Adrenal cortical hormones
By- Dr Shafali Singh
Learning objectives
• Layers of the adrenal cortex and their role in
hormone synthesis
• Biosynthetic pathways of steroid hormone
synthesis and result of the enzyme
deficiencies.
• Physiological action of glucocorticoids and
mineralocorticoids
• Applied aspect
Aldosterone and cortisol secretion are regulated by
independent mechanisms
Actions of Aldosterone
↑Aldosterone
↓Aldosterone
• Hypokalemia - muscle
weakness,
• Hyperkalemia -cardiac
arrhythmia ,mus
paralysis
• Metabolic alkalosis
• Metabolic acidosis
MINERALOCORTICOID DISORDERS
Hyperaldosteronism
with Hypertension
with Hypotension
LOW RENIN
Primary
hyperaldostero
nism (Conn’s
syndrome)
HIGH RENIN
Secondary
hyperaldostero
nism
HIGH RENIN
Secondary
hyperaldosteronism
Primary hyperaldosteronism (Conn’s syndrome)
• Most common cause is a small unilateral
adenoma, on either side
• lncreased whole body sodium, fluid, and
circulating blood volume
• Edema rare (sodium escape*)
• Blood pressure from borderline to severe
hypertension
• Modest left ventricular hypertrophy
• weakness and fatigue.
• Increased hydrogen ion excretion and new
bicarbonate create metabolic alkalosis.
• A positive Chvostek’s or Trousseau’s sign
suggestive of alkalosis
• Cortisol is normal.
• Suppression of renin a major feature
high BP + low renin = pri hyper aldo
Secondary hyperaldosteronism with hypertension
• In most cases a primary over-secretion of
renin secondary to a decrease in renal blood
flow and/or pressure
• Renal arterial stenosis, narrowing via
atherosclerosis, fibromuscular hyperplasia.
• Modest to highly elevated renin
• Modest to highly elevated aldosterone
• Hypokalemia and metabolic alkalosis
high BP+ High renin = renal artery stenosis
Differential diagnosis: Hypokalemia in a
hypertensive patient not taking diuretics
• Hyposecretion of renin with elevated
aldosterone that fails to respond to a volume
contraction – Conn’s syndrome
• Hypersecretion of renin with elevated
aldosterone – renal artery atenosis
Secondary hyperaldosteronism with hypotension
• Cause--Sequestration of blood on the venous side of
the systemic circulation. This results in decreased
cardiac output and thus decreased blood flow and
pressure in the renal artery.
• causes:
Congestive heart failure
Constriction of the vena cava
Hepatic cirrhosis
nephrotic syndrome
low B.P + high renin + high aldosterone =secondory
hyp aldo
Concerning Secondary Hyperaldosteronism with hypotension
Aldosterone Secretion
Increased
Decreased
• decreases pressure in the
renal artery (e.g., hemorrhage,
prolonged sweating)
• High potassium intake
• Low sodium intake
• Constriction of inferior vena
cava in thorax
• Standing
• Secondary hyperaldosteronism
(in some cases of congestive
heart failure, cirrhosis, and
nephrosis)
• increases blood pressure in
the renal artery. This
includes weightlessness,
because blood no longer
pools in the extremities
when the individual is
standing or sitting
Consequences of the Loss of Regional
Adrenal Function
Zona glomerulosa: The absence of the
mineralocorticoid, aldosterone, results in:
• Loss of Na+
• Decreased volume of the ECF
• Low blood pressure
• Circulatory shock
• Death
(mineralocorticoid is generally required for
survival)
Hypocortisolism
Primary Hypocortisolism (in primary adrenal insufficiency,
Addison’s disease)
Cortisol deficiency
• leads to weakness,
fatigue, anorexia,
hypotension,
hyponatremia,
hypoglycemia.
• Increases in ACTH result
in hyperpigmentation of
skin and mucous
membranes.
Aldosterone deficiency
• leads to sodium wasting
and hyponatremia,
• Potassium retention
• Hyperkalemia,
dehydration,
• Hypotension, and
acidosis
Androgen deficiency
• Loss of axillary and pubic
hair
A) Tan and vitiligo. B) Pigmentation of scars from lesions that occurred after the development of the
disease. C) Pigmentation of skin creases. D) Darkening of areolas. E) Pigmentation of pressure points. F)
Pigmentation of the gums.
