The Hypothalamo-Pituitary-

Adrenocortical Axis

DR. NOELLE ORATA

MOUNT KENYA UNIVERSITY
Objectives:
• Identify the components of the Hypothalamo-
Pitutary-Adrenal (HPA) Axis
• Identify the factors involved in its control
• Describe the biosynthesis, structure and actions of
ACTH
• Identify the functional zones of the adrenal gland,
the hormones secreted and their actions
• Discuss Cushing’s syndrome( and ectopic ACTH
secretion), Addison’s disease, Conn syndrome and
Congenital adrenal Hyperplasia
 A. Hypothalamus
• Contains neurosecretory neurons which synthesize
peptides and catecholamines.
• Hormones are released into the systemic
circulation (target distant tissues) or released in
the portal circulation to the anterior pituitary
where they stimulate or inhibit release of the
anterior pituitary hormones.
• All the hypothalamic hormones are peptides
except dopamine, which is a catecholamine.
HYPOTHALAMIC HORMONES AND THEIR ACTIONS.
Hormones acting on the anterior pituitary
GnRH
GHRH
Action
Stimulates release of leutinizing hormone
(LH) and follicular stimulating hormone
(FSH)
stimulates release of growth hormone (GH)

Somatostatin inhibits GH release

TRH stimulates release of thyroid stimulating

hormone (TSH) and prolactin

Dopamine inhibits prolactin release

CRH stimulates ACTH release

Hormones acting on distant tissues Action

ADH
Oxytocin
 Anterior pituitary
A. Glycoprotein family
Peptide hormones with α(homologous) and β
subunits (differ)
• LH: stimulates ovulation and the gonadal
production of sex
hormones.
• FSH:stimulates development of ovarian
follicules, sperms and estrogen.
production .
• TSH: stimulates production and release of
thyroid hormones
B. POMC family
• ACTH
• ß-lipotropin,
• ß-MSH)
• ß-endorphin.
C. Growth hormone/prolactin family
• GH
• Prolactin
• Actions of ACTH
– Steroidogenesis.
– Adrenal growth and responsiveness.
• Release of ACTH
– CRH
– Negative feedback.
 The Adrenal gland
Cortex (80% of the adrenal)
Secretions: steroid hormones
– mineralocorticoids - glomerulosa
– glucocorticoids - fasciculata
– androgens- reticularis
Medulla
– Epinephrine
– norepinephrine
Steroid hormone production
• Cortisol Effects: Body Responses to
Stress
• Permissive effect on glucagon
• Memory, learning & mood
• Gluconeogenesis
• Skeletal muscle breakdown
• Lipolysis, calcium balance
• Immune depression
• Circadian rhythms
Circardian Rythm
• Aldosterone
– mediates action at the level of the distal
convoluted tubules and collecting tubules of
the kidneys.
– Na+ resorption.
– Increasing plasma Na+ inhibits o further
aldosterone secretion.
– In the absence of aldosterone, the ratio of K+
to Na+ increases; high K+ is a direct
stimulus to aldosterone secretion.
a. Sex steroids (testosterone)

supplemental to gonadal
production (not crucial to life)
• Control of Cortisol Secretion: Feedback
Loops
– External stimuli
– Hypothalamic
– Anterior Pituitary
– Adrenal cortex
– Tissues
 Disorders
• Diseases of the Anterior Pituitary
• Hypopituitarism
– Pituitary infarction
• Sheehan syndrome
• Hemorrhage
• Shock
– Others: head trauma, infections, and tumors
• Hyperpituitarism
– e.g. due to pituitary adenoma
Alterations of Adrenal Function
• Hyperaldosteronism
– Primary hyperaldosteronism (Conn
disease)
– Secondary hyperaldosteronism
• Adrenocortical hypofunction
– Secondary hypocortisolism
– Primary adrenal insufficiency
(Addison disease)
» Idiopathic Addison disease
 Cushing Syndrome
Cause:prolonged exposure to elevated levels of either endogenous or
exogenous glucocorticoids.
• endogenous
– hypercortisolism :primary adrenocortical neoplasm (usually an adenoma but
rarely a carcinoma)
• Carney complex(autosomal dominant micronodular hyperplasia of the
adrenal)
• McCune-Albright syndrome(hyperfunction of the adrenal glands that
may lead to Cushing syndrome.cause of precociouspuberty)
– Cushing disease( Corticotropinoma)
(80%). anterior pituitary tumor
– Nonpituitary ACTH
• oat cell ca
• small-cell lung carcinoma,
• carcinoid tumor,
• ectopic CRH (rare)

•
• Majority : due to exogenous
gluccocorticoids
• Of endogenous :70% due to
Cushing disease, 15% ectopic
ACTH, 15% primary adrenal
tumor( Nelson syndrome is
caused by a large ACTH
secreting pituitary tumor)
• F:M -5:1
• Peak: 25-40 years.
 Differentials
- Renal failure
-Strenuous exercise
-Phenobarbital, phenytoin,Rifampicin
-Psychiatric illness
-Chronic alcoholism
- Depression
 Lab Studies

• Biochemical evaluation of Cushing

syndrome if due to endogenous
overproduction of cortisol:demonstrate high
serum or urine cortisol levels
 • Urinary free cortisol
• Urinary free cortisol (UFC) :over a 24-hour
period.Urinary creatinine excretion used to
assess the reliability of the collection.
• Urine free cortisol values higher than 3-4
times the upper limit of normal are highly
suggestive of Cushing syndrome
Dexamethasone suppression tests
Mimic the physiology of the pituitary
• 1 mg of dexamethasone at 11 pm with
measurement of cortisol level at 8 am.
The serum cortisol level should be less than 2-3
mcg/dL.
• 8-mg overnight dexamethasone suppression test, 8
mg orally at 11 pm, cortisol level at 8 am
Suppression to less than 50% is suggestive of
pituitary ACTH production
 CRH

