leads to a rapid
diagnosis. Disorders that must be differentiated in such cases include
true hermaphorditism, pseudohermaphroditism and certain types of sex
chromosome abnormalities, none of which should have high
concentrations of 17-hydroxyprogesterone
Classical and nonclassical 21-OHD CAH are diagnosed by serum elevations of

the hormone 17-hydroxyprogesterone before and after a 60-minute
adrenocorticotropin (ACTH) stimulation test (Figure 3). Confirmation by
molecular genetic analysis of the CYP21 gene is advised.
Nomogram relating baseline to ACTH-stimulated serum concentrations of 17hydroxyprogesterone (17-OHP). The scales are logarithmic. A regression line
for all data points is shown.
Prenatal diagnosis : Prenatal diagnosis and treatment are available. Prenatal diagnosis is
done by analysis of fetal DNA obtained by amniocentesis or chorionic villus sampling (CVS).
Prenatal treatment with the drug dexamethasone prevents virilization of the genitalia of
classically affected females and must be started prior to the 9th week of pregnancy, as
outlined in the algorithm below (Figure 4).
Figure 4. Algorithm for prenatal diagnosis and treatment of CAH.
Treatment
All patients with CAH, regardless of form, are treated with
glucocorticoid replacment therapy. This not only alleviates
glucocorticoid (i.e. cortisol) deficiency, but more importantly, provides
negative feedback to suppress ACTH secretion and prevent continued
adrenal stimulation. As a result, excessive 17-hydroxyprogesterone is
not available as a substrate for excessive androgen production.
Patients with the salt-wasting form of deficiency must also receive
mineralocorticoid therapy to normalize the abnormalities in sodium
balance associated with aldosterone deficiency.
Prenatal treatment of the mother with glucocorticoids can prevent or
reduce that the virilizing effects of fetal 21-hydroxylase deficiency. This
procedure has been used in cases where couples have previously had a
child with virilizing CAH. In such cases, it is known that both parents are
carriers, and since only female children require prenatal treatment, the
probability that the current fetus is affected is 1 in 8. Treatment of the
mother with glucocorticoids must begin at 6 to 7 weeks of gestation, at
which time it is almost never known whether the fetus is affected.
Hence, in 7 of 8 cases, the fetus does not actually require therapy. The
long term effect and safety of this procedure is poorly defined
A number of surigical procedures have been developed to correct the
genital abnormalities of girls with the virilizing form of CAH. These
procedures are complicated by concerns about when the surgery
Deficiency
11 beta-hydroxylase
17 alpha-hydroxylase
3 beta-hydroxysteroid
dehydrogenase
aldosterone synthase
StAR
Incidence
Comments
~1 in 100,000 livebirths
Females virilized; saltwasting is rare
rare
Males virilized; females

fail to achieve puberty.
Salt-wasting not
observed.
rare
Males virilized; female

virilization mild. Saltwasting may be seen.
rare
Cortisol concentrations
normal and virilization not
seen. Salt-wasting
occurs.
rare
Males virilized; females

fail to achieve puberty.
Salt-wasting occurs.
Lipoid congenital adrenal hyperplasia

*Gene map locus 15q23-q24, 8p11.2
Adrenal hyperplasia I
Lipoid hyperplasia, congenital, of adrenal cortex with male pseudohermaphroditism
[Clinical features: complete absence of steroid hormone biosynthesis; male
pseudohermaphroditism; salt loss; hyperkalemic acidosis; dehydration]
[Inheritance: autosomal recessive]
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Congenital Lipoid Adrenal Hyperplasia Caused by
a Novel Splicing Mutation in the Gene for the St
eroidogenic Acute Regulatory Protein
Phenotypic Features Associated with Mutations in

Steroidogenic Acute Regulatory Protein
Phenotypic Features Associated with Mutations in

Steroidogenic Acute Regulatory Protein
Journal of Clinical Endocrinology and Metabolism
SCREENING
Infant females with CAH often come to medical attention because the
disorder causes affected females to exhibit recognizable genital
abnormalities and therefore receive prompt treatment for adrenal
failure and salt-wasting. However, newborn males and females that,
due to the extent of their genital abnormalities are miscast as males,
show no other outward signs of the disorder and are sent home.
Newborn screening allows for these children to be identified as
possibly having CAH before they go into adrenal crisis and present for
urgent medical attention at a time when they are beyond
resuscitation. A second diagnostic test then is ordered and the
diagnosis of CAH either confirmed or denied.
Current newborn testing is quite effective in identifying infants with
the severe form of CAH, Classical Salt-Wasting CAH. Some babies with
Simple Virilizing CAH also are detected through this process. It is rare
that a child with Non-classical or Late-onset CAH will be picked-up
through this type of testing. To learn more about Non-classical CAH
diagnosis, please visit our page on Genetic Testing.
The majority of infants detected through newborn screening have
Salt-wasting CAH.
SCREENING
Infant females with CAH often come to medical attention because the
disorder causes affected females to exhibit recognizable genital
abnormalities and therefore receive prompt treatment for adrenal
failure and salt-wasting. However, newborn males and females that,
due to the extent of their genital abnormalities are miscast as males,
show no other outward signs of the disorder and are sent home.
Newborn screening allows for these children to be identified as
possibly having CAH before they go into adrenal crisis and present for
urgent medical attention at a time when they are beyond
resuscitation. A second diagnostic test then is ordered and the
diagnosis of CAH either confirmed or denied.
Current newborn testing is quite effective in identifying infants with
the severe form of CAH, Classical Salt-Wasting CAH. Some babies with
Simple Virilizing CAH also are detected through this process. It is rare
that a child with Non-classical or Late-onset CAH will be picked-up
through this type of testing. To learn more about Non-classical CAH
diagnosis, please visit our page on Genetic Testing.
The majority of infants detected through newborn screening have
Salt-wasting CAH.
Genetic Testing for CAH

The polymerase chain reaction (PCR) is a common method used for
genetic testing that can tell one gene apart from another. PCR can be
thought of as a "genetic Xerox machine." By using PCR, the laboratory
can make up to a million copies of a specific gene or piece of a gene
from a DNA sample for studies.
Some laboratories use a technique called a Southern blot. In this
method, extracted DNA is cut at specific sites near or within the gene
and pseudogene. A specially made piece of DNA, referred to as a probe,
is used to detect the specific DNA pattern of the gene and pseudogene.
A Southern blot will usually find large gene deletions and
rearrangements. After a lab performs a Southern blot, it will also need to
perform PCR and some other method, like sequencing, in order to find
those smaller changes.
PCR can also be used to distinguish the pseudogene and functional
gene, and in most cases can determine the number of functional genes
and pseudogenes a person has in their DNA without using the Southern
blot technique. Unique landmarks outside the gene and pseudogene are
used to separately copy and identify the gene, the pseudogene, as well
as any rearranged copies of the gene and pseudogene that might be
present.
In families where the diagnosis of CAH due to 21-hydroxylase

deficiency has been proven but a mutation cannot be identified,
another test called linkage can be used to determine if a relative
has the mutation or if a pregnancy is affected. Linkage cannot be
performed without testing multiple family members. At least both
parents must be tested, as well as a previously born affected child.
Unique genetic landmarks either within the gene or pseudogene, or
close to, or "linked" to the CYP21A2 gene are used to identify and
follow copies of the mutated gene causing CAH from generation to
generation without actually knowing the exact mutation involved.
Sequencing small areas of the pseudogene and functional gene can
provide good genetic information for linkage analysis. Linkage can
be used to predict whether or not a subsequent child will be
affected with a high degree of accuracy. Because linkage does not
test for the actual mutation, however, there is a small risk that the
linked genetic landmark will become unlinked and thus an incorrect
result will be obtained.
Who Might Consider Genetic Testing?

Genetic testing can be used to confirm the diagnosis of CAH and
identify the mutations present in a person who is suspected of having
classic or non-classic CAH. For example, genetic testing can help
confirm the diagnosis in infants that have a positive newborn screen
for CAH. Adults with suspected CAH due to infertility problems or
women who have symptoms of androgen excess might also have
their diagnosis confirmed through genetic testing.
Parents of a child with CAH may want to know the genetic alterations
present in their affected child. This information can be used, early in
pregnancy, to determine whether a subsequent child has CAH by
testing the baby through amniocentesis or chorionic villus sampling.
The information could help direct prenatal treatment with
dexamethasone or help families and doctors anticipate and prepare
for the birth of an affected child. Genetic information can also be
used for preimplantation genetic diagnosis in future pregnancies in
order to significantly reduce the chance of a having another child
affected with CAH
Genetic testing can also be used to screen an unaffected person who

has no family history of CAH to determine if they carry CAH. This can
be especially useful for the partners of individuals who are either
affected by CAH, or are known carriers of CAH, for the purpose of
family planning and pregnancy management. If both members of a
couple are known carriers, they can consider the option of starting
dexamethasone treatment early in the pregnancy which would
reduce the degree of masculinization of the female genitalia in an
affected female infant.
For couples that have no known personal or family history of CAH,
but are currently pregnant with a female fetus that has ambiguous
genitalia detected by prenatal ultrasound, genetic testing for CAH
may be appropriate after other causes have been ruled out. The
advance knowledge can help the family and physicians prepare for
the medical, social and emotional issues related to the diagnosis and
birth of an affected child.
Prenatal Testing for CAH

Prenatal testing can be performed by two methods. Chorionic villus
sampling (CVS) is a procedure that obtains fetal cells by sampling
cells from the developing placenta. The procedure is usually done
with ultrasound guidance to see the physical structures of the patient
and fetus. CVS is typically offered at 10-12 weeks from the last
known menstrual period. As with any prenatal procedure, CVS carries
with it a small risk of miscarriage. The advantage of CVS is that the
procedure takes place in the first trimester and genetic test results
can be obtained early in the pregnancy.
The cells obtained are taken to a laboratory and grown so that the
DNA can ultimately be obtained and tested.
Prenatal Testing for CAH

The cells obtained are taken to a laboratory and grown so that the
DNA can ultimately be obtained and tested.
Amniocentesis is another technique that can be used to obtain a
sample of fetal cells for genetic testing. This method is typically
performed at 15-20 weeks from the last menstrual period. This
procedure requires that a thin needle is passed through the
abdomen, under ultrasound guidance, into the fluid filled sac that
surrounds the fetus. A few tablespoons of the fluid are taken from the
sac. This fluid contains cells from the baby that are then grown in a
laboratory. As is the case with CVS, amniocentesis is not a risk-free
procedure. With amniocentesis, there is a small risk of about 1 in 200
that the procedure will cause a miscarriage. The risks and benefits
must be taken into consideration when considering prenatal testing.
Your doctor and genetic counselor are good resources for additional
information regarding these procedures.
Treatment
Research has shown Congenital Adrenal Hyperplasia to be a spectrum
disease. That is, a condition that manifests itself in varying degrees: the
severe form being Classical Salt-wasting CAH and the mild form being Nonclassical CAH with Simple-Virilizing CAH somewhere in between. In all
cases, however, CAH is caused by an adrenal insufficiency resulting in
impaired production of hormones.
All individuals affected by Classical CAH require glucocorticoid
(hydrocortisone, prednisone, dexamethasone) replacement therapy. Those
with a salt-wasting component to their insufficiency also require
mineralocorticoids (fludrocortisone and sodium). The following pages
outline medication dose guidelines for all individuals with CAH as agreed
upon by the leading pediatric endocrinologists in the United States and
Europe in 2002.
As always, this information is provided for your reference to help you better
understand decisions made regarding medication dosing and in no way
should be taken to be the provision or practice of medical, nursing or
professional healthcare advice or services. This information should not
be considered complete or exhaustive and should not be used in
place of the visit, call, consultation or advice of your physician or
other healthcare provider.
Dosing of Medications - from the Joint LWPES/ESPE