• Excessive secretion of ACTH (e.g., Addison’s
disease) causes darkening of the skin.
• This is due to the melanocyte-stimulating
hormone (α-MSH) sequence within the ACTH
molecule, and the β-MSH activity of βlipotropin.
_
Regulation
of
glucocorti
coids
secretion
+
_
_
+
Transport, Metabolism, & Excretion of
Adrenocortical Hormones
Metabolic Actions of Cortisol
• Effects on carbohydrate metabolismCortisol raises blood glucose, making more glucose
available for nervous tissue.
Two mechanisms are involved:
cortisol inhibits glucose uptake in most tissues
(muscle, lymphoid, and fat).
cortisol increases hepatic output of glucose via
gluconeogenesis from amino acids in particular (not
from liver glycogenolysis)
• Effects on protein metabolismCortisol promotes degradation and increased
delivery of amino acids.
Effects on lipid metabolism
• ↑ Mobilisation of fatty acids from adipose tissue
• ↑ FFA in plasma, ↑ oxidation of fat
• Redistribution of fat – ‘Centripetal distribution’
• Utilises fat for energy
• Potentiates lipolytic actions of GH, Glucagon,
Catecholamines & Thyroxine
Anti-inflammatory Action
Decreases
• capillary permeability
• prostaglandin and
leukotriene synthesis
Disadvantage:
As the glucocorticoids
prevent inflammation,
silent spread of
infection occurs rapidly
Immune supression
Decreased production
of
• lymphocytes
• interleukins 1 and 6
(IL-1 and IL-6)
• T-cells
Anti-allergic effect
• Glucocorticoids prevent liberation of histamine from
the mast cells by antigen-antibody complexes &
prevent allergic manifestations.
• Blocks inflammatory response to allergy
Clinical uses :
1. Treatment of allergic diseases like eczema
2. Treatment of Bronchial Asthma
Stress (Includes States Such as Trauma, Exposure to
Cold, Illness and Exercise)
Main agent to
fight stress.
Secretion of
glucocorticoids
increases during
stress through
activation of
hypothalamopituitary-adrenal
axis
Resistance to stress
• Stress - ↑ ACTH - ↑ cortisol - ↑ resistance
• Rapid mobilisation of fat – energy changes
Stress hormones
(counter regulatory hormones)
• G Growth hormone: mobilizes fatty acids by
increasing lipolysis in adipose tissue
• G Glucagon: mobilizes glucose by increasing liver
glycogenolysis
• G glucocorticoids;Cortisol (does not increase in
starvation): mobilizes fat, protein, carbohydrate
• Epinephrine, in some forms of stress such as
exercise: mobilizes glucose via glycogenolysis and
fat via lipolysis
Effects on vascular system
Effects on Mineral metabolism
Effects on Nervous system:
Effect on gasrtointestinal tract
During foetal life
Positive inotrophic
By increasing the effect of
catecholamines (Permissive
Action ), it increases the smooth
muscle tone & maintains B.P.
Overlapping Action
It increases Na+ store and
deplete K+ like mineralocorticoids
Calciuric Action
modulate excitabilitybehavoiour
and mood.
Increase gastric acid secretion
Decrease proliferation of
gastric mucosal cells
Maturation of lungs,gastro
intestinal tract,CNS, retina ,skin
Permissive Actions of Cortisol
Glucagon
• Promotes glycogenolysis in the liver (some
lipolysis from adipocytes as well).
• Without cortisol, fasting hypoglycemia rapidly
develops.
Catecholamines
• Promote glycogenolysis and lipolysis in liver and
muscle. Promote vasoconstriction and
bronchodilation.
• Without cortisol, blood pressure decreases.
Hypercortisolism
Primary
(Adrenal adenoma –
Benign, unilateral)
Secondary( High ACTH)
1. Pituitary –cushing
disease
2.Ectopic ACTH
production
Hypocortisolism
Primary
(Adrenal insufficiencyAddison’s disease)
Secondary( Low ACTH)
1. Exogenous cortisol
withdrawl
2. Pituitary tumor
Glucocorticoid Excess
• Cushing syndrome: hypercortisolism
regardless of origin, including chronic
glucocorticoid therapy
• Cushing disease: hypercortisolism due to an
adenoma of the anterior pituitary
(microadenoma)
Excessive cortisol
• Muscle weakness (excessive proteolysis ; hypokalemia
(via mineralocorticoid actions),
• Skin thins and is more readily damaged(Cortisol
inhibits fibroblast proliferation and collagen
formation).
