Adrenal gland

Dr (Mrs.)Geeta Arvind Kurhade, B. Sc., M.B.B.S., D.G.O., M.D.

Senior Lecturer, Physiology Unit, Department of Basic Sciences, EWMSC,Mt.Hope


John F. Kennedy's Addison's Disease
Addison's disease- a
disorder of the adrenal
system affecting
digestion and causes a
brownish coloration to
the skin.
Although it isn't fatal, it
is uncomfortable.


Left untreated, an Addison's Crisis can be fatal.

Symptoms of an Adrenal
Crisis include:
sudden penetrating pain
in the lower back,
abdomen, or legs
severe vomiting and
diarrhea
dehydration
low blood pressure
loss of consciousness


Moon face
Cushings syndrome-parched skin and Buffalo
hump
Some features of Cushings syndrome:
Adrenal gland
Complex
Multifunctional endocrine organs.
Essential for life.
Severe illness results from their atrophy.
Death follows their complete removal, unless
life-essential hormones are replaced
Introduction
Adrenal cortex surrounds adrenal medulla.

Adrenal Medulla- sympathetic ganglion in which neurones
have lost the axons to become secretory cells) - not essential
for life.

It has two types of cells which secrete catecholamines

a) 90% large cells with dense granules Epinephrine

b) 10% small cells with very dense granules Norepinephrine.

Dopamine


Adrenal cortex-Salt, sugar, and sex: the deeper
you go, the sweeter it gets.
secretes steroids- essential for life

Zona glomerulosa ( whorls of cells) mineralocorticoids
(for Na balance & ECF )
aldosterone
deoxycorticosterone
Zona fasciculata (columns of cells) glucocorticoids
(for metabolic effect on CHO & proteins)
cortisol
corticosterone
Zona Reticularis ( network of cells) sex hormones
(minor effect on reproductive function )
Dehydroepiandrosterone (DHEA)
Androstenedione
(produces) estrogen)


Adrenal medulla acts as sympathetic ganglion
Postganglionic neurons have lost their axons &
became secretory cells.

Adrenal cortical hormones are controlled by ACTH
from anterior pituitary.

Mineralocorticoids are ALSO independently
controlled by circulating factors like Angiotensin II

Each adrenal gland 4 gm.


Permissive action of glucocorticoids
After removal of both adrenals humans will not survive for
long without glucocorticoid replacement.

Cortisol has a wide range of actions, many of which are
considered permissive.

This is because it does not always initiate processes but allows
them to occur by
increasing the activity of enzymes,
inducing enzymes or
augmenting/ inhibiting the action of other hormones.
Foetal adrenal
Large & under pituitary control
20% of foetal gland permanent cortex
80% foetal adrenal cortex degenerates at birth.
The foetal adrenal cortex synthesizes & secretes conjugated
androgens which are converted to estrogens in placenta.
Zona glomerulosa secrets aldosterone & also forms new
cortical cells.
Adrenal medulla does not regenerate.
What will happen immediately to Zona glomerulosa,Zona
fasciculata and zona reticularis after hypophysectomy and
why? (HW)
Actions of catecholamines (half life 2 min in
circulation)
Norepinephrine Epinephrine Dopamine
Formed by hydroxylation
&decarboxylation of
tyrosine
Formed by methylation of
NE
70% of NE is conjugated &
inactive
70% of E is conjugated &
inactive

95% conjugated
Normal plasma level in
recumbent human:
Free NE= 300pg/ml
up to 50-100% on
standing
Free E=30 pg/ml Plasma free dopamine
level=35pg/ml
Other substances secreted by adrenal
medulla:
Opioid peptide
Metenkephalin
Adrenomedullin (vasopressor)
Effects of epinephrine & norepinephrine
Glycogenolysis in liver & SKM
Mobilization of FFA
plasma lactate
Stimulates metabolic rate
force & rate of contraction of isolated heart.
myocardial excitability causes extra systole & serious
cardiac arrhythmia.
NE acts on 1 receptors causes vasoconstriction
E acts on 2 receptors vasodilation which overbalances
vasoconstriction & total PR .