2002 CAH Consensus Statement (pages 4050-51, footnotes
omitted):
Optimal Glucocorticoids Dosing. During infancy, initial reduction of
markedly elevated adrenal sex hormones may require up to 25 mg
hydrocortisone (HC)/m 2 .d, but typical dosing is 10-15 mg/m 2.d
divided three times daily. HC oral suspension is not recommended;
divided or crushed tablets of HC should be used in growing
children. ...HC is considered the first drug of choice. Excessive doses,
especially during infancy, may causes persistent growth suppression,
obesity and other Cushingoid features. Insufficient data exist to
recommend higher morning or evening dosages.
Whereas HC is preferred during infancy and childhood, long-acting
glucocorticoids may be an option at or near completion of linear
growth. Prednisone and prednisolone need to be given twice daily.
The dose (2-4 mg/m 2.d) should be approximately one-fifth the dose
of HC. The dosage of Dexamethasone is 0.25-0.375 mg/m 2.d, given
once daily. Monitoring of these more potent glucocorticoids should
include BP, in addition to weight, and other clinical and laboratory
variables. These steroids have minimal mineralocorticoid effect,
compared with HC. In children with advanced bone age, such as boys
with non-salt losing CAH, initiation of therapy may precipitate central
precocious puberty, requiring treatment with a GnRH agonist.
Mineralocorticoid use. All classic CAH patients should be treated

with fludrocortisone at diagnosis in the newborn period. Dosage
requirements in early infancy range from 0.05-0.30 mg/d, whereas
typical maintenance doses are 0.05-0.2 mg/d, depending on the
sodium intake.Sodium chloride supplements are often needed in
infancy at 1-3gm/d(17-51mEq/d), distributed in several feedings.
body surface area calculator for medications
Although it may seem that monitoring and testing in CAH is

confusing, there are several approaches that can be used to
adequately assess hormone production. It is also very important to
emphasize that monitoring changes in physical growth and
maturation is as important, if not more important, as the
laboratory testing in CAH.
Growth & Bone Density
Monitoring growth and maturation in CAH.
Growth and weight: The rate of growth provides very important
clues about treatment in CAH. In general, with proper treatment
the child with CAH should grow along the same percentile for
height, which reflects the height of the parents.
Between two years of age and puberty, the average child grows
about 2-1/2 inches per year and gains 2-3 pounds for every inch of
height gain. During infancy and puberty, rates of growth are even
faster than during childhood. In general, a child will usually grow
along the same percentile on growth charts from infancy though
adolescence. Thus, height and weight need to be both monitored
and plotted on standard growth charts to assess growth in CAH.
Looking at growth charts and following changes in height and

weight, one can detect signs of over- and undertreatment. If
glucocorticoid (hydrocortisone, prednisone, dexamethasone) doses
are too high, growth will slow and weight will increase. It takes
about 3-6 months to appreciate changes in growth rates (changes
in height). Changes in weight, though, can be seen much sooner.
Increases in weight, above and beyond that which are normally
expected (more than 3 lbs per inch of growth; more than 7 lbs per
year), can be a sign of overtreatment. Thus, it is very useful for
families to monitor weight at home. For example, if the weight
increases by more than one pound over 2-4 weeks after a dose
change, it may be a sign that the dose is too high.
Whereas slowing of growth can represent signs of overtreatment,
increased growth can reflect undertreatment. With
undertreatment, there is increased androgen production, which
can stimulate growth. Undertreated children may therefore climb
to higher height percentiles on growth charts.
The importance of regular follow-up

To assess physical changes in CAH and be able to respond to signs of
over- or undertreatment in a timely manner, many practitioners will
see individuals with CAH every 3-4 months. Because signs of overtreatment (facial roundness) can be subtle, it is preferable to see the
same practitioner at each visit.
There are physical signs that clinicians can see that suggest either
over- or undertreatment. With overtreatment, the face can become
round. With significant overtreatment, striae (purple "stretch-marks")
can occur. Features of undertreatment include dark or "dirty"-looking
knuckles caused by excessive ACTH secretion. Stomach pain and
being excessively tired are also symptoms of undertreatment.
The blood pressure can provide clues about mineralocorticoid
(Florinef, fludrocortisone) treatment. If the blood pressure is elevated,
this may indicate that the mineralocorticoid dose or salt
supplementation is too high and should be reduced. Yet, if the dose is
normal or too low, the blood pressure is normal.
Signs of pubertal development are also monitored. In girls, one of the
earliest signs of puberty is breast development. In boys, enlargement
of the size of the testes is the earliest signs that puberty has started.
If puberty begins less than seven years of age in girls and less than
nine years of age in boys, it is said to be early or "precocious".
Because the adrenal hormones can affect the pituitary gland,
The Usefulness of Bone Ages

One of the best tools for monitoring changes in physical maturation is
the "bone age". The growth centers, which can be easily visualized
with an x-ray of the hand, provide a wonderful marker of long-term
androgen secretion. As children get older, the shape of the growth
centers change and have characteristic appearances at each age. By
comparing the size and shapes of the growth centers in the child's
hand to those found in a book of standards, a "bone age" can be
determined. Because there is variability from practitioner to
practitioner in bone age interpretation, it is useful to have bone ages
interpreted by the same individual. Also, some pediatric
endocrinologists may be more experienced in interpreting bone ages
than general radiologists.
When there is excessive androgen secretion, the skeleton matures at
a more rapid pace than usual. This will result in an advanced bone
age. Thus, an undertreated child at 6 years of age may have a bone
age of 9 years of age. Yet, if the bone age is within a year or so of the
actual age, this suggests that treatment has been fine.
The bone age also reflects hormone secretion over the preceding 612 months. Changes in the bone age may lag behind recent periods
of excess androgen secretion. Many practitioners therefore obtain
bone ages every 6 to 12 months.
Laboratory Testing
Monitoring of Hormone Levels in CAH
The levels of adrenal hormones in the blood vary over the 24-hour
day. Cortisol and androgen production is highest in the morning and
lowest in the afternoon and evening. Hormone levels are also
affected by medications. Following a dose of glucocorticoids,
androgen levels will fall. Yet, as the medication wears off, hormone
levels may rise excessively. Care must be taken to consider the time
of day and the timing of doses when interpreting hormone levels.
There are several different approaches that can be used to assess
adrenal hormone production. Urine testing is a "gold standard" and
can be used to measure hormone production throughout the day.
Blood testing provides important information about hormone
production and is preferred by many clinicians due to convenience.
Testing of hormone levels several times a day using filter paper
specimens has also been shown to be an effective monitoring tool,
but is not widely available.
Laboratory Testing
Blood Testing
Assessing control from a single blood test is very commonly used due
to its convenience. However, a single test may not always reflect if
there is adequate control of adrenal gland activity. One also needs to
consider the time of day and the timing of doses in interpreting blood
levels. Some hormone levels are also better than others in assessing
treatment.
A number of hormones that reflect adrenal gland activity can be
measured in the blood. These factors include ACTH, 17
hydroxyprogesterone (17 OHP), androstenedione, and testosterone.
Electrolytes and renin are used to assess mineralocorticoid
replacement.
Of these different hormones, androstenedione and testosterone most
closely match 24-hour 17 KS production and reflect adrenal androgen
production. These hormones are especially useful in prepubertal
children and females. Because testosterone levels rise in puberty in
males, testosterone levels are not as useful in adolescent or adult
males. In comparison with androstenedione and testosterone, 17 OHP
levels can fluctuate widely and may be elevated even when there is
good control. The pituitary hormone ACTH has been shown to provide
a nice measure of control and is elevated 75% of the time when there
Laboratory Testing
Blood Testing
For children without CAH and who are not in puberty, average levels
of androstenedione are 25 ng/dl, average levels of testosterone levels
are 5 ng/dl, and average 17OHP levels are 50 ng/dl. During puberty,
levels of these hormones rise. It is possible to achieve normal levels
of these hormones in children with CAH. Yet, treating CAH to
"normalize" all hormone levels, especially 17 OHP levels, can result in
growth suppression and weight gain. Thus, many clinicians aim for
androstenedione and testosterone levels that are normal or modestly
(about 25%) above normal. Because 17 OHP levels can fluctuate
widely and be elevated when there is adequate treatment, some
clinicians will accept mid-day 17 OHP levels of 500-1000 ng/dl; others
will aim for lower levels.
Morning levels of 17 OHP, androstenedione, and testosterone are
much higher than mid-day levels, especially when there is
undertreatment. This occurrence reflects the general observation that
adrenal glands become more active in the early morning hours and at
a time when the medication from the day before is wearing off. It can
therefore be very useful to obtain morning hormone levels.
It has been recently shown that when there is good control of adrenal
gland activity, 17 OHP levels are less than less than 600 ng/dl in the
morning before medication is given and less than 200 ng/dl during
Laboratory Testing
Blood Testing
To measure if the child is getting enough salt and/or fludrocortisone,
renin and electrolyte levels are measured. An elevated renin levels
indicates a need for more salt and/or fludrocortisone. A suppressed
renin suggests that the dose of salt and/or fludrocortisone is too high.
Filter Paper Specimens
Whereas a single blood test during the day can provide important
insights into CAH control, they can sometimes be misleading. If a
sample is obtained in an undertreated child a few hours after a dose
of hydrocortisone has been given, levels of 17OHP can decrease. As
the medication wears off, 17 OHP levels can increase dramatically.
One can overcome potential pitfalls of obtaining once daily samples
by obtaining filter-paper specimens over the course of the day.
Children with diabetes check their blood sugar by finger stick 3-4
times a day to be able to properly dose insulin levels. Similarly, one
can measure 17 OHP levels on filter paper specimens taken at
different times of day. Thus, one can identify times of day when levels
are high and others when levels are low and adjust doses accordingly.
Filter paper 17OHP levels can be measured by state laboratories that
perform newborn screening for CAH using filter-paper specimens.
Hormone Prepubertal Mid-Pubertal Pubertal and adult

Blood testing
ACTH (pg/ml) 30 (10-60)30 (10-60)30 (10-60)
Androstenedione(ng/dl)25 (8-50)70 (50-100)115 (70-200)
17 OHP (ng/dl)40 (3-100) 80 (10-150)100 (25-250)T
estosterone (ng/dl)5 (3-10)
Males:150 (100-300)600 (300-1000)
Female: 25 (15-35) 30 (10-55)Urine testing
17 Ketosteroids (mg/24 hr) 1.5 (0.2- 3) Males 5 (3-10) 15 (10-25)
Female 3.5 (2.5-8) 10 (6-14)
Pregnanetriol (mg/24 hr) 0.5 1.0 2.0
-In CAH, levels of androstenedione, testosterone and 17 ketosteroids
that are normal or modestly (about 25%) above normal are
acceptable. Because blood 17 OHP levels can vary widely in CAH,
higher 17 OHP levels are acceptable, but are usually less than 1000
ng/dl with adequate treatment.
-To convert ng/dl units to pmol/L, multiply androstenedione levels by
34, 17 OHP by 30, testosterone by 34.
CARES strongly recommends that no surgery be done until:

1) the child is medically stable;
2) the parents are fully informed of the risks and benefits;
and
3) an expert surgeon is found.
Ultimately, the decision about whether and when to perform
surgery is intensely personal. Whatever you choose, you must be
comfortable and confident in your decision and your choice of
surgeon. Below are some frequently asked questions that may help
guide you through the decision-making process.
How different are our daughters genitals from other female

children?
Your daughter may look different, but she has all of the female
reproductive organs. She has a uterus, vagina and ovaries. She will be
able to bear children. The degree of virilization (masculinization)
affecting your daughter will be can be graded on a classification
known as the Prader Scale. Your daughters pediatric urologist or
pediatric endocrinologist will be able to tell you what Prader Level she
is.
Typical Prader 4
What is the Prader Scale and what are the Prader Scale
levels?
The Prader Scale is a scoring system for grading the degrees of
genital masculinization. The Prader Scale starts at 0, which is
an unvirilized female, and ends at 5 which is a completely
virilized female (a female who appears externally male at birth
with the labial/scrotal sac empty since there are no testicles). The
picture below shows the Prader Virilization Scores.
(From Speiser and White; Congenital Adrenal Hyperplasia due to
21-Hydroxylase Deficiency; Endocrine Reviews 21(3): 245-291;
2000)
When should surgery be performed?

The decision of when to have surgery can be one of the hardest.
How can we be sure that we are doing the right thing? There is
no right decision. There is only what is right for you and your
daughter. Gather as much information as you can, and work to
make the best decision you can.
The 2002 CAH Consensus Statement states, [b]ased on recent
clinical experience, the recommended time for surgery is at 2-6
months, although this is not universal practice. It is important to
note that surgery at this stage is technically easier than at later
stages. Technically easier, refers to how easy it is for the
surgeon and to the benefits of faster healing in babies. Very
young children tend to heal faster following surgery, and the
surgery is easier because the area disturbed is smaller. Also,
following surgery, babies not yet walking, crawling or standing
are less likely to pull stitches out with their movement.
How do Adult Women with CAH Feel about the Timing of
Surgery?
Some adult women with CAH recommend that parents wait and
allow the child to make the decision as an adult. Some adult
women with CAH recommend that parents wait until the child is
old enough to be consulted about her desires for surgical
reconstruction. Others are grateful that their parents made the
What are the differences among reduction clitoroplasty,

vaginoplasty and labioplasty?
Genital reconstruction in CAH generally involves three separate
procedures. These are often done at the same time when early
surgery is chosen.
Clitoral reduction surgery (clitoroplasty) involves reducing the size of
the clitoris by removing a portion of the erectile tissue. If done
properly, the nerve bundles are preserved and left intact. The CAH
Consensus Statement states that, [s]urgery to reduce the clitoral size
requires careful consideration. Total removal of the clitoris should
never be performed. If clitoral reduction is elected, it is crucial to
preserve the neurovascular bundle, the glans, and the preputial skin
related to the glans.
Vaginoplasty involves rebuilding the vaginal area to improve
functioning of the vagina and urethra. This involves creating a vaginal
opening on the perineum separate from the urethra. It is often done
by moving the recessed vagina out to the perineum or can include
complete separation of the vagina from urethra at the site of
confluence.
Confluence in CAH: where the urethra and vagina meet.