• The connective tissue support of capillaries is impaired,
and capillary injury, or bruising, is increased .
• Incr Glucose
• Redistribution of Fat
• Incr B.P
• Euphoria
Suppression Tests
1. Low-dose dexamethasone (for the presence of
Cushing syndrome)
cortisol decreases
Normal
cortisol not suppressed
Hypercortisolism;
2. High-dose dexamethasone( To differentiate Cushing
disease from ectopic ACTH secretion and adrenal tumors)
cortisol decreases
Cushing disease;
cortisol not suppressed
Ectopic ACTH, or
adrenal tumor;
Metyrapone testing
• Mainly to access pituitary-adrenal reserve
• Inhibits 11 beta hydroxylase, thereby
decreases cortisol
• Normal pituitary ; ACTH increases, 11deoxycortisol increases
• ACTH level no change, pituitary not
functioning
Hypercortisolism
Primary hypercortisolism (adrenal origin)
• Cortisol elevated, ACTH depressed
• Most are benign adrenocortico adenomas
• Adrenal adenoma usually unilateral and
secretes only cortisol; decreased adrenal
androgen and deoxycorticosterone (hirsutism
absent)
Presence of androgen or mineralocorticoid excess suggests a
carcinoma.
Secondary hypercortisolism (pituitary/ectopic)
• ACTH dependent
• Elevated ACTH, cortisol, adrenal androgen,
deoxycorticosterone
• Hypersecretion of ACTH results in bilateral
hyperplasia of the adrenal zona fasciculata
and reticularis
Cushing disease
Ectopic ACTH syndrome
• Cause is a pituitary
adenoma usually a
microadenoma.
• Most common pathological
cause of Cushing syndrome
• Increased ACTH not
sufficient to cause
hyperpigmentation
• Dexamethasone
suppressible
• Most frequently in patients
with small cell carcinoma of
the lung
• Greater secretion of ACTH
than in Cushing disease and
hyperpigmentation often
present
• Ectopic site nonsupressible
with dexamethasone
• Typical features of Cushing
syndrome often absent due
to malignancy
Hypocortisolism
Primary Hypocortisolism (in primary adrenal insufficiency,
Addison’s disease)
Cortisol deficiency
• leads to weakness,
fatigue, anorexia,
hypotension,
hyponatremia,
hypoglycemia.
• Increases in ACTH result
in hyperpigmentation of
skin and mucous
membranes.
Aldosterone deficiency
• leads to sodium wasting
and hyponatremia,
• Potassium retention
• Hyperkalemia,
dehydration,
• Hypotension, and
acidosis
Androgen deficiency
• Loss of axillary and pubic
hair
Absence of the glucocorticoid, cortisol,
The contributes to:
• Circulatory failure, because without cortisol,
catecholamines do not exert their normal
vasoconstrictive action
• An inability to readily mobilize energy sources
(glucose and free fatty acids) from glycogen or
fat.
• Under normal living conditions, this is not lifethreatening; however, under stressful situations,
severe problems can arise. For example, fasting
can result in fatal hypoglycemia.
A) Tan and vitiligo. B) Pigmentation of scars from lesions that occurred after the development of the
disease. C) Pigmentation of skin creases. D) Darkening of areolas. E) Pigmentation of pressure points. F)
Pigmentation of the gums.
Q The signs and symptoms of a patient with
primary adrenal insufficiency include
a. Pallor
b. Low ACTH levels
c. High cortisol levels
d. Hyperkalemia
e. Hypertension
Addisonian crisis:
Minor stress precipitates collapse
• After adrenalectomy
• Abrupt withdrawal of cortisol
• Treatment:
IV cortisol, glucose, NaCl
Maintenance: lifetime cortisol & aldosterone
Stimulation Tests
• Rapid ACTH stimulation test
• To diagnose both primary and secondary
hypocortisolism (atrophied adrenal
nonresponsive)
• Normal; cortisol increases
• Primary Hypocortisolism; cortisol no change
Secondary hypocortisolism(central)
• Most commonly due to sudden withdrawal of
exogenous glucocorticoid therapy
• Pituitary or hypothalamic tumors most common
natural origin of ACTH deficiency
• May be associated with the loss of other anterior
pituitary hormones (pan-hypopituitarism) or
adenomas secreting prolactin or growth hormone
• Atrophy of the zona fasciculata and zona reticularis
• Zona glomerulosa and aldosterone normal; no
manifestations of miner-alocorticoid deficiency
When prolonged treatment with anti-inflammatory
doses of glucocorticoids is stopped
adrenal is atrophic and unresponsive after cortisol
treatment,
pituitary unable to secrete normal amounts of ACTH for as
long as a month.