• Intravenous administration of CRH causes a

rise in plasma ACTH and cortisol levels in
pituitary ACTH secretion,
• In patients with ectopic secretion of ACTH,
CRH does not affect ACTH or cortisol
levels.
 17-ketosteroid or other cortisol
precursors- DHEAS
• adrenal carcinoma
 plasma ACTH level

• undetectable in ACTH-independent
Cushing syndrome
 Alterations of Adrenal Function
• Disorders of the adrenal cortex
– Cushing disease
• Excessive anterior pituitary secretion of ACTH
– Cushing syndrome
• Excessive level of cortisol, regardless of cause
– Hyperaldosteronism
• Primary hyperaldosteronism (Conn disease)
• Secondary hyperaldosteronism
Ct..
– Adrenocortical hypofunction
• Primary adrenal insufficiency (Addison disease)
– Idiopathic Addison disease
• Secondary hypocortisolism
– Hypersecretion of adrenal androgens and
estrogens
• Feminization
• Virilization
 Alterations of Adrenal Function

Disorders of the adrenal medulla

– Adrenal medulla hyperfunction
• Caused by tumors derived from the chromaffin cells
of the adrenal medulla
– Pheochromocytomas
• Secrete catecholamines on a continuous or episodic
basis
Primary Hyperaldosteronism
 Aetiology
• Conn syndrome (50-60% of cases)-
aldosterone producing adenoma
• Idiopathic hyperaldosteronism(40-50%)
• Ectopic aldosterone (cell rests in kidney or
ovary)
• Adrenocortical carcinomas (rare)
• Glucocorticoid-remediable
aldosteronism (GRA) Autosomal
dominant- gene on chromosome 8
 Secondary hyperaldosteronism
• Common
– Congestive cardiac failure
– Liver cirrhosis with ascites
– Nephrotic syndrome
• Less common
– Renal artery stenosis
– Sodium losin nephritis
– Barter syndrome
– Renin secreting tunors
 Symptoms
• Few symptoms are specific, and mostly
they result from hypokalemia and
alkalosis.
• Aldosterone, by inducing renal distal
tubular reabsorption of sodium,
enhances secretion of potassium and
hydrogen ions, causing hypernatremia,
hypokalemia, and alkalosis.
 Differentials
C-11 hydroxylase deficiency
• C-17 hydroxylase deficiency
• Cushing syndrome
• Hypertension
• Renin-secreting tumor
• Exogenous mineralocorticoid
 Lab Studies
• Routine laboratory studies
– hypernatremia,
– hypokalemia,
– metabolic alkalosis
• impaired glucose tolerance (20%)( inhibitory
effect of hypokalemia on insulin action)
Ct..
• suppressed renin levels
• confirmatory test is a 24-hour urine
aldosterone level obtained after 3 days
of salt loading.
 Primary adrenocortical insufficiency
(Adddison disease)
• due to the destruction or dysfunction of the entire
adrenal cortex.
• Acquired immunodeficiency syndrome
– Opportunistic infections CMV, Mycobacterium
avium intracellulare, cryptococci, Kaposi sarcoma.
– glucocorticoid resistance syndrome.
– use of megestrol acetate(appetite stimulant)
suppress pituitary ACTH
Ct..
• Idiopathic autoimmune Addison
disease(80%)
• Chronic granulomatous diseases
– TB, sarcoidosis, histoplasmosis,
blastomycosis, and cryptococcosis
• Hematologic malignancies
e.g leukemia,lymphomas
• Metastatic malignant disease- breast ,lung
 Other causes
• Infiltrative metabolic disorders
– Amyloidosis and hemochromatosis
• Abnormalities of beta-oxidation of very-
long-chain fatty acids(acc. of FA)
• Drug related causes e.g
ketoconazole,methadone
• Abdominal irradiation
 Causes of acute Addison disease

• Stress:
– Acute adrenal crisis precipitated by
infection, trauma, surgery, emotional
turmoil
• Bilateral adrenal artery emboli and
bilateral vein thrombosis
• Bilateral adrenal hemorrhage eg. due to
septicaemia
• Bilateral adrenalectomy
Secondary Adrenal insufficiency

Hypothalamic or pituitary
disease or exogenous steroid causing
suppression of the hypothalamic /
pituitary axis leading to atrophy of the
adrenal cortex
 Lab Studies
• ACTH stimulation test (Cortrosyn, cosyntropin, or
Synacthen).
– increase in the plasma cortisol and aldosterone
• Other laboratory tests
– Urinary and sweat sodium also may be elevated
– elevated blood urea nitrogen (BUN) and creatinine
due to the hypovolemia
– Hypercalcemia,
– Hypoglycemia-increased glucose sensitivity
– Low thyroid hormone levels with increased TSH
levels
– Hyperprolactinemia
 Congenital Adrenal Hyperplasia
Defn.
A group of inherited metabolic disorders of adrenal steroid
hormone biosynthesis
Etiology:
• 21Hydroxylase deficiency (95%)- often incomplete-
adequate cortisol synthesis maintained by increased ACTH
leading to adrenal hyperlasia
• 11β Hydroxylase deficiency(majority of the remaining
5%)
Pathogenesis
Accumulation of 17α hydroxyprogestrone and increased
formation of adrenal androgens
Clinical features
• Female
– Born with ambiguous genitalia
– If partial later hirsuitism,ammenrrhoea,
infertility
• Male
– Precocious puberty
Diagnosis
– Elevated levels of 17α hydroxyprogestrone at least 2
days after birth
Management
– Replacement of cotisol and mineralcorticoids