Effects of E & NE contd...
alertness.

secretion of insulin & glucagon via adrenergic
mechanism.

metabolic rate: Prompt & delayed rise

a) prompt rise due to cutaneous vasoconstriction heat
loss in body temperature.

b) delayed rise due to oxidation of lactate in liver.

Pheochromocytoma-adrenal medullary tumors

Secrete NE & E or both sustained hypertension.


Sometimes episodic secretions Pt gets bouts of
palpitations, head ache, glycosuria & extreme systemic
HT.
Dopamine
Physiological fn unknown.

systolic BP & no change in diastolic BP.

Useful in traumatic & cardiogenic shock.
Regulation of medullary secretions

Physiologic stimuli affect medullary secretions through
nervous system.

Catecholamine levels are low & are further low during sleep.

Diffuse sympathetic discharge adrenal medullary
secretions.

NE secretions by emotional stress.
E secretions when the individual doesnt know what to
expect.

Adrenal cortical
hormones
Average daily secretions & Plasma concentrations
(free & bound) of various cortical hormones
Mineralocorticoids:
aldosterone-Daily secretion= .15 mg/day.
Plasma concentration= .006g/dl
deoxycorticosterone=Daily secretion= .20 mg/day.
plasma concentration = .006g/dl (3% of aldosterone activity)
Glucocorticoids:
cortisol Daily secretion= 10 mg /day.
plasma concentration= 13.9g/dl
corticosterone Daily secretion= 3 mg/day.
plasma concentration= .4g/dl
Androgens:
Dehydroepiandrosterone (DHEA) - daily secretion =20 mg/day
Plasma concentration =175g/dl
Androstenedione -daily secretion 2-3 mg/day
Plasma concentration
forms estrogens that are not formed in the ovary.



Relative potencies of corticosteroids as
compared to cortisol
Steroid Glucocorticoid activity Mineralocorticoid activity
Cortisol 1 1
Corticosterone .3 15
Aldosterone .3 3000
Deoxycorticosterone .2 100
Corticosterone .7 .8
Prednisolone 4 .8
Dexamethasone 25 -0
Measure of glucocorticoid activity in this table was
i) liver glycogen deposition
2) anti-inflammatory assay
Measure of mineralocorticoid activity was
1) Effect on urinary Na+/K+

Cholesterol desmolase X1
3 hydroxysteroid
dehydrogenase X2
21 hydroxylase X3
21 hydroxylase X4
17 hydroxylase
17 ,20 lyase
x2
Enzyme deficiencies
X1- Deficiency in cholesterol desmolase-fatal (why?)
X2- deficiency of 3 hydroxysteroid dehydrogenase deficiency-
causes masculinisation in female.
In genetic male-not adequate to produce full masculinisation
hypospadias
X3- 21 hydroxylase deficiency causes virilization (Why?)
What does it cause in females??( AGS)
What is salt losing form of congenital virilising adrenal
hyperplasia? [21 hydroxylase deficiency-underlying mechanism]
X4- What is hypertensive form of virilising adrenal hyperplasia?
[11 hydroxylase deficiency-underlying mechanism]

Transport, Metabolism & Excretion of Adrenocortical
Hormones
Glucocorticoid- cortisol bound to globulin k/as transcortin or
corticosteroid-binding globulin (CBG).
Half life of cortisol is longer (60-90 min) as compared to
corticosterone (50 min)as it binds to a lesser degree.
Bound form is physiologically inactive acts as reservoir of Hr to
keeps supply available to tissues.
Normal level of cortisol are 13.5 g/dl
Corticosteroid binding globulin is produced in liver & its
production es by estrogen.
Level of CBG es in pregnancy (implications?) & decrease in
liver cirrhosis, nephrosis, multiple myeloma.
Cortisol is metabolized in liver where it is conjugated to glucoronic
acid.
Metabolism and excretion of aldosterone
Binds to protein to slight extent.
Half time is 20 min.
Total plasma level =.006g/dl.
Adrenal androgens
1) 17-ketosteroids dehydroepiandrosterone
(DHEA)
2) Testosterone also converted to 17
ketosteroids.
2/3
rd
of urinary ketosteroids in male secreted by
adrenal or formed from cortisol in liver.
1/3
rd
are formed testicular in origin
Notes on physiological action of adrenal
cortical hormones.
Page:35 of notes.
MCQs
Q. Which of the following are functions of
glucocorticoids in normal individuals? Key: D
I. protein catabolism
II. gluconeogenesis
III. ketone body formation
IV. hepatic glycogenolysis
A. I only
B. II and III only
C. I and IV only
D. I, II, and IV only