(courtesy RC Rink)
Labioplasty is the construction of the labia majora and/or
minora when absent or inadequate. Most children with CAH are
lacking labia minora so they are created. The labia majora ,
while present often require repositioning.
The Consensus Statement on Management of Intersex Disorders

(Hughes, et als, 2006), states:
The surgeon has a responsibility to outline the surgical sequence
and subsequent consequences from infancy to adulthood. Only
surgeons with expertise in the care of children and specific training
in the surgery of DSD should perform these procedures. Parents now
appear to be less inclined to choose surgery for less severe
clitoromegaly. Surgery should only be considered in cases of severe
virilization (Prader III, IV and V) and be performed in conjunction,
when appropriate, with repair of the common urogenital sinus. As
orgasmic function and erectile sensation may be disturbed by
clitoral surgery, the surgical procedure should be anatomically
based to preserve erectile function and the innervation of the
clitoris. Emphasis is on functional outcome, rather than a strictly
cosmetic appearance. It is generally felt that surgery that is
performed for cosmetic reasons in the first year of life relieves
parental distress and improves attachment between the child and
the parents. The systematic evidence for this belief is lacking.
Hence, clitoroplasty should not be performed on mildly virilized girls
those whose virilization is below Prader 3.
When is vaginoplasty appropriate?

When the vagina, because of internal fusion with the urethra
(common urogenital sinus), does not extend all the way to the
perineum (the front of the body), urine may pool in the vagina or
backflow into the bladder where it can cause infection and
discomfort. In addition, in some girls, the common urogenital sinus
may be inadequate for the flow of menstrual blood. Therefore,
vaginoplasty is often performed in these girls to avoid backup of the
menstrual flow, discomfort and possible infections.
Possible Backflow Problems (courtesy RC Rink)
How will my daughter look after the surgery?

First ask to see some pictures of the surgeons work. They will be
happy to show you. Please remember that directly after the surgery
the area will appear swollen and bruised as would any surgical site
of the body. The actual results will not be seen for about six months
when the swelling and bruising subside. There may be some exterior
scarring, but an experienced surgeon should deliver a good cosmetic
result. Functional results (loss of sexual sensation) will not be known
until the girl is much older.
What has been the outcome of previous surgeries?
There are many female adults living with CAH and the consequences
of genital surgeries. Unfortunately, there have been few studies that
look at long-term follow-up of CAH reconstructive surgery. Also, the
techniques for performing both clitoroplasty and vaginoplasty have
improved significantly over the years, resulting in better functional
and cosmetic results. In the past, techniques used did cause
significant problems for women with CAH.
COMPLICATII INCLUZII TESTICULARE DE

TESUT ADRENAL
Weight Management for Children with CAH

by Michelle May, MD
Hot from the headlines: Obesity has reached epidemic
proportions in our society, fast approaching smoking as the
leading cause of preventable disease and death. Although this is
a frightening statement, obesity can be prevented.
Prevention of obesity and the development of lifetime healthy
eating habits begins in childhood. Currently, 15 percent of
children and adolescents are overweight or obese, putting them
at risk for high cholesterol, high blood pressure, and type 2
diabetes. They may also face social stigmatization, have low selfesteem, and face an increased chance of adult obesity.
Children with CAH are particularly at risk for weight problems due
to the bodys reaction to glucocorticoid therapy. Some children
complain of increased appetite with medication increases, and
oversuppression can cause excess weight gain. Even once the
oversuppression is eliminated, excess weight may still continue
to be a problem.
Weight Management for Children with CAH

by Michelle May, MD
Children with CAH are particularly at risk for weight problems due
to the bodys reaction to glucocorticoid therapy. Some children
complain of increased appetite with medication increases, and
oversuppression can cause excess weight gain. Even once the
oversuppression is eliminated, excess weight may still continue
to be a problem.
So what can you do? Consult your childs endocrinologist and
primary care physician to discuss whether your child is
significantly overweight. Then, determine if there are medical
issues contributing to their weight problems (such as
oversuppression), or if their weight is causing any medical
problems. Then together, you can determine the best approach
for helping your child reach a healthier weight.
Many overweight children do not actually need to lose weight,
but instead, can maintain their weight while they "grow into it."
Even for extremely overweight children, weight loss should be
gradual. Since many overweight children are still growing, their
diet must be nutritious and their exercise program should be safe
and enjoyable.
Build Healthy Attitudes

Demonstrate your unconditional love for your child. Children
especially overweight childrenneed support, acceptance, and
encouragement from their parents.
Build self-esteem by focusing on all of your childs positive
qualities, unique talents, and individuality. By developing
interests and skills that increase their success and pleasure, they
will be less likely to turn to food for fulfillment.
Help your child develop good communication skills, encourage
them to express their feelings, and teach them effective coping
skills to decrease the chance that food will serve that purpose.
Emphasize the importance of good health, not ideal weight.
Never tease or criticize a child or adolescent about their weight.
Such comments are hurtful and can stick with a person for a
lifetime.
Be a positive role model. When your child observes you enjoying
healthful foods and physical activity, they are more likely to do
the same.
Develop Healthy Eating Habits

Children have the ability to regulate their caloric intake to meet their
needs. Respect these internal cues of hunger and satisfaction.
Do not force children to clean their plates or bribe them with dessert
for finishing their meal.
Never use food as a reward. Reward desired behavior with praise,
extra attention, and privileges.
Do not comfort your child with food.
Do not impose stringent food rules, since this may lead to rebellious
eating when the child is away from parental control.
Dont say or imply that some foods are "good" while others are "bad."
Instead, teach children that some foods are healthier than others. This
will help them learn to balance eating for health with eating for
pleasure.
Involve children in shopping, meal planning, and preparation. This is a
great opportunity to teach them about nutritionand they will be more
likely to try new foods if they helped make them!
Develop Healthy Eating Habits

Since children (and adults!) have a natural preference for sweet and
high fat foods, its reasonable to limit the amount of sugary and fatty
foods that are readily available to encourage intake of more nutrient
dense foods.
Provide a variety of delicious healthy choices for snacks and
mealtimes. Suggestions include fresh or dried fruits, vegetables with
tasty low fat dips, pretzels, reduced fat cheese or peanut butter and
crackers, yogurt, fruit smoothies, whole fruit ice pops, granola bars,
turkey roll-ups, or snack mixes made of cereal, dried fruit, and nuts.
A healthy breakfast is a great way to start the day and is important for
achieving and maintaining a healthy weight.
Encourage children to drink water and fat free or low fat milk instead
of sugary sodas, fruit drinks, and sports drinks.
Promote a high fiber diet by giving your child whole wheat breads and
pastas, brown rice, and five servings of fruits and vegetables daily.
They will prefer these types of foods if that is what they are used to.
Perhaps most importantly, sit down and eat together as a family.
Mealtimes should be a pleasant time to reconnect with one another.
Enjoy an Active Lifestyle

Help your child build a lifetime exercise habit by making consistent
physical activity a high priority in your family.
For children that have been relatively inactive, an exercise program
should be initiated very gradually to avoid injury and discouragement.
Encourage active play like biking, swimming, and playing ball.
Participation in individual and team sports can be a great way to build
coordination, athletic skills, and self-confidence.
Reduce the amount of time your family spends in sedentary activities
like TV and video games. Instead, plan fun family activities that
provide everyone with exercise and enjoyment.
While management of weight problems in childhood can be difficult,
the benefits can last a lifetime!
Ehrhardt (1975) studied 17 female CAH patients: age 4.3

to 19.9 years,
CAH appears to have a significant effect on gender role

behaviours. Patients exhibit significantly more male-typical
behaviours than unaffected siblings.
Money, Schwartz & Lewis (1984) asked 30 women born with CAH
about their sexual orientation. Their replies are shown in this
diagram together with an estimate of the base rate of female
homosexuality according to Kinsey 1953. See Carlson for further
details.
40% of CAH patients were exclusively heterosexual
37% were bisexual or homosexual
Zucker et al (1996) review eight studies that have explored sexual
orientation in women with CAH.
Zucker et al (1996) found that most women with CAH have a female
gender identity. However, significantly more women with CAH live
as men than would be expected by chance
4. Metabolic Syndrome Manifestations in Classic Congenital

Adrenal Hyperplasia (Evangelia Charmandari, George P. Chrousos)
Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase
deficiency is an autosomal recessive disorder characterized by
impaired adrenocortical and adrenomedullary function, and adrenal
hyperandrogenism. Compared to normal subjects, patients with
classic CAH have increased incidence of obesity and visceral
adiposity, hyperinsulinism and insulin insensitivity, hypertension and
hyperandrogenism. The impaired adrenomedullary function,
intermittent hypercortisolism, and adrenal and/or ovarian
hyperandrogenism in the not adequately controlled patients and
females with polycystic ovarian syndrome, may account for the above
abnormalities and may predispose these subjects to the development
of metabolic syndrome-related atherosclerotic cardiovascular disease
in adulthood. The aim of the present study is to investigate whether
treatment with insulin sensitizers improves the metabolic profile of
patients with classic CAH.
BMD si CAH
Adrenal Cortex Hormone Synthesis
There is
enzyme
deficienc
y
In CAH???
What is Congenital Adrenal

Hyperplasia (CAH)?
Congenital Adrenal Hyperplasia (CAH) is a family
of inherited disorders affecting the adrenal

glands.
Autosomal recessive (mutation of chromosome
6 21-hydroxylase enzyme impairment)
Commoner in consanguineous marriage
Types of CAH
1. 21-hydroxylase deficiency (>90%)
Classical - salt wasting(75%; 1 in 15,000)
- simple virilizing (25%; 1 in 60,000)
Nonclassic (1 in 1,000)
2. Others :
. 11-hydroxylase deficiency(3-5 %, 1 in 100,000)
. 17-hydroxylase deficiency / C 17 lyase deficiency
(1%)
. 3 -hydroxysteroid dehydrogenase deficiency(1%)
CAH due to 21-OH

deficiency
Classic salt
Classic simple
wasting
Nonclassic
virilizing
Males
Females
Males
Females
Age at dx
Birth-6mo
Birth-1mo
2-4 yr
Birth-2yr
External
genitalia
Normal
Ambiguou
s
Normal
Ambiguou
s
Males
Females
Child to adult
Normal
Usually
normal;
may have
clitoromeg
aly
Aldosteron
e
Low
Normal
Normal
Cortisol
Low
Low
Normal
17-OHP
Basal>20,000 ng/dL
Basal> 10,000 20,000

ng/dL
ACTH stimulated 1,500

10,000 ng/dL
% of
normal 21OH activity
1-2
20-50
Pediatrics Endocrinology, Mechanisms, Manifestations and

Management, Ora H. Pescovitz, Erica A. Eugster, 2004 by
Lippincott Williams & Wilkins.
Clinical Manifestation
Cortisol deficiency hypoglycemia, inability to withstand
stress, vasomotor collapse, hyperpigmentation, apneic spells,
muscle weakness & fatigue.
Aldosterone deficiency hyponatremia, hyperkalemia,
vomiting, urinary sodium wasting, salt craving, acidosis, failure
to thrive, volume depletion, hypotension, dehydration, shock,
diarrhea.
Androgen excess ambiguous genitalia, virilization of
external genitalia , hirsutism, early appearance of pubic hair,
penile enlargement , excessive height gain and skeletal
advance.
*Late onset CAH normal genitalia, have acne, hirsutism,
irregular menses/amenorrhea.
Investigation
Karyotyping (determine sex
chromosome)
Abdominal Ultrasound to detect
presence of uterus, cervix and
vagina.
Serum 17-hydroxyprogesterone
17-OHP
Classic
Basal>20,000 ng/dL
salt
wasting
Diagnosis
Basal> 10,000
Classic simple
virilizing 20,000 ng/dL
Biochemical diagnostic studies:

- elevated serum 17-OHP (0.25mg IV bolus of ACTH after
60min) 100,00
0
ACTH
stimulated
10,000
1,000
10
0
0
10
0
1,000
Basal 17-OHP,
ng/dL
10,000
100,00
0
Management
Glucocorticoids (oral hydrocortisone etc.) 13-18 mg/m/24hr in 3 divided
doses.
Monitoring: serum concentration of adrenal precursors (17-OHP) & linear
growth and skeletal age assessment.
*During stressful state ie febrile ilnesses or surgery, 3x higher dose.
*In severe emergency: intramuscular SC glucocorticoid (Solu-Cortef)
Mineralocorticoid therapy (fludrocortisone) at a dose of 0.1-0.2 mg/24hr

+ sodium chloride supplement 1-2g daily.
Monitoring: serum sodium & potassium, plasma renin activity levels.
Surgical correction of ambiguous genitalia by 1-2 y/o normal

development of gender identity.
CYP21 genotyping can be performed

in a family with history of CAH.
Treatment with dexamethasone to
suppress fetal ACTH-induced
androgen production can
reduce/eliminate ambiguity of
external genitalia in affected female
fetuses.
Complications
Females suboptimal breast
enlargement, late menarche,
amenorrhea, irregular menses,
*reduced insulin sensitivity, PCOS
Males oligospermia, testicular

tumor
Adrenal Crisis
important to recognize because of its potentially life-threatening
implications
when the adrenal is prevented from producing normal amounts of
its vital hormones
Symptoms and signs of adrenal crisis are varied and nonspecific.
In infancy these include lethargy, vomiting, poor appetite and
failure to thrive.
In older children chronic fatigue, headache, gastrointestinal
symptoms, salt-craving and excess skin pigmentation may be
noted.
the underlying problems include low blood sugar, low blood
sodium, dehydration, low blood pressure, all predisposing the
individual to heart failure and shock (collapse).
Cushings syndrome
Cushings Syndrome
Results from increased adrenocortical
secretion of cortisol
Causes include:
ACTH-secreting tumor of the pituitary
(Cushings disease)
excess secretion of cortisol by a
neoplasm within the adrenal cortex
ectopic secretion of ACTH by a malignant
growth outside the adrenal gland
excessive or prolonged administration of
steroids
Cushings syndrome
Cushings Syndrome
Characterized by:
truncal obesity
moon face
buffalo hump
acne, hirsutism
abdominal striae
hypertension
psychiatric disturbances
osteoporosis
Amenorrhea
Diabetes
Frequency of signs and

symptoms in Cushings
syndrome Occurrence
Sign
or
symptom
Sign
or
symptom
Occurrence
%
Central obesity
94
Easy bruisability
60
Hypertension
82
Osteoporosis
60
Glucose intolerance
80
Personality
changes
55
Hirsutism
75
Acne
50
Amenorrhea or impotency
75
Edema
50
Purple striae
65
Headache
40
Plethoric faces
60
Poor wound healing
40
Pre treatment
Post treatment
Treatment of Cushings
syndrome
Treatment of underline cause
Surgery for neoplasia
ACTH
Steroid Biosynthesis
Cholestero
l
StAR, 20,22desmolase
17Pregnenolon
hydroxylase17-OH-
17,20-lyase
DHEA
Pregnenolone
3HSD
3HS
D
17Progesteron
hydroxylase17-OHe
21hydroxylase
DOC
11hydroxylase
Corticostero
ne
18-hydroxylase
18-OHCorticosterone
18-oxidase
Aldostero
ne
17,20-lyase
Progesterone
21hydroxylase
11deoxycortisol
11-hydroxylase
Cortiso
l
3HS
D
Androstenedio
aromatase
ne
17HSD
Estrone
Testosteron
e
aromatase
17HSD
Estradiol
Primary adrenal
insufficiency:
Etiologies
Acquired
Syndromes
Adrenoleukodystrop
Autoimmune
hy
AIDS
Kearns-Sayre
Congenital
Tuberculosis
Autoimmune
Congenital
adrenal
Bilateral injury
polyglandular
hyperplasia
Hemorrhag
syndrome 1 (APS1)
Wolman disease
e
APS2
Adrenal hypoplasia
Necrosis
congenita
Metastasis
Allgrove syndrome
Idiopathic
(AAA)
Primary adrenal
insufficiency:
Etiologies
Acquired
Autoimmune
AIDS
Tuberculosis
Bilateral injury
Hemorrha
ge
Necrosis
Metastasis
Idiopathic
ADRENAL INSUFFICIENCY
Adrenal Anatomy &

Physiology
The adrenals are endocrine organs that sit
on top of each kidney
Each adrenal gland has two parts

Adrenal Medulla (inner area)
Secretes catecholamines which
mediate stress response (help prepare
a person for emergencies).
Norepinephrine
Epinephrine
Dopamine
Adrenal Cortex (outer area, encloses
Adrenal Medulla)
Secretes steroid hormones
Glucocorticoids: exert a widespread
effect on metabolism of
carbohydrates and proteins
Mineralocorticoids: are essential to
maintain sodium and fluid balance
sex hormones (secondary source)
A person can survive without a functioning

adrenal medulla.
A functioning adrenal cortex (or the steady

availability of replacement hormone) is
essential for survival.
The Essential Steroids

Primary glucocorticoid:
Cortisol (a.k.a. hydrocortisone)
Primary mineralocorticoid:
Aldosterone
Cortisol
A glucocorticoid
Frequently referred to as the stress
hormone
Released in response to physiological or
psychological stress
Examples: exercise, illness, injury,
starvation, extreme dehydration,
electrolyte imbalance, emotional
stress, surgery, etc.
Cortisol
Critical actions on many physiologic
systems, including:
Maintains cardiovascular function
Provides blood pressure regulation
Enables carbohydrate metabolism
acts on the liver to maintain normal
glucose levels
Immune function actions
Reduces inflammation
Suppresses immune system
Cortisol
When cortisol is not produced or released
by the adrenal glands, humans are unable
to respond appropriately to physiologic
stressors.
Rapid deterioration resulting in organ

damage and shock/coma/death can occur,
especially in children
Aldosterone
a mineralocorticoid
Regulates body fluid by influencing sodium
balance
The human body requires certain amounts
of sodium and water in order to maintain
normal metabolism of fats, carbohydrates
and proteins.
Water/sodium balance is maintained by

aldosterone.
Without aldosterone, significant water and

sodium imbalances can result in organ
failure/death.
Why we need cortisol

Cortisol has a necessary effect on the
vascular system (blood vessels, heart) and
liver during episodes of physiologic stress
Vascular Reactivity
In adrenally-insufficient individuals
experiencing a physiologic stressor, the

vascular smooth muscle will become nonresponsive to the effects of norepinephrine
and epinephrine, resulting in vasodilation
and capillary leaking.
The patient may be unable to maintain an
adequate blood pressure
The blood vessels cannot respond to the
stress and will eventually collapse
Energy Metabolism
In adrenally-insufficient individuals under
increased physiologic stress, the liver is
unable to metabolize carbohydrates
properly, which may result in profoundly
low blood sugar that is difficult to reverse
without administration of replacement
cortisol
The speed at which patient

deterioration occurs is difficult to
predict and is related to the
underlying stressor, patient age,
general health, etc.
Young children can be at high risk for

rapid deterioration, even when
experiencing a simple
Endocrinologist Testimony
In adrenal insufficiency, because
of the inability to produce
glucocorticoids and often
mineralocorticoids from the adrenal
glands, there is a risk of lifethreatening hyponatremia,
hyperkalemia, hypoglycemia,
seizures and cardiovascular collapse,
in particular at times of physiologic
stress to the body, such as in injury
or illness
Who has adrenal

insufficiency?
Anyone whose adrenal glands have stopped producing
steroids as a result of:

Long-term administration of steroids
Pituitary gland problems, including growth hormone
deficiency, tumor, etc.
Trauma, including head trauma that affects pituitary
Loss of circulation to adrenals/removal of tissue
Auto-immune disease
Cancer and other diseases (TB and HIV may cause)
There is also an inherited form of adrenal insufficiency

(CAH)
Congenital Adrenal Hyperplasia

CAH is inherited (recessive gene,
each parent contributes)
Diagnosed by newborn screening; prior to
successful screening techniques most children
died
Daily replacement oral hormones are required
at a maintenance dose for LIFE
I.M. or I.V. hormones necessary for stressors
(illness, surgery, fever, trauma, etc.)
Parent testimony
People without adrenal insufficiencies naturally produce
up to ten times the normal amount of cortisol during times

of physical stress. If an unaffected person is unresponsive,
goes into cardiac arrest or is vomiting, you can treat the
shock, heart, or dehydration and help them. For James,
however, immediate, appropriate emergency response is
vital. I have watched James, as a fever quickly spiked, go
from alert and playful to grayish-white and lethargic, in a
matter of minutes. It is scary. I have seen how a stress
dose of Cortef quickly brought him back to where I could
then manage his illness with the common treatment of
Motrin and fluids
Oral Testimony, Alex Dubois, December 12, 2009
Adrenal Insufficiency
Can occur from long-term administration
of steroids (over-rides bodys own steroid

production) Examples:
Organ transplant patients

Long-term COPD
Long-term Asthma
Severe arthritis
Certain cancer treatments
Why?
Adrenal glands tend to get lazy when
steroids are regularly administered by
mouth, I.M. injection or I.V. infusion.
To illustrate how quicklyJust 4 weeks of

daily oral cortisone administration is
sufficient to cause the adrenals to be
slightly less responsive to stressors.
Organ Transplant Patients

These individuals must take
immunosuppressive medications (usually
steroids) DAILY for life.
Their own adrenal glands stop producing

cortisol because of external source of
steroid.
Long-term Asthma and

COPD
These individuals are at high risk of

adrenal crisis from illness or trauma
Keep in mind that many children and

teens with severe asthma take
steroid medication every day and
may be at significant risk of adrenal
crisis.
A severely asthmatic teen may have
Primary Adrenal
Insufficiency= Addisons
Disease
The adrenal glands are damaged and

cannot produce sufficient steroid
80% of the time, damage is caused

by an auto-immune response that
destroys the adrenal cortex
Addisons can affect both sexes and

all age groups
Addisons symptoms
This disease has a gradual onset and
can be difficult to diagnose:
Chronic, worsening fatigue

Weight loss
Muscle weakness
Loss of appetite
Nausea/vomiting
Low blood pressure
Low blood sugar
Skin hyperpigmentation
Salt-craving
Acute manifestation of Addisons

is called Addison Crisis
Severe vomiting/diarrhea
Dehydration
Hypotension
Sudden, severe pain in back, belly or
legs
Loss of consciousness
Can be fatal
How Many in MA have some

form of Adrenal
Insufficiency?
Short answer: we dont really know.
The CARES Foundation estimates
that the number of adrenally

-insufficient persons in MA is more
than 3800, not including visitors to
the state.
Numbers will most likely continue to
increase as the number of successful
organ transplants increases. Many
Presentation of Adrenal
Crisis
The patient may present with any
illness or injury as the precipitating

event.
A patient history of adrenal insufficiency warrants a careful

assessment under specific protocols
Children may deteriorate into adrenal crisis from a simple
fever, a gastrointestinal illness, a fall from a bicycle or some

other injury.
A mild illness or injury can easily precipitate

an adrenal crisis in any age group
Parent testimony
In April of this year, we experienced how much the
inability of emergency medical responders to help us

impacts our lives. One of my daughters was at my sisters
home playing a game of tag with her cousins and two
friends Alissa was on a slight incline, lost her footing and
fell head first onto a rock. She was unconscious and
severely injured. My sister had not ever mixed, withdrawn
or injected the medicine during an emergency. (She had
practiced before, but never actually gave a shot to one to
her nieces.) Fortunately, she was able to inject it, but
was unsure if she gave the correct dosage. As it turns out,
Alissa was sent via ambulance and needed to be
admitted for three days with a concussion and some broken
bones. My sister told me that she, herself, was pretty
traumatized from having to give the injection and for
having had that responsibility
Krupski letter of support, 12/12/09
Critical Clinical Presentation

The early indicators of an adrenal-
crisis onset can be vague and nonspecific. Some or all signs/symptoms

may be present.
Infants:
Poor appetite
Vomiting/diarrhea
Lethargy/unresponsive
Unexplained hypoglycemia
Seizure/cardiovascular collapse/death
Critical Clinical Presentation

(not all S&S may be
present)
Older Children/Adults
Vomiting
Hypotensive, often unresponsive to
fluids/pressors
Pallor, gray, diaphoretic