Thereafter, ACTH secretion slowly increases to
supranormal levels.
These in turn stimulate the adrenal, and glucocorticoid
output rises, with feedback inhibition gradually reducing
the elevated ACTH levels to normal ..
Primary and Secondary Disorders of
Cortisol Secretion
Q. Cortisol administration to a patient with
adrenal insufficiency will
a. Increase insulin sensitivity in muscle
b. Enhance wound healing
c. Increase corticotropin-releasing hormone
secretion
d. Increase ACTH secretion
e. Increase gluconeogenesis
ADRENAL ANDROGENS
• Major-DHEA, Androstenedione
Minor-oestrogen,progestrone
Androgens are the hormones that exert masculinizing effects
and they promote protein anabolism and growth
•
•
•
•
Actions:
Less than 20% of testosterone activity
Little masculinising effect
Early development of male sex organs
Growth of pubic hair, axillary hair
Control:
• By ACTH
• Medulla: The absence of the catecholamine,
epinephrine (the major hormone of the
adrenal medulla), results in:
• Decreased capacity of the individual to
mobilize glycogen or fat during exercise or
cold exposure;
• however, the adrenal medulla is not essential
for survival
• Synthesis and Secretion of
Adrenocortical Hormones
Pathway to aldosterone synthesis
Control of Steroid Hormone Synthesis in the Zonas Fasciculata and Reticularis
C19 steroids (19 carbon atoms)
Adrenal Androgens
• Have a keto group at position 17 and are therefore called
17-ketosteroids.
• DHEA, DHEA sulfate, and androstenedione have very low
androgenic activity. They function primarily as precursors
for the peripheral conversion to the more potent
testosterone and dihydrotestosterone (men and women).
• In adult males, excessive production of adrenal androgens
has no clinical Consequences.
• In prepubertal males it causes premature penile
enlargement and early development of secondary sexual
characteristics.
• In women excessive adrenal androgens cause hirsutism and
virilization.
Adrenal androgen
• Are conjugated with sulfate in the adrenal
cortex, making them water soluble.
• As water-soluble metabolites, they circulate in
the bloodstream, are filtered by the kidney,
and are excreted in the urine.
• The sulfated form is not produced in the
gonads and is thus considered an index of
androgen production by the adrenals
Urinary 17-ketosteroids
Are an index of all androgens, adrenal and
testicular.
In females and prepubertal males, urinary 17ketosteroids are an index of adrenal androgen
secretion.
In adult males (postpuberty), urinary 17ketosteroids are 2/3 adrenal and 1/3 testicular,
and thus mainly an index of adrenal secretion.
Which step in steroid hormone biosynthesis is
stimulated by adrenocorticotropic hormone
(ACTH)?
(A) Cholesterol → pregnenolone
(B) Progesterone → 11-deoxycorticosterone
(C) 17-Hydroxypregnenolone →
dehydroepiandrosterone
(D) Testosterone → estradiol
(E) Testosterone → dihydrotestosterone
Which step in steroid hormone biosynthesis, if
inhibited, blocks the production of all
androgenic compounds but does not block the
production of glucocorticoids?
(A) Cholesterol → pregnenolone
(B) Progesterone → 11-deoxycorticosterone
(C) 17-Hydroxypregnenolone →
dehydroepiandrosterone
(D) Testosterone → estradiol
(E) Testosterone → dihydrotestosterone
Enzyme Deficiencies
• Single enzyme defects can occur as congenital
“inborn errors of metabolism.”
• Congenital defects in any of the enzymes lead
to deficient cortisol secretion and the
syndrome called congenital adrenal
hyperplasia.