explanation
Because glucocorticoids plasma lipid levels
and ketone body formation in diabetics. In
the normal individual this does not happen
since insulin secretion es in response to
blood sugar levels.
MCQs
Q4. Patients with obstructive jaundice have pale-
colored stools because in obstructive jaundice,
urobilinogens are absent from the stool.
(Key: B)
A. The assertion and the reason are both correct, and the
reason is valid.
B. The assertion and the reason are both correct, but the
reason is invalid.
C. The assertion is correct but the reason is incorrect.
D. The assertion is incorrect but the reason is correct.
E. Both the assertion and the reason are incorrect.

MCQ
Q4. The glucocorticoids the lymphocytes in
circulation because they stimulate the lymphocytic
mitotic activity. (Key: E)
A. The assertion and the reason are both correct, and
the reason is valid.
B. The assertion and the reason are both correct, but
the reason is invalid.
C. The assertion is correct but the reason is incorrect.
D. The assertion is incorrect but the reason is correct.
E. Both the assertion and the reason are incorrect.

Etiocholanolone fever ?

Plasma cortisol levels are increased by

Stress of surgery
Burns
Infection
Fever
Psychosis
Electroconvulsive therapy
Acute anxiety
Prolonged and strenuous exercise
Hypoglycaemia.
Z. Glomerulosa (15%) ECF
conc of AgII & [K
+
]

Aldosterone (very potent
90% of all
mineralocorticoid activity)
(Aldosterone synthetase)
Desoxycorticosterone
(1/30
th
as potent as
alodsterone) secreted in
very small quantity)
Corticosterone slight
moneralocorticoid
activity)
9 Fluorocortisol
(synthetic and slightly
more potent than
aldosterone.
Cortisol & Cortisone
very slight
mineralocorticoid activity
of both.


Z. Fasciculata(75%)- ACTH
regulation

Glucocorticoids:Cortisol-
very potent 95% activity
Corticosterone 4%
activity- less potent than
cortisol.
Cortisone synthetic
activity as much as
cortisol.
Methylprednisone-
(synthetic-5 times potent
than cortisol.
Dexamethasone-synthetic
30 times more potent
than cortisol- no
mineralocorticoid activity
Some have both
glucocorticoid &
mineralocorticoid
activities.
Small amount of
androgens
Estrogens

Z.Reticularis
Deeper layer of cortex
Adrenal androgens
Dehydroepiandrosterone
(DHEA)
Androstenedione
Small amounts of
estrogens
Some amount of
glucocrticoids
Controlled by ACTH
Quiz: If the cells show following signs; then whats up
in the size and number of cells in the fasciculata and
reticularis.
Their mitochondria become larger and more numerous,
They develop central ribosomes and vesicular cristae.
The mitochondria also develop polylamellar membranes that
extend to nearby cholesterol-containing vacuoles.
The endoplasmic reticulum also increases.
These changes relate to ACTH stimulation and its effects on
steroid hormone synthesis.
Regulation of Zona Glomerulosa Function:

Aldosterone- the major mineralocorticoid.
Sustain ECF volume by conserving body
sodium.
Hence, aldosterone is largely secreted in
response to signals that arise from the kidney
in response to reduction in circulating fluid.
Regulation of aldosterone secretion.
Body Na
+
depletion -
ECF & hypovolemia.
Activation of the renin-
angiotensin - the
predominant stimulus to
aldosterone production.
Elevation of plasma
potassium is the other
major stimulus.
ACTH has a minor tonic
stimulatory role.
Sodium sparing action of aldosterone
Aldosterone controls body fluids and electrolytes balance by
acting on renal epithelium.