Hypoglycemia, often refractory to D50
May have neurologic deficits

Headache/confusion/seizure
lethargy/unresponsive
Cardiovascular collapse
Death
Clearly, the signs/symptoms of

adrenal crisis are similar to other
serious shock-type presentations.
For these patients, standard shock
management requires
supplementation with corticosteroid
medication (Solu-Cortef or SoluMedrol)
It is important to ANTICIPATE the
Patient Management
Follow standard ABC and shock
management treatment.
BLS/ILS: notify ALS intercept as soon
as possible; transport without
delay
ALS: administer steroid IM/IV/IO as
soon as possible after initial lifethreat and shock management have
been initiated.
It is important to note that you are

caring for a patient with multiple
issues:
1. The precipitating event (a trauma/illness that may be
a critical issue on its own)
and
2. The evolution towards adrenal crisis, which will result
in organ failure/death if not reversed.
MA EMS Protocol Updates

This phrase has been added to
Paramedic Standing Orders in certain
ADULT treatment protocols:
For patients with confirmed adrenal
insufficiency, give hydrocortisone 100 mg
IV, IM or IO OR methylprednisolone 125
mg IV, IM or IO
Link to main MA EMS Protoc

ol page
Relevant ADULT treatment protocols:
3.3 Altered Mental/Neurological
Emergencies
3.10 Shock (Hypoperfusion) of Unknown

Etiology
4.5
Multi-systems Trauma
MA EMS PEDIATRIC Protocol

Updates
This phrase has been added to
Paramedic Standing Orders in certain
PEDIATRIC protocols:
For patients with confirmed adrenal
insufficiency, give hydrocortisone 2mg/kg
to maximum 100 mg IV, IM or IO OR
methylprednisolone 2mg/kg to maximum
125 mg IV, IM or IO
Relevant protocols:
5.6 Pediatric Coma/Altered
Mental/Neurological Status/Diabetic in
Children
5.8 Pediatric Shock
5.10 Pediatric Trauma and Traumatic
Cardiac Arrest
Administration of steroid medication

should come as soon after appropriate AB-C assessment and interventions as
possible
Your emergency management priorities

remain the same, with the addition of
steroid administration.
Please define Confirmed

Confirmation of a pediatric patients
condition is determined by the
presence of a medic-alert
bracelet/necklace, OR by the child,
parent or care provider verbally
confirming a history of adrenal
insufficiency
In a school or daycare setting, it is
acceptable for the school nurse or
Adults
Confirmation of adrenal insufficiency
in adults is achieved by viewing a
medic alert bracelet/necklace, or
medical record, or when the patient,
family member or care provider
verbally confirms that the patient has
a history of adrenal insufficiency.
Be sure to document manner of
Patients Own Medication

Many adrenally-insufficient patients
carry an emergency Act-O-Vial of
Solu-Cortef.
Solu-Cortef is included in the

required medication formulary,
making it acceptable for
paramedics to administer the
patients own medication to the
Profile: Solu-Cortef
Trade name: Solu-Cortef
Generic name: hydrocortisone sodium
succinate
Class:
corticosteroid, Pregnancy
Class C
Mechanism:
acts to suppress
inflammation; replaces
absent
glucocorticoids, acts to
suppress
immune response
Solu-Cortef
MA EMS Indications: replacement of
absent corticosteroid in identified
adrenally-insufficient patients being
managed under specific treatment
protocol; many other uses as well
Contra-Indications: Do not use in the

newly-born or any individual with a known
hypersensitivity to Solu-Cortef
Solu-Cortef
Side Effects: in emergency use, transient
hypertension and/or headache,

sodium/water retention may occur. Not
usual in a 1-time dose
Dosage: Adult:
100 mg IV, IM, IO
Pediatric:
2 mg/kg to a max
of
100 mg, IV, IM, IO
Protect from heat
Solu-Cortef
Administration route: IM or slow IV
bolus. Give IV Bolus over 30 seconds.
IV infusion is not acceptable for
emergency administration
For young children, the preferred IM
site is the vastus lateralis muscle
Solu-Cortef
How supplied: self-contained ActoVial
Dry powder is in the lower of a twochambered vial. Diluent is in upper
chamber.
Do not reconstitute until ready to use
Using Act-O-Vial
Press down on plastic activator to
force diluent into the lower

compartment.
Gently agitate to effect solution.
Remove plastic tab covering center
of stopper.
Swab top of stopper with a suitable
antiseptic.
Insert needle squarely through centre
Onset of action: for the indicated use

(emergency steroid replacement in patient
experiencing stressor) the onset of action
is minutes. Do not delay transport.
Additional Notes
This product contains the
preservative Benzyl Alcohol which is

found in many medications. The
amount of Benzyl Alcohol is
negligible in comparison to other
products and this medication is
considered very safe and effective
for emergency administration.
The exception is the newly-born
and/or significantly underweight
neonates. In these groups there is
insufficient data; this medication
may cause gasping syndrome,
Additional Notes
Solu-Cortef is the first choice for
management of adrenal
insufficiency/adrenal crisis.
The other approved medication, SoluMedrol, is an acceptable alternative choice

for specific management of adrenal
insufficiency/adrenal crisis
Solu-Medrol
Generic: methylpredisolone sodium
succinate
Trade:
Class:
Solu-Medrol
steroid
Pregnancy Class: C
Solu-Medrol
Indications: Ma EMS Protocol:
replacement of absent corticosteroid

in identified adrenally-insufficient
patients being managed under
specific treatment protocol; Other:
many uses, including acute bronchial
asthma (not first-line); anaphylaxis
(not first-line); acute exacerbation of
multiple sclerosis
Contraindications: any patient with
Solu-Medrol
Dose: Adult: 125 mg IM/IV/IO
Pediatric: 2mg/kg to a max
of 125 mg
IM/IV/IO
Administration route: IM or slow IV

bolus. Give IV Bolus over 30 seconds.
IV infusion is not acceptable for
emergency administration
For young children, the preferred IM
Solu-Medrol
Onset of action: for the indicated use
(emergency steroid replacement in patient
experiencing stressor) the onset of action
is minutes. Do not delay transport.
Using the Act-O-Vial

Press down on plastic activator to
force diluent into the lower

compartment.
Gently agitate to effect solution.
Remove plastic tab covering center
of stopper.
Swab top of stopper with a suitable
antiseptic.
Insert needle squarely through centre
Additional Notes
This product contains the
preservative Benzyl Alcohol which is

found in many medications. The
amount of Benzyl Alcohol is
negligible in comparison to other
products and this medication is
considered very safe and effective
for emergency administration.
The exception is the newly-born
and/or significantly underweight
neonates. In these groups there is
Heartfelt Appreciation
is extended to the many people whose hard work helped
make these protocol changes possible, including:
Alex Dubois and son James (MA CAH family advocates)
Dr. Christine Leudke and the many other pediatric endocrinologists
across the state of Massachusetts
Dr. Jon Burstein, OEMS staff and members of the MA Medical Services
Committee
Gretchen Alger Lin, CARES Foundation
family members, state legislators and others for their letters of support
and kind words
Adrenal cortex
Hyperadrenalism
Excessive secretion of any one of the three
basic types of corticosteroids gives rise to a
distinct clinical syndrome:
1. Aldosterone hyperaldosteronism (Conns
syndrome)
2. Cortisol Cushings syndrome
3. Androgens adrenogenital syndromes
Aldosterone is primarily involved with

fluid and electrolyte balance.
Aldosterone secretion causes sodium
reabsorption in the distal renal tubule
in exchange for potassium and
hydrogen ions.
The net effects are, fluid retention,
decrease in plasma potassium and
metabolic alkalosis.
Hyperadrenalisms
Adrenal cortex
Primary Hyperaldosteronism
Primary hyperaldosteronism excess aldosterone secretion

which is independent of the renin-angiotensin system
(Conns syndrome)
Causes:
Aldosterone secreting adenoma
Bilateral hyperplasia of the cortex
Rarely carcinoma
Clinical features:
Hypertension, hypokalemia, sodium retention, muscle weakness,
paraesthesia, ECG changes, cardiac decompensation
Aldosterone, by inducing renal

distal tubular reabsorption of
sodium, enhances secretion of
potassium and hydrogen ions,
causing hypernatremia,
hypokalemia, and metabolic
alkalosis.
Frequency:
Prevalence for Conn syndrome; 0.05-2% of the
population.
Mortality/Morbidity:
The morbidity and mortality associated with Conn
syndrome, are primarily related to;
1- Hypertension, especially if left untreated for
many years, can lead to many complications,
including heart disease (eg, coronary artery
disease, congestive heart failure), stroke, and
intracerebral hemorrhage (with very high blood
pressure).
2-Hypokalemia, especially if severe, causes

cardiac arrhythmias, which can be fatal
Age
Peak incidence occurs in the third to sixth decades
of life.
Sex
Primary hyperaldosteronism is twice as common in
women as in men.
II- 2ry hyperaldosteronism:

There is increased renin-angiotensin with
increased aldosterone secretion;
-CHF
-Liver cirrhosis and ascites
-Nephrotic syndrome
-Renal artery stenosis
Clinical features
Clinical suspicions should be raised when
Hypertension occur with hypokalemia.
Moderate to sever hypertension
Hypokalemia
Muscle weakness
Malaise
Polyuria polydipsia
Investigations
Blood : Hypokalemia
Plasma aldosterone
Urine : Increase urinary potassium
Imaging : U S
CT
MRI
Iodocholesrerol isotope
scan
Adrenal vein sampling
Treatment
Spironolactone
Adrenalectomy
Congenital Adrenal
Hyperplasia (CAH)
By:
Dr. Atif Ali Bashir
Pathology Department
Faculty of Medicine
Majmaah University
Congenital Adrenal
Hyperplasia
CAH refers to a
group of disorders
characterized by
genital
abornomalities
due to deficiencies
of the adrenal
gland
Causes
Lack of an enzyme needed by the
adrenal gland to make the hormones
cortisol and aldosterone.
Without these hormones, the body
produces more androgen which is a
type of male sex hormone.
This causes male characteristics to
appear early or inappropriately.
Congenital Adrenal
Hyperplasia
The first case was described in 1865
Family of inherited disorders of adrenal
steroidogenesis
Each disorder results from a deficiency of
one of several enzymes necessary for
steroid synthesis
Autosomal Recessive (M=F)
21-hydroxylase is the commonest form
Location of Defective
Gene
CAH is caused by
mutations of the
CYP11B1 gene.
The CYP11B1 gene is

found on chromosomes
13 and 18
Congenital Adrenal
Hyperplasia
Congenital Adrenal Hyperplasia
CAH due to 21-Hydroxylase

Deficiency
9095% of CAH cases are caused by 21OHD
Females affected with severe, classic 21OHD are exposed to excess androgens
prenatally and are born with virilized
external genitalia
Symptoms
Male
Enlarged penis
Failure to regain birth
weight
Weight loss
Dehydration
Vomiting
Precocious puberty
Rapid growth during
childhood, but shorter
than average final height.
Female
Ambiguous genitalia
Failure to regain birth weight
Weight loss
Dehydration
Vomiting
Precocious puberty
Rapid growth during
childhood, but shorter than
average final height.
Infertility
Irregular or absent
menstruation
Masculine characteristics
Presentations of 21 HCAH
Ambiguous genitalia in girls

Dehydration
Shock
Salt-loss presentations with electrolytes
imbalance
Hyponatremia
Hyperkalaemia
Hypoglycemia
Hyperpigementations
Symptoms
Young woman with
excess hair growth
Baby girl with

ambiguous genitalia.
BOYS WITH CAH

Are unrecognized at birth because their genitalia are normal.
Present early with salt wasting

hyperkalemia
Or present later in childhood with
early pubic hair, precocious
puberty and accelerated growth
Non classical
CAH
Diagnosis
Serum electrolytes & glucose
Low Na & high K

Fasting hypoglycemia
Elevated serum urea due to associated dehydration
Elevated plasma Renin & ACTH levels

Low Cortisol
High 17 OHP
High androgens especially testosterone level
Low Aldosterone
Urinary steroid profile
Chromosomes
Pelvic US
Treatment
To treat CAH, children are usually
referred to a pediatric
endocrinologist.
Oral drugs are prescribed to boost
the hormone levels
Hydrocortisone and Dexamethasone are
common meds to replace cortisol
Fludrocortisone might be prescribed to
replace aldosterone.
Pedigree Chart
CAH is
autosomal
recessive.
This pedigree
chart
illustrates a
childs
chances of
inheriting the
condition if
both parents
are carriers.
Adrenal Neoplasms
Cortex:
Adenoma
Usually Non-Functioning
Carcinoma
Usually Functional
Medulla:
Pheochromocytoma
Neuroblastoma
Adrenal Cortical Adenoma