21 β-Hydroxylase Deficiency
Summary of overall pathway changes:
• Zona glomerulosa: decreased aldosterone
• : decreased production of 11-deoxycorticosterone, a weak mineralocorticoid.
• Therefore, a mineralocorticoid deficiency, loss of
Na+, volume and a hypotensive state.
• Increased renin secretion and increased
circulating angiotensin II.
• Decreased production of corticosterone, a weak
glucocorticoid, and cortisol.
• Therefore, glucocorticoid deficiency and
increased ACTH, which drive increases in adrenal
androgen secretion
21 β-Hydroxylase deficiency cont..
• Accounts for about 90% of the cases
• Neonates may present with a salt-wasting crisis.
• Salt wasters tend to have hyponatremia,
hyperkalemia, and raised plasma renin.
• 17-hydroxyprogesterone is elevated.
• Increased androgens lead to virilization of the female
fetus and sexual ambiguity at birth
• Males are phenotypically normal at birth but develop
precocious pseudopuberty, growth acceleration,
premature epiphyseal plate closure, and diminished
final height.
• Goal in treatment is to bring glucocorticoid and
mineralocorticoid back to the normal range which
would also suppress adrenal androgen secretion.
11 β-Hydroxylase Deficiency
Summary of overall pathway changes:
decreased corticosterone and cortisol,
increased ACTH and overproduction of steroids above the
blockade,
including:
• – Androgens and the consequences in women and
prepubertal males
• – 11-deoxycorticosterone, a mineralocorticoid that leads
to hypertension and a decrease in circulating
angiotensin II
Zona glomerulosa: decreased stimulation of the steroid
pathway and aldosterone production due to the
hypertensive decrease in circulating angiotensin II
11 β-Hydroxylase deficiency
Accounts for about 7% of all cases
• Clinical features of increased androgens similar to
the preceding form, including virilization of female
fetus.
• The principal difference with this form is the
hypertension produced by 11 deoxycorticosterone,
along with hypokalemia and suppressed renin
secretion.
• Milder forms do not present with hypertension
and its consequences.
17 α-Hydroxylase Deficiency
Effect in the testes
Effect in the ovaries
• Zona fasciculata, reticularis: decreased adrenal
androgens, decreased cortisol, and increased ACTH.
Increased 11-deoxycorticosterone leading to
hypertension.
• The reduced circulating angiotensin II reduces
stimulation of zona glomerulosa and aldosterone
secretion
• Extremely rare
• no sex hormones are produced, so female external
genitalia are present.
• Usually diagnosed at the time of puberty when the
patient presents with hypertension, hypokalemia, and
hypogonadism
• Individuals have eunuchoid characteristics
Summary of enzyme deficiency
• Cholesterol desmolase deficiency is fatal in
utero because it prevents the placenta from
making the progesterone necessary for
pregnancy to continue.
• Mutation of the gene for the steroidogenic
acute regulatory (StAR) protein A cause of
severe congenital adrenal hyperplasia in
newborns. This protein is required for the
normal movement of cholesterol into the
mitochondria to reach cholesterol desmolase.
• A new born female is hypotensive and hypoactive .She
also has a labial fusion and clitromegaly .The prenatal
period and delivery were uncomplicated .Laboratory
investigations reveal increased urinary 17hydroxyprogesterone exceretion and decreased 11 –
deoxycortisone excretion. Which of the following
enzymes is most likely to be deficient in this patient?
•
•
•
•
•
17- hydroxylase
21- hydroxylase
11- hydroxylase
Desmolase
5 α reductase
Which step in steroid hormone biosynthesis
occurs in the accessory sex target tissues of
the male and is catalyzed by 5α-reductase?
(A) Cholesterol → pregnenolone
(B) Progesterone → 11-deoxycorticosterone
(C) 17-Hydroxypregnenolone →
dehydroepiandrosterone
(D) Testosterone → estradiol
(E) Testosterone → dihydrotestosterone
Q. If a heart transplant patient receives
prednisone (a glucocorticoid) to help
prevent rejection of the transplanted
tissue, will blood levels of ACTH and CRH
be high or low?
Q The secretion of ACTH is correctly described in
which of the follow-ing statements?
• a. It shows circadian rhythm in humans
• b. It is decreased during periods of stress
• c. It is inhibited by aldosterone
• d. It is stimulated by glucocorticoids
• e. It is stimulated by epinephrine