Whenever

blood pressure falls below a certain threshold, the
renin-angiotensin-aldosterone

system (RAAS) is activated and
more salt and water are reabsorbed

in the kidney.

Vascular

endothelium is another target for mineralocorticoids.
Probably endothelium and kidney join forces in the regulation
of

body fluids.

Adosterone acts not only on epithelial cells of kidney

and
colon but also at nonepithelial sites in brain, heart, and

vasculature.
Na
+
absorption in sweat glands, colon.

Source: News in Physiological Sciences, Vol. 19, No. 2, 51-54, April 2004 2004 Int. Union Physiol. Sci./Am. Physiol. Soc
Functions of mineralocorticoid
Acute life saving

Aldosterone deficiency causes severe renal NaCl wasting and
hyperkalemia.

The person will soon develop ECF volume and blood
volume- COP-shock like state.

Total loss of adrenocortical secretion may cayse death within
3 days to 2 weeks unless person receives extensive salt
therapy or mineralocorticoids.
Aldosterone- negative feedback relationship with
potassium
K
+
acts to stimulate aldosterone secretion
which facilitates the clearance of K
+
from the
ECF.
Conversely, K
+
depletion lowers aldosterone
secretion.
Excess aldosterone-hypokalemia (implications?)
From normal value of 4.5 mEq/L to low as 2 mEq/L.

If [K
+
+ to < half of normal severe muscle weakness
because alteration of the electrical excitability of the nerve
and muscle fibre membrane preventing the transmission of
normal action potential.

Deficiency of aldosterone: [K
+
+ in ECF (if > 60-100%- serious
cardiac toxicity, weakness of heart contraction, arrhythmia
and heart failure.
Excess aldosterone tubular H
+
secretion & causes
mild alkalosis

H
+
are exchanged for Na
+
which are excreted.
[Na
+
+ in ECF causing mild alkalosis.

Regulation of aldosterone secretion
Regulation of aldosterone by Z glomerulosa cells is
independent of the regulation of corisol by Z fasciculata and
androgens by Z reticularis.
FOUR factors in order of their importance are:
i) *K
+
+ in ECF aldosterone secretion
ii) Renin Ag II activity aldosterone secretion
iii) *Na
+
+ in ECF very slightly aldosterone secretion
iv) ACTH is necessary but has little effect in controlling the
rate of aldosterone secretion.
Aldosterone acts on kidney to excrete excess K+ and the
blood volume and arterial pressure thus returning renin AgII
system towards normal level of activity.
OK
Glucocorticoids
Cortisol-very potent 95% activity
Corticosterone 4% activity-much less potent than cortisol.
Cortisone synthetic activity as much as cortisol.
Methylprednisone- (synthetic-5 times potent than cortisol.
Dexamethasone-synthetic 30 times more potent than cortisol-
has no mineralocorticoid activity
Some of these hormones have both glucocorticoid and
mineralocorticoid activities.
Effects on Carbohydrate metabolism-
Diabetogenic
Cortisol stimulates the release of
amino acids from muscle. These are
taken up by the liver and converted
to glucose.
The increased circulating
concentration of glucose stimulates
insulin release. Cortisol inhibits the
insulin-stimulated uptake of glucose
in muscle via the GLUT4 transporter.
Cortisol has mild lipolytic effects.
These are overpowered by the
lipogenic action of insulin secreted in
response to the diabetogenic action
of cortisol.
Cortisol also has varied actions on a
wide range of other tissues
Gluconeogenesis

Pulsatile and diurnal nature of cortisol secretion.
(From Weitzman ED et al: J Clin Endocrinol Metab 33:14, 1971.)
The plasma peaks of cortisol are
determined by the frequency and
duration of secretory bursts,
rather than by gradual changes
within a range of cortisol secretion
rates.