F >> M 30-50 years of age
gross: well-circumscribed
encapsulated nodule
solid yellow cut surface. Some
have hemorrhage/cystic
degeneration.
Adrenal Cortical Adenoma
Adrenal Adenoma
Adrenal Cortical Carcinoma

wide age spectrum
often functional associated with
hyperadrenalism
large, often >100 grams
gross: foci of hemorrhage, necrosis
micro: foci of necrosis, cytologic
atypia, frequent mitoses, solid
pattern
Cortical Carcinoma
Adrenal Carcinoma
Pheochromocytoma
a tumor of adrenal medulla
30-60 yrs.; F > M
rule of 10s: 10% bilateral,
malignant, occur in children,

familial, extra-adrenal
Gross: solid, pale to light brown
masses
clinical: hypertension,
tachycardia, tremor, headache,
Pheochromocytoma
Pheochromocytoma
Tuberculosis
Adrenal Hemorrhage:
Meningiococcemia
Addisons Disease
1st described in 1855
by Dr. Thomas
Addison
Refers to acquired
primary adrenal
insufficiency
Does not confer
specific etiology
Usually autoimmune
(~80%)
Addisons Disease
Addisons
Normal
Primary adrenal
insufficiency:
Fatigue
Symptoms
Weakness
Orthostatsis
Weight loss
Poor appetite
Neuropsychiatric
Apathy
Confusion
Nausea, vomiting
Abdominal pain
Salt craving
Primary adrenal
insufficiency:
Physical findings
Hyperpigmentation
Hypotension
Orthostatic changes
Weak pulses
Shock
Loss of axillary/pubic
hair (women)
Primary adrenal
insufficiency:
Physical findings
Primary adrenal
insufficiency:
Laboratory findings
Hyponatremia
Hyperkalemia
Hypoglycemia
Narrow cardiac silhouette on CXR
Low voltage EKG
Primary adrenal
insufficiency:
Etiologies
Congenital
Congenital adrenal
hyperplasia
Wolman disease
Adrenal hypoplasia
congenita
Allgrove syndrome
(AAA)
21-hydroxylase
deficiency:
Pathophysiology
Testosterone
CAH: Pathophysiology
Cholestero
l
17Pregnenolon
hydroxylase17-OH-
17,20-lyase
DHEA
Pregnenolone
3HSD
3HS
D
17Progesteron
hydroxylase17-OHe
21hydroxylase
DOC
11hydroxylase
Corticostero
ne
18-hydroxylase
18-OHCorticosterone
18-oxidase
Aldostero
ne
17,20-lyase
Progesterone
21hydroxylase
3HS
D
Androstenedio
ne
11deoxycortisol
11-hydroxylase
Cortiso
l
Estrone
Testosteron
e
Estradiol
CAH: Pathophysiology
Cholestero
l
17Pregnenolon
hydroxylase17-OH-
17,20-lyase
DHEA
Pregnenolone
3HSD
3HS
D
17Progesteron
hydroxylase17-OHe
21hydroxylase
DOC
11hydroxylase
Corticostero
ne
18-hydroxylase
18-OHCorticosterone
18-oxidase
Aldostero
ne
17,20-lyase
Progesterone
21hydroxylase
3HS
D
Androstenedio
ne
11deoxycortisol
11-hydroxylase
Cortiso
l
Estrone
Testosteron
e
Estradiol
21-hydroxylase
deficiency:
Physical exam
Females are unremarkable

other than genitalia
GU exam Clitoromegaly,
posterior labial fusion, no
vaginal opening
Males appear normal
21-hydroxylase deficiency
CAH
Classification based on enzyme
activity
Classic
Salt wasting (Complete deficiency)
Simple virilizing (Significant but partial
defect)
Non Classic
Elevated enzyme levels (Mild deficiency)
Primary adrenal
insufficiency:
Etiologies
Syndromes
Adrenoleukodystrop
hy
Kearns-Sayre
Autoimmune
polyglandular
syndrome 1
(APS1)
APS2
Primary adrenal
insufficiency:
Associated conditions
Autoimmune Polyglandular Syndrome

I
Hypoparathyroidism
Chronic mucocutaneous candidiasis
Atrophic gastritis
Adrenal insufficiency in childhood
Pernicious anemia
Vitiligo
AIRE mutation
Transcription factor
Affects immune regulation
Primary adrenal
insufficiency:
Associated conditions
Autoimmune Polyglandular Syndrome

II
Autoimmune thyroiditis
Type I diabetes mellitus
Adrenal insufficiency
Pernicious anemia
Premature ovarian failure
Genetic associations
HLA haplotype, CLTA4
Evaluatio
n
Primary adrenal
insufficiency:
Evaluation
0800 cortisol level

ACTH level
Random cortisol in ill patient
ACTH stimulation test
Suspected CAH
Needs special evaluation
Primary adrenal
insufficiency:
Evaluation
0800 cortisol level
Levels less than 3 mcg/dL are

suggestive of AI
Levels greater than 11 mcg/dL exclude
AI
ACTH level
Elevated in adrenal insufficiency
ACTH readily degraded if not properly
processed
Primary adrenal
insufficiency:
Evaluation
Random cortisol in ill patient

>20 mcg/dL reassuring
Adrenal Autoantibodies
ACAadrenal cortex antibody
Anti-21-OH-hydroxylase antibody
Primary adrenal
insufficiency:
EvaluationACTH
Stimulation
Low dose (1 mcg) test
Baseline and 30 minute cortisol levels

More physiological ACTH level/stimulation
Useful in central AI
Useful for assessing recovery after chronic steroid
treatment
High dose (250 mcg) test

Baseline, 30 and 60 minute levels
Can be done IM
Stronger stimulation than 1 mcg test
Primary adrenal
insufficiency:
EvaluationACTH
Stimulation
Cortisol peaks are controversial
Reported normals range between 16-25
mcg/dl
Some providers also look at the
magnitude of rise
Also use ACTH to help differentiate

primary vs secondary deficiency
Secondary may respond to high dose,
but not low
Primary should fail both high and low
Suspected CAH:
Evaluation
Newborn screening
Call endo before you
treat
Need special
evaluation
ACTH stimulation
can be helpful in
well patients with
suspected
nonclassic disease
17-OH progesterone
17-OH pregnenolone
11-deoxycortisol
Deoxycorticosterone
Androstenedione
DHEA
Aldosterone
Cortisol
ACTH
Plasma renin activity
Diagnosis with 17-OH

progesterone
Baseline 10,000 - 90,000
Stimulated 20,000 - 100,000
Baseline
500 - 1,000
Stimulated 2,000-15,000
Baseline
20 - 1,000
Stimulated 200 - 1,000
Treatmen
t
Primary adrenal
insufficiency:
Acute treatment
NS volume resusitation
Reverse shock
Look for/treat hypoglycemia

25% dextrose
New problem, suspected AI

Labssteroids
Established patient with AI

Steroids
Stress dose steroids

Loading dose
50-100 mg/M2 hydrocortisone IV/IM
Small/medium/large approach
Infants: Hydrocortisone 25 mg
Small children: Hydrocortisone 50 mg
Larger children/teens: Hydrocortisone 100
mg
Continue hydrocortisone with 50-100

mg/M2/day
Divide q6-8 hours

May be 2-3x home dose
Primary adrenal
insufficiency:
Long term treatment
Daily glucocorticoid replacement
(hydrocortisone)
10-15 mg/m2/day divided TID
Option to change to prednisone in teen years
Daily mineralocorticoid replacement

Fludrocortisone 0.05-0.2 mg daily
Patient education
Stress coverage
Emergency steroid administration
IM hydrocortisone (Solucortef Actovial)
Medic Alert ID
Relative Steroid Potencies

Glucocorticoid Mineralocorticoid
1
++
3-5
5-6
Dexamethasone
25-50
Fludrocortisone
15-20
+++++
Hydrocortisone
Prednisone/
Prednisolone
Methylprednisone
Relative Steroid Potencies

Glucocorticoid Mineralocorticoid
1
++
3-5
5-6
Dexamethasone
25-50
Fludrocortisone
15-20
+++++
Hydrocortisone
Prednisone/
Prednisolone
Methylprednisone
When to consider AI:

Patients at riskPrimary AI
History of TB
Refractory shock
Particularly meningococcal disease
Dehydration/shock with
hyperpigmentation
Neonate with
vomiting/dehydration/shock
Other autoimmune endocrine disease
History consistent with APS1
Immunodeficiency/chronic
When to consider AI:

Patients at riskSecondary
AI
Pituitary trauma/surgery
Brain tumor
Craniopharyngioma
Suprasellar germ cell tumor
Infiltrative pituitary disease

Sarcoidosis
Histiocytosis
Congenital pituitary abnormalities

May have progressive loss of corticotroph
function
Chronic glucocorticoid therapy
Summary
May be primary or secondary

May be congenital or acquired
Treatment is relatively simple
Diagnosis is often controversial
Baseline cortisol/ACTH before steroids
ACTH stim test if possible
Additional testing if CAH is suspected
Dont forget to check the blood

sugar!
Congenital Adrenal
Hyperplasia
What is CAH?
It is a familial disorder of adrenal

steroid biosynthesis with
autosomal recessive mode of
inheritance.
The defect is expressed as adrenal
enzyme deficiency.
5 major Enzymes deficiency are
clinically important
21-Hydroxylase
11-b-Hydroxylase
17-a-Hydroxylase
3-b-Hsteroid hydrogenese
CAH
The enzyme deficiency causes
reduction in end-products,
accumulation of hormone
precursors & increased ACTH
production.
The clinical picture reflects the
effects of inadequate production
of cortisol & aldosterone and the
increased production of
21-Hydroxylase
Deficiency
Most common type, accounts for

>80% of cases.
Incidence is 1:5000 to 1:15000
live birth.
Gene is located on the short arm
of chromosome 6 near the C4
locus in close association with
HLA genes.
Heterozygous carriers can be
21-Hydroxylase
deficiency/2
It is characterized by reduced
production of cortisol and
aldosterone and increased
production of progesterone;
17-OHprogesterone, and sex steroids.
The urinary steroid metabolites
(17-ketosteroids
and pregnanetriol) are elevated
21-Hydroxylase
deficiency/3
Decreased secretion of
aldosterone results in salt loss
with hyponatremia and
hyperkalemia; plasma renin
activity is therefore elevated.
In partial enzyme deficiencies,
the aldosterone deficiency is not
expressed, and patients remain
normonatremic and
21-Hydroxylase
Deficiency/4
2 forms, classic early
virilization type with or
without salt-losing crisis and
non-classic type with lateonset virilization.
Male babies with non saltlosing non-classic type remains
asymptomatic till late
childhood when they may show
21-Hydroxylase
Deficiency/5
Because members of the same
family may have classic, nonclassic & asymptomatic forms,
the disorder may be due to
allelic variations of the same
enzyme.
Mass neonatal screening using
filter paper blood sample for 17OH-Progesterone is used in the
11--Hydroxylase
Deficiency
Accounts for 5-10% of cases of

CAH.
Gene is located on the long arm of
chromosome 8.
It is characterized by low plasma
renin activity & elevation of serum
11-Deoxycortisol and 11deoxycorticosterone.
Because of the strong
mineralocorticoid activity of
17--Hydroxylase
deficiency
Genetic defect is on
chromosome 10.
Presents with similar features
of those of 11-Hydroxylase
deficiency except that
Androgens are low, so no
virilization in girls & genitalia is
3--hydroxysteroid
dehydrogenase deficiency
This is a very rare disorder
that results in accumulation of
DHEA, which is converted to
testosterone in peripheral
tissues.
It can cause virilization of
female fetus and leads to
ambiguous genitalia in the
newborn.
Pathophysiology
Anatomically, the adrenal gland
can be divided into 3 zones:
Zona glomerulosa, which
produces predominately
mineralocorticoid
Zona fasciculata, which
produces predominately
glucocorticoid
Zona reticularis, which produces
predominately androgens
Enzyme pathway
Result of a 21-Hydroxylase
Deficiency
ESSENTAILS OF
DIAGNOSIS
Increased linear growth with
advanced bone age and
eventual short stature
Pseudohermaphorditism in girls
due to androgen virilizing effect
Isosexual precocity in boys with
small infantile testes.
ESSENTAILS OF
DIAGNOSIS/2
Adrenal crisis with salt-loss &
metabolic acidosis or
Hypertension & hypokalemic
alkalosis.
Low cortisol with high
androgens, ACTH and steroid
precursors e.g. 17-OH-Progest.
or 11-Deoxycortisol.
ESSENTIALS OF
DIAGNOSIS/3
Diagnosis is confirmed by
measurement of ACTH, Cortisol,
Aldosterone,
17-OH-progesterone,
Testosterone & urinary 17ketosteroids.
Needs alertness for the
possibility in all babies with
Diarrhea & Vomiting,
hypoglycemia or BP.
CLINICAL COURSE
The clinical phenotype depends
upon the nature and severity of

the enzyme deficiency.
Approximately 50% of patients
with classic congenital adrenal
hyperplasia due to 21hydroxylase (CYP21) deficiency
have salt wasting due to
inadequate aldosterone
synthesis.
Girls are usually recognized at
CLINICAL COURSE/2
Non salt losing CAH present late
in childhood with precocious
pubic hair and/or clitoromegaly,
often accompanied by
accelerated growth and
advanced bone age.
Those individuals with mild
deficiencies of the enzyme

present in adolescence or
adulthood with varying virilizing
GIRLS WITH CAH

Have ambiguous genitalia at
birth:
complete fusion of the
labioscrotal folds and a phallic
urethra. clitoromegaly and
partial fusion of the labioscrotal
folds
In less severe forms, genitalia is
normal at birth. Precocious pubic
hair & clitoromegaly and excess
BOYS WITH CAH