Thus, the basal unstimulated rate
of secretion is actually near zero,
and acute ACTH pulses produce
essentially all-or-none adrenal
responses.

The reason for each of the
daytime bursts of cortisol is
unknown
Functions of glucocorticoids
Although cortisol has some minor lipolytic activity, this effect is overshadowed in a
patient with Cushing's syndrome by the increased insulin secretion in response to
the diabetogenic actions of cortisol.
Insulin has a strong lipogenic action- excess glucocorticoids and increased fat
deposition.
The reason for the centripetal distribution of fat is not fully explained but probably
results from metabolic differences between adipocytes in the omentum and those
situated in subcutaneous tissues.
Bruising, scarring and purple striae around the abdomen are other classical signs
of Cushing's syndrome . Cortisol inhibits fibroblast proliferation and also the
formation of interstitial materials such as collagen. Excess glucocorticoids result in
a thinning of the skin and the loss of connective tissue support of capillaries. This
makes them more susceptible to injury and leads to bruising. Bones are also
affected by excess glucocorticoids.
Cortisol decreases osteoblast function and decreases new bone formation;
osteoclast numbers increase and measures of their activity increase. Furthermore,
glucocorticoids decrease gut calcium absorption and decrease renal calcium
reabsorption, thus adversely affecting calcium balance. Overall excess
glucocorticoids cause osteoporosis.

Glucocorticoids have other diverse actions including those on the
cardiovascular system, central nervous system, kidney and the fetus.
In the cardiovascular system, it is required for sustaining normal blood
pressure by maintaining normal myocardial function and the
responsiveness of arterioles to catecholamines and angiotensin II.
In the CNS, cortisol can alter the excitability of neurons, induce neuronal
death (particularly in the hippocampus) and can affect the mood and
behavior of individuals. Depression may be a feature of glucocorticoid
therapy. Furthermore, depressed patients may show increased cortisol
secretion with alteration in the circadian rhythm of cortisol secretion.
In the kidney, cortisol increases glomerular filtration rate by increasing
glomerular blood flow and increases phosphate excretion by decreasing its
reabsorption in the proximal tubules.
In excess, cortisol has aldosterone-like effects in the kidney causing salt
and water retention. This is because the capacity of 11-hydroxysteroid
dehydrogenase type 1 enzyme that converts active cortisol to inactive
cortisone in the kidney tubule is overwhelmed.
Cortisol is then available to interact with the aldosterone receptor for
which it has equal affinity .
This may be a factor in the hypertension seen in patients with Cushing's
syndrome.

Cortisol also facilitates fetal maturation of the central nervous
system, retina, skin, gastrointestinal tract and lungs.

It is particularly important in the synthesis of alveolar surfactant
which occurs during the last weeks of gestation. Babies born
prematurely may suffer respiratory distress syndrome and mothers
with pre-term labor may be treated with glucocorticoids to
stimulate fetal synthesis of surfactant.

One of the most important actions of glucocorticoids is on
inflammatory and immune responses .

Inflammation (increased capillary permeability, attraction of
leukocytes etc.) results from injury and these effects are mediated
by several factors the production of which is inhibited by cortisol.

Corticosteroids & organ transplant:

After an organ transplant- immunosuppressant.
Because immune system will try to destroy the new
organ.
Corticosteroids e.g.prednisone or methylprednisolone is
given right before transplant, to decrease immune
system's activity, reduce inflammation, and prevent
rejection.
Why?
High doses of corticosteroids
Corticosteroids are usually continued for a few days after your surgery and
then tapered to the lowest dose that helps prevent rejection.
Taking high doses of corticosteroids for just a few days : causes temporary
side effects such as high BP, high cholesterol, weight gain, sleep problems,
and anxiety.
High doses can sometimes cause more severe side effects, such as
extreme agitation, paranoia, and psychosis (trouble telling the difference
between what is real and what is not real) or have hallucinations.

Prolonged use of corticosteroids :cause glaucoma, steroid-induced
diabetes, risk of getting an opportunistic infection (such as
pneumocystic pneumonia),due to weakened immune systems.
Glucocorticoids inhibit the conversion
of phosphatidyl choline to
arachidonic acid by inducing the
production of lipocortin which
inhibits phospholipase-A
2
(PL-A
2
).
They inhibit the production of
inflammatory prostaglandins and
thromboxanes by inhibiting
cycloxygenase (COX).
They inhibit the production and
action of leukotrienes which are also
formed from arachidonic acid by lipo-
oxygenase (L-O).
They block cytokine (IL-1)
production, reduce the number of
circulating T cells and so reduce
antibody production.
x = inhibitory effects of
glucocorticoids

Some of these factors are synthesized from arachidonic acid and
cortisol inhibits the synthesis and release of arachidonic acid by
inducing lipocortin which inhibits phospholipase A
2
.
This enzyme releases arachidonic acid from phosphatidyl choline
and, thus, the availability of arachidonic acid for the synthesis of
inflammatory mediators is reduced.
In addition glucocorticoids stabilize lysosomes, preventing the
release of proteolytic enzymes.
They inhibit the proliferation of mast cells, production of cytokines
and also the recruitment of leukocytes to the site of infection or
trauma.
They also affect the numbers and functions of circulating
neutrophils, eosinophils and fibroblasts.
In addition, glucorticocoids reduce the number of circulating
thymus derived lymphocytes (T- cells) and as a result the
recruitment of B lymphocytes.
The net result is to reduce both cellular and humoral immunity
Effects of cortisol on circulating leukocytes. Note the increase in neutrophils and decrease in
monocytes and lymphocytes of all types. T
4
helper lymphocytes were disproportionately
reduced. Eosinophils (not shown) also decrease.
(From Calvano SE et al: Surg Gynecol Obstet 164:509, 1987.)
Adrenal cortical androgens
DHEA and its sulfate have an ill-defined role in normal
physiology.
Together with androstenedione, they are generally termed
weak androgens and have a much lower affinity for the
androgen receptor than testosterone.
These adrenal androgens are, however, converted
peripherally to the more active testosterone .
In males, the amount released from the adrenal glands and
converted to testosterone is physiologically insignificant
compared to the amount secreted by the testes.
but, in females, adrenal-derived testosterone is important
in maintaining normal pubic and axillary hair.
After the menopause, adrenal androgens may
also be an important source of estradiol, again
due to peripheral conversion. Adrenal
androgen hypersecretion does not cause any
clinical signs in adult males but is detectable in
females by signs of hirsutism and
masculinization.
Symptoms of Adrenal Insufficiency (AI)

In patients with secondary AI, these symptoms often occur immediately. In people
with primary insufficiency the symptoms of adrenal insufficiency usually begin
gradually.

In either case the characteristics of AI are:
chronic, worsening fatigue
muscle weakness
loss of appetite
weight loss
headache
slow, sluggish, lethargic movement
dehydration
high fever
chills, shaking
confusion or coma
rapid heart rate
joint pain
abdominal pain
unintentional weight loss
rapid respiratory rate
unusual and excessive sweating on face and/or palms
possible skin rash or lesion
flank pain
irritability and depression
a craving for salty foods due to salt loss
Hypoglycemia, or low blood glucose, is more severe in
children than in adults




Addisons Disease
About 50 percent of the time, one will notice:
nausea
vomiting
diarrhea
Other symptoms may include:
low blood pressure that falls further when standing, causing dizziness or
fainting
skin changes in Addison's disease, with areas of hyper pigmentation, or
dark tanning, covering exposed and nonexposed parts of the body.

This darkening of the skin is most visible on scars; skin folds; pressure
points such as the elbows, knees, knuckles, and toes; lips; and mucous
membranes.
menstrual periods may become irregular or stop