Are unrecognized at birth
because their genitalia are
normal.
They are not diagnosed until
later, often with a salt wasting
hyperkalemia or later in childhood
with early pubic hair & phallic
enlargement accompanied by
accelerated linear growth and
Laboratory Findings
Demonstration of inadequate
production of cortisol and/or
aldosterone in the presence of
accumulation of excess
concentrations of precursor
hormones is diagnostic.
In 21-hydroxylase deficiency,
very high serum
17-
Laboratory Findings/2
11--hydroxylase deficiency is
characterized by high serum 11deoxycorticosterone and 11deoxycortisol concentrations
with elevation of its urinary
metabolites
(tetrahydrocompound-S).
Both are accompanied by
elevated 24-hour urinary 17ketosteroids, the urinary
Laboratory Findings/3
Salt wasting forms of adrenal
hyperplasia are accompanied by
low serum aldosterone,
hyponatremia, hyperkalemia and
elevated plasma renin activity
indicating hypovolemia.
In contrast hypertensive forms
of adrenal hyperplasia (11-hydroxylase deficiency and 17-hydroxylase deficiency) are

associated with suppressed
Other Tests
A karyotype
is essential in the evaluation
of the infant with ambiguous
genitalia in order to establish
the chromosomal sex.
Prenatal diagnosis of adrenal
hyperplasia is possible through
biochemical and genetic tests.
Imaging studies
A pelvic ultrasound: in the infant
with ambiguous genitalia to

demonstrate the presence or
absence of a uterus or associated
renal anomalies
A urogenitogram is often helpful
to define the anatomy of the
internal genitalia.
A CT scan of the adrenal gland to
R/O bilateral adrenal hemorrhage
in the patient with signs of acute
TREATMENT PRINCIPLES
Treatment is life-long
Treatment goals are:
to maintain growth velocity &
skeletal maturation.
to normalize electrolytes &
hormone levels using the
smallest dose of glucocorticoids
that will suppress the ACTH to
normal. Mineralocorticoid
replacement may be needed to
sustain normal electrolyte
MODES OF TREATMENT
Steroid replacement
Supportive therapy when
needed
Treatment is life-long
Plastic surgery for ambiguous
genitalia at early age
Genetic counseling
Psychological support
Acute Medical
Management
Fluid therapy in babies with salt

losing crisis 0.9% sodium chloride
20 ml/kg as IV bolus, followed by
a continuous IV infusion of 0.9%
or 0.45% saline 3200 ml/m2/day.
If the patient is hypoglycemic, 24 ml of 10% dextrose will correct
the hypoglycemia.
Patients with 11--hydroxylase
and 17-alpha-hydroxylase
deficiency, may be hypokalemic
Long Term Therapy

Glucocorticoids Replacement
Hydrocortisone 10-15
mg/m2/day divided in 3 oral
doses. Dose should doubled
during crisis & stressful
conditions. The goals of
therapy are:
To replace the body's
requirement under normal
conditions and during stress.
Long Term Therapy/2

Mineralocorticoids Treatment
Fludrocortisone acetate 0.050.2 mg once daily orally is
indicated for patients who
have salt-wasting forms of
CAH to replace the aldosterone
that is insufficiently produced
by the adrenal cortex. It will
restore the sodium- potassium
balance.
New Trends of
treatment
A New approach therapy is the

combined use of 4 drugs:
glucocorticoid (to suppress ACTH

and adrenal androgen
production),
mineralocorticoid (to reduce

angiotensin II concentrations),
aromatase inhibitor (to slow

skeletal maturation),
Surgical Management
Infants with CAH may require
surgical evaluation and, if
needed, corrective surgery.
Traditional approach is
clitroplasty early in life, followed
by vaginoplasty after puberty.
Some female infants with adrenal
hyperplasia are only mildly
virilized and may not require
Further Outpatient
Care
Monitor patients adequacy of
dosing of glucocorticoid and/or
mineralocorticoid.
Too little glucocorticoid results in
symptoms of adrenal
insufficiency (e.g., anorexia,
nausea, vomiting, abdominal
pain, asthenia) and will result in
progressive virilization and
advancement of skeletal
Patient Education
Educate the caretakers and
patients about the nature of
the disease.
Patients & parents must
understand the need for
additional glucocorticoids in
times of illness and stress in
order to avoid an adrenal crisis
which may be life-threatening.
Neonatal Screening
Is done by measuring 17hydroxyprogesterone from heel
blood samples collected on filter
paper.
Mass neonatal screening program
is adopted in the USA.
This approach has permitted
early identification of newborns
with CAH and prevented salt
wasting crisis in boys who are
Prenatal diagnosis
Done by chorionic villus
sampling at 8-12 wk &
amniocentesis at 18-20 wk.
HLA typing in combination
with measurement of 17-OHprogesterone &
androstenedion in amniotic
fluid is used for antenatal
Prenatal Treatment
Prenatal treatment of 21hydroxylase deficiency prevents
intrauterine virilization of female
fetuses.
According to the protocol
proposed by Carlson et al, the
mother is treated with
dexamethasone (20 /kg/d in 3
divided doses) as soon as the
pregnancy is recognized to
PROGNOSIS
Is good and complications like
short stature, sexual precocity
& metabolic effects are not seen
with early adequate therapy.
However, children with CAH are
at risk of developing
mesodermal tumours e.g.
osteogenic sarcoma, pulmonary
liposarcoma, uterine
leiomyomata and brain
PROGNOSIS /2
Late diagnosis & inadequate
therapy may cause:
Death of newborns with saltlosing types & if patients are not
provided with stress doses of
glucocorticoid in times of illness,
trauma, or surgery.
Psychological problems in girls
with ambiguous genitalia.
Short stature and infertility.
Adrenal Incidentaloma
Case
A 40 y.o. male presents with Rt flank
pain radiating to his groin that
started acutely last night. He has
noted some hematuria as well. On
physical exam you note Rt sided CVA
tenderness.
Given concerns for abdominal
pathology you order a CT A/P
Case
Adrenal Incidentaloma
Lesion > 1 cm in diameter
Found in 4-6% on CT scans
Functioning or nonfunctioning
Adrenal Masses
Differential Diagnosis
Cold (nonsecreting) adenoma

Cortisol secreting adenoma
Aldosterone secreting adenoma
Adrenocortical Carcinoma
Metastatic Carcinoma
Pheochromocytoma (medullary)
Work-up
Step 1
Does the patient have an adrenal syndrome
Step 2
Screening tests
Step 3
Repeat imaging
Cross Sectional Anatomy

Normal size (Lt or Rt adrenal) : 3 cm
6 mm
Retroperitoneum organ
Gerotas fascia : connect the gland to
upper pole of the kidney
Introduction
Mass lesion greater than 1 cm.
Serendipitiously discovered by
radiologic examinations
Such as : - Computed tomography
(CT)
- Magnetic resonance
imaging (MRI)
Two questions
- Is it malignancy ?
- Is it functioning ?
Prevalence
Autopsy : Total 739 cases
(adrenal masses between 2 mm 4
cm)
- 9 % normotensive
- 12 % hypertension
The Mayo clinic
- 61,054 abdominal CT scans
- 1985 1990
- adrenal masses : 2,066 cases
(3.4%)
Prevalence
The Mayo clinic
2,066 cases :
- 50% metastasis cancer
- 25% other known lesions
- 7.5% symptomatic tumors
- 16.5% incidental (include
nodules < 1cm)
- Overall incidental adrenal
tumor
(> 1cm) = 0.4 %
Prevalence
Recent study : high resolution scanner
- report prevalence from CT
abdomen = 4.4%
Demonstration : enlarged & unusually
shaped
1. one adrenal mass
2. bilateral adrenal masses
Bilateral masses
Studies : 887 and 202 cases (with adrenal
incidentaloma)
- bilateral 10-15%
- causes :
- metastasis
pheochromocytoma
- congenital adrenal hyperplasia
- amyloidosis
- cortical adenoma
- infiltrative
disease of adrenal gl.
- lymphoma
- Infections : TB,
fungus
- hemorrhage
- ACTH-dependent
Cushings
- ACTH-independent bilateral macronodular adrenal
Bilateral masses
One adrenal mass : non-functioning
cortical adenoma
Contralateral adrenal mass : hormone
secreting
+++ All patients with bilateral adrenal
masses should be screened for
adrenocortical hyper/hypo function ++
+
Evaluate for malignancy

Primary adrenal carcinoma : quite
rare
Others : - metastasis
(particularly lung cancers)
Evaluate : size and imaging
characteristics (imaging phenotype)
Size
The maximum diameter is predictive
of malignancy
Important : if the smaller is at the
time of diagnosis, the better overall
prognosis
Adenocortical carcinomas
- significantly asso. with mass size
- 90% > 4 cm
Size
The National Italian Study Groups
- 4 cm cutoff
- sensitivity 93 %
- specificity 76 %
Imaging phenotype
MRI or CT
3-5 mm. cuts : predict histological type
of adrenal tumor
Characteristics of the mass
example ; lipid-rich nature of cortical
adenomas
(benign tumor)
CT scan
Density (black is less dense)

Spectrum : Air -black, Bone-white
Hounfield scale is a semiquantitative
method of measuring x-ray

attenuation
Typical precontrast Hounsfield unit
(HU) valves
adipose tissue = -20 to 150
HU
kidney
= 20 to 150 HU
if adrenal mass < 10 HU on
CT scan
contrast-enhanced CT
- adenoma : rapid contrast medium
washout
- non-adenoma : delayed contrast
medium washout
10 mins after administration pf
contrast
- adenoma : absolute contrast
media washout > 50 % ( 100%
sensitivity & specificity)
CT scan
Imaging phenotype does not predict
hormone function, it can predict
underlying pathology, and surgical
resection
MRI
Although CT : primary adrenal
imaging
MRI has advantages in certain
clinical situations
Several difference MRI
1. - conventional spin-echo MRI
- was the first
- T1 and T2
- distinguish benign adenomas
from
malignancy and
MRI
2- gadolinium-DPTA-enhanced MRI
- adenoma : mild enhancement
and rapid
washout of contrast
- malignancy : rapid and marked
enhancement and a slower
washout
pattern
MRI
3 - Chemical shift imaging (CSI)
- lipid sensitive imaging
- principle : hydrogen protons in
water,
lipid molecules
- chemical shift technique
1. in-phase : water & lipid are
aligned
: signal intensity high
2. out of phase : opposite from
each other
MRI
Interpretation
- benign adrenal cortical adenoma :
lose signal on out-of-phase images,
but appear relatively bright on inphase images
Others
PET (Positron emission tomography)
- fluoro-2-deoxy-D-glucose (FDG)
- high sensitivity for detect
malignancy
- however : 16% benign cortical
lesions may
have FDG-PET uptake
- Metomidate (MTO) PET
: lack of MTO specific to nonadrenal
cortical origin (metastasis &
Others
PET (Positron emission tomography)
- FDG-PET and MTO-PET are not
recommend
(cost and insufficiency data to
support their
routine use)
Imaging
characteristics
Benign adenoma
Benign cortical adenoma
Round & homogenous
density
< 4 cm, unilateral
low unenhanced CT
attenuate values (<10HU)
Rapid contrast washout (10
min)
Absolute contrast washout
>50%
Isointensity with liver on
both T-1 & T-2 (MRI)
Chemical shift : lipid on MRI
Pheochromocytoma
nonenhanced CT
Increase attenuate on
(>20HU)
Increase mass
vascularity
Delayed contrast
washout
(<10 cm)
Absolute contrast
washout <50 %
High signal intensity
on T-2 MRI
Cystic and
hemorrhage
Variable size
Pheochromocytoma
Irregular shape
Adrenocortical carcinoma
Inhomogenous density
(central necrosis)
> 4 cm, unilateral, calcify
High unenhanced CT (>20HU)
Delayed contrast washout (10
min)
Absolute contrast washout <
50 %
Hypointensity compared with
liver T-1 and high to
intermidiateintensity T-2 MRI
High standard uptake value
(SUV) on FDG-PET-CT study
Evidence of local invasion or
metas.
Metastasis
Irregular, inhomogenous
Bilateral
High enhanced CT (>20 HU)
Enhancement with contrast
Delayed contrast washout (10 min)
Absolute contrast washout < 50%
Isointensity or slightly less intense than liver T-1 ,
high to intermediate intensity T-2 MRI (represent
water increase)
Others
Adrenal cysts
Adrenal hemorrhage
myelolipoma
Fine-needle aspiration
biopsy
Cannot distinguish a benign adrenal
mass from the rare adrenal
carcinoma
Thus; FNA biopsy
- indicated a suspicion of cancer
outside the adrenal gland
- staging evaluation for a known
cancer
- not useful routine evaluation
IS IT FUNCTIONAL?
6% - 20% of adrenal incidentalomas
have hormonal abnormality.
Hormonal hypersecretion is most
likely in mass are at least 3 cm in
diameter.
Occurs mostly within the first 3 years
after diagnosis.
85 percent of the masses were non

fuctioning.
9 percent secreted sufficient
cortisol to produce subclinical
Cushing's syndrome .
4 percent were
pheochromocytomas (less than
half caused hypertension) .
2 percent were aldosteronomas .
A careful personal and family

history, review of systems, PE.
At minimum for the following
condition.
Pheochromocytoma
Cushing syndrome (including
subclinical disease)
Primary aldosteronism (only if
hypertensive)
Pheochromocytoma
3-10% of adrenal incidentalomas
prove to be pheochromocytomas.
Screening for pheochromocytoma is
mandatory in all case.
Because high rate morbidity and
mortality.
It is symptomatic up to 15% of case.
Screening test is measurement of

plasma free metanephrines or 24 hr
urine metanephrine .
Plasma free metanephrines is 99%
sensitive.
Not very specific 85-89%
Cushing syndrome
5-20% of pt with adrenal
incidentaloma are report to have
subclinical Cushing syndrome.
Subclinical Cushing's syndrome
mild hypercortisolism without
clinical manifestations of Cushing's
syndrome .
most frequent hormonal abnormality
detected in patients with adrenal
In 2002 ,a National institutes of

Health consensus panel
recommened a 1 mg over night
dexamethasone supression test.
Lack of supression interfering
condition.
Decrease dexamethason absorbtion.
Drug : barbiturate, phenyltoin,
carbamazepine, rifampicin.
Increase concentration of
corticosteroid-binding globulin
Hormonal evaluation in subclinical

Cushing's syndrome showed the
following
Low baseline secretion of
corticotropine (ACTH) in 79 percent
Lack of suppressibility of cortisol
secretion after 1 mg dexamethasone
in 73 percent
Supranormal 24-hour urinary cortisol
excretion in 75 percent
Disturbed cortisol circadian rhythm in 43

percent
Blunted plasma ACTH responses to
corticotropin-releasing hormone in 55
percent
If the post-overnight DST

Then baseline serum ACTH, two-day
high-dose DST is indicated to confirm
the excess hormone secretion.
Primary Hyperaldosteronism
1.6-3.8% of adrenal incidentalomas.
Pt with hypertension should be
evaluated for primary aldosteronism.

Hypokalemia suggest aldosteronism.
Normal K not exclude.
The best screening test is the ratio of
the plasma aldosterone to the
plasma renin activity.
Management of
adrenal
incidentaloma
Clinical and CT
apperance
True cyst
adrenolipoma
Metastasis
carcinoma
FNAB
investigation
Metastasia CA
Treatment
Aspirate?
resect
or
F/U
Repeat CT at 1 yr
Resect if
appropriate
Diagnosis
unclear
BP
serumK
Catecholamine
Overnigth 1 gm DST
Urine 17 OHCS 17KS
Non fuctioning
FNA < 6 CM
functioning
> 6CM
Adenal tissue
resect
Repeat CT at 2,8,18 mo
resect
subclinical Cushing's syndrome and
unilateral adrenalectomy?
absence of a prospective randomized
study
candidates for adrenalectomy.
who have attributable to excess
glucocorticoid secretion (eg, recent
onset of hypertension, diabetes,
obesity, and low bone mass)
lack of suppression to both an overnight
DST) and a two-day high-dose DST.
Bilateral adrenal masses

The management of bilateral adrenal
masses is different from that for
unilateral masses.
SUMMARY
All patients should be evaluated for
subclinical hormonal hyperfunction
and cancer.
History and physical examination are
important in the initial assessment.
Benign cortical adenoma.
A homogeneous adrenal mass <4 cm

in diameter,
with a smooth border,
and an attenuation value <10 HU on
unenhanced CT,
and rapid contrast medium washout
(eg, >50 percent at 10 minutes)
The imaging suggest adrenal
carcinoma or metastases include:

irregular shape.
inhomogeneous density.
high unenhanced CT attenuation
values (>20 HU), delayed contrast
medium washout (eg, <50 percent at
10 minutes),
diameter >4 cm, and tumor
calcification. Other characteristics are
described above.
Pheochromocytoma should be
excluded by measuring 24-hour

urinary fractionated
metanephrines and
catecholamines.
Subclinical Cushing's syndrome
should be ruled out by the 1-mg
overnight dexamethasone.
primary aldosteronism. should be
screen in patient is hypertensive
by a plasma aldosterone-to-plasma
renin activity ratio and plasma
Recommend surgery:
pheochromocytoma, aldosteronoma.
Suggest surgery for patients with
subclinical Cushing's syndrome who
are younger and who have disorders
potentially attributable to
autonomous glucocorticoid secretion.
Suggest surgery for patients with

adrenal masses greater than 4 cm in
diameter .
If there is evidence of metastasis and
after excluding pheochromocytoma
with biochemical testing, suggest
performing a diagnostic CT-guided
FNA biopsy .
THANK YOU
Cushings Syndrome
Symptoms: weight gain, central obesity, rounded

facies, dorsocervical (back of the neck) fat pad,
easy bruising, thin skin, poor wound healing,
purple abdominal striae, acne, hirsutism,
infertility, depression, irritability, opportunistic
infections
Signs: hypertension, diabetes, impaired glucose

tolerance, osteoporosis, osteopenia, hypokalemia,
leukocytosis with relative lymphopenia
Cushings Syndrome
Screening tests
*24 hour urine cortisol
Values higher than 3-4 times normal are highly suggestive of

autonomous cortisol secretion. Values above normal but
less than 3-4 times normal are inconclusive.
*Overnight 1-mg dexamethasone suppression test
Patient takes 1 mg dex pill at 11 PM, then fasts, then

presents to lab at 8:00 AM for measurement of serum
cortisol. Serum cortisol level > 5 mcg/dl is highly suggestive
of autonomous cortisol secretion. Serum cortisol level < 1.8
mcg/dl excludes Cushings syndrome.
Primary Aldosteronism
Symptoms: Nocturia, polyuria,
muscle cramps, palpitations
Signs: Hypertension, hypernatremia,

hypokalemia
Primary Aldosteronism
Plasma renin activity (PRA) and plasma aldosterone
concentration
Should be measured in the AM. Can be performed with
patient on any medicines except spironolactone, eplerenone,
or amiloride.
*Aldo/PRA ratio of 20 with aldo level of 15 ng/dl is positive
result
* This test is highly dependent on the denominator. Consider the
level of aldosterone required to achieve a ratio of 20:1 in the case
where renin level is measured to be 1, versus when the renin level
is measured to be 0.1. Different labs have different sensitivities for
measuring renin activity, thus the requirement of not only a ratio of
20: 1 but also an aldosterone level of 15 ng/dl for a positive test.
Pheochromocytoma
Symptoms: (in paroxysms) tachycardia,
palpitations, pallor, tremor, headache,
diaphoresis. May be precipitated by maneuvers
that increase intra-abdominal pressure (Valsalva,
lifting, pregnancy, postural), or by anxiety, or by
medicines such as reglan.
Signs: Hypertension, orthostatic hypotension,

pallor, retinopathy, fever, tremor
Pheochromocytoma
Pheos may be
Benign or malignant (10%)
Inherited (25%) or de novo
In the adrenal gland or in other
sympathetic chain/ganglia cells outside
the adrenal gland (10%).
Typically pheos are adrenal medullary
tumors that secrete catecholamines.
Pheochromocytoma
Catecholamines: epinephrine, norepinephrine,
dopamine
- Problem with measuring spot serum catecholamines?
Episodic secretion
- To enhance sensitivity, can measure 24 hr urine
catecholamines.
- However, measuring catecholamines can yield false
positives (too many substances both endogenous and
exogenous cross react w/ the catecholamine assay).
Metanephrines: metanephrine, normetanephrine

- More specific than measuring catecholamines is measuring
24 hr urine metanephrines, which are the breakdown
products of catecholamines
Pheochromocytoma
What about measuring spot plasma free
metanephrines?
Very high sensitivity (~98%).
Appealing because it is just a simple blood
draw.
May be too sensitive at the expense of
specificity. Of patients over 60 with
hypertension and elevated plasma free
metanephrines, 97% will NOT have
pheochromocytoma.
Pheochromocytoma
Recommendation
24 hr urine fractionated catecholamines and
24 hr urine fractionated metanephrines.
Always fractionate; pheos typically secrete
norepinephrine (and normetanephrine) out of
proportion to epinephrine (and metanephrine).
(Consider) Plasma free metanephrines

Must understand the test properties; high sensitivity,
low specificity thus may lead to excessive testing,
procedures, surgeries and health care expenditures.
Adrenocortical Carcinoma
Symptoms/Signs:
Salt c/w Aldosteronsim
Sugar c/w Cushings syndrome
Sex
androgens: hirsutism, acne, oily skin,
amenorrhea, oligomenorrhea, increased libido
estrogens: gynecomastia, testicular atrophy
> 4 cm in size worrisome for carcinoma

Consider excision of mass
Follow-Up
If functional studies are normal
Recommend repeat imaging at 6-12 months

Recommend repeat adrenal screening annually
for 4 years
If concern for malignant potential based on
imaging the biopsy or excision
Take Home Points

1. If there is no adrenal syndrome on history and physical, and the adrenal
incidentaloma is less than 1 cm, dont worry about it.
2. Of adrenal incidentalomas (>1 cm) without a clinical syndrome:
5.3% subclinical Cushings
5% subclinical pheo
4.7% adrenocortical carcinoma
2.5% metastatic carcinoma
1% subclinical aldo
3. Treating patients (the treatment is usually surgical) with subclinical

adrenal syndromes usually results in easier to control HTN, weight loss,
better DM control, lower risk of osteoporosis, etc.
However, the major concern with discovery of an adrenal incidentaloma is the possibility of
malignant disease!
4. Of the adrenal syndromes mentioned above, the only one which presents
with signs and symptoms of hyperandrogenism or estroginism is
adrenocortical carcinoma.
Terima kasih
ASS WR WB

Kelenjar Adrenal

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dr M. Arman Nasution SpPD

Hormones are Regulated by the

In this Presentation, Mainly we are

Hypothalamus and Pituitary Gland

What makes up the endocrine

We typically leave out local

They are important

Remember that it is an artificial system

Endocrine Key Concepts

Endocrine Key Concepts

Endocrine Key Concepts

Endocrine Key Concepts

Endocrine Key Concepts

Endocrine Key Concepts

Hypothalamic Pituitary Adrenal

Endocrine Key Concepts

Endocrine Key Concepts

Endocrine Key Concepts

A minority of the pancreas is

These collections of endocrine cells

Alpha Cells - Glucagon

Epsilon Cells Ghrelin? (<0.5%)

Alpha Cells - Glucagon

Beta Cells - Insulin

Delta Cells - Somatostatin

Blood Supply is in three steps

from the Hypothalamus goes

This is called the

Just like in the gut and liver

The venous blood, carrying

This portal system gives the

Hypothalamus and Pituitary

Some cells dont:

peptides have different

Third and Fourth Arches

Right and Left

Third and Fourth Arches

Medulla forms second

This should remind you of the kidney

Well save these for

Orphan Endocrine Cells

Generate tissue and organ levels of

Orphan Endocrine Glands

Atrial-natriuretic peptide (ANP)

Stomach and intestines

Insulin-like growth factor

Orphan Endocrine Glands

the "third eye" by ancient people.

and usually weighs less than one

The thyroid cartilage covers the

Humans have four parathyroid

located in variable manner on the

It is situated in the upper part of the

made up of two lobes that join in front of

pancreas has two main functions:

o produce a female hormone

Testes is male gonads.

Formation, Developmet and

Endocrine system is the

1)Steroid hormones including

prostaglandins which function especially in

3) Peptide hormones (like insulin)