o

Adrenal Gland

Outer cortex: Steroid hormones

o Outer zona glomerulosa: minerelocorticoid hormone
Aldosterone: the principal minerelocorticoid
Controlled by renin-angiotensin system
renin released from juxtaglomerular
cells of the Kidney
Reduced renal perfusion
pressure
decreased circulating blood
volume
sympathetic stimulation
Renin-Angiotensin 1- Angiotensin 11stimulate zona glomerulosa
Aldosterone increases tranepithelial transport
of sodium by Kidney
Promotes secretion of potassium
o Inner zona faciculata and reticularis: Glucocorticoids,
androgens, estrogens
Major glucocorticoid: Cortisol
Under control of ACTH(pituitary) which in turn
is regulated by CRF (hypothalamus)
Negative feedback control
Pulsatile secretion with diurnal variation
Inner medulla: Catecholamines
o Sympathetic system

Adrenal cortical hypofunction

Primary
o Combined Minerelocorticoid and Glucocorticoid
deficiency
o Isolated Aldosterone deficiency
Secondary

Hypopituitarism
No Minerelocorticoid deficiency (not regulated
by ACTH)
Hyperpigmentation is absent
co-existent thyroid and gonadal deficiency
o Exogenous glucocorticoids
o Hyporeninemic hypoaldosteronism
Symptoms of Addisons disease
o Anorexia and weight loss
o Weakness
o Apathy
o Hypotension / Hypovolemia
o Inability to withstand stress
o Hyponatremia
o Hyperkalemia
o Acidosis
o Pigmentation - Increased ACTH
o Increased renin
Etiology
o Autoimmune process
o Tuberculosis
o Histoplasmosis
o Metastatic carcinoma
o Amyloidosis
o Bilateral adrenal hemorrhage
o Inherited disorders - biosynthetic enzymes
Diagnosis
o subnormal plasma levels of cortisol and aldosterone
o reduced urinary excretion of 17-hydroxycorticoids
and aldosterone-18-glucuronide
o ACTH increased
o ACTH stimulation- subnormal response
o Increased renin
Treatment
o IV fluids and supportive care

Glucocorticoid
Life long hydrocortisone
Double the dose during minor stress
10x usual dose for major stress IV
hydrocortisone
Minerelocorticoid
High sodium chloride intake is sufficient in
most
Fludrocortisone in selected cases with special
attention
Medic alert bracelet

o
o

Adrenal cortical hyperfunction

Glucocorticoid: Cushing's syndrome

o Hypothalamic-pituitary abnormality (Cushing's
disease)
Adenoma - small to be recognized in most
o Ectopic ACTH
level of cortisol very high
rapid onset
mostly presents as electrolyte and acid base
disturbance
not enough time for overt manifestations of
Cushing's syndrome
Small cell cancer, Carcinoid, Medullary
carcinoma Thyroid
o Primary adrenal tumor (Carcinoma, Adenoma)
(ACTH independant)
o Exogenous Glucocorticoid therapy (ACTH
independant)
Minerelocorticoid: Disturbance in electrolyte and blood
pressure homeostasis
o Adrenal tumors: (Adenoma, Carcinoma)
o Bilateral adrenal hyperplasia

Adrenal enzyme defects

Exogenous minerelocorticoids (Licorice,
Carbenoxolone)
Clinical manifestations
o Obesity (centripedal, buffalo hump, supraclavicular
fat pads, moon facies)
o Carbohydrate intolerance
o Muscle wasting
o Osteoporosis
o Easy bruisability
o Abdominal striae
o Hypertension
o Mood swings, depression, psychosis
o Hirsutism, acne, menstrual disorders
Diagnosis
o Typical clinical features
o Excess of hormone
Random serum cortisol level
24 hour urinary excretion of 17-hyrdoxycortisol
o Dexamethasone suppression test
Plasma cortisol >5 mcg/dl suggests
Cushing's syndrome
o High dose Dexamethasone suppression test
ACTH dependant: Pituitary (Cushing's
disease): 50% or greater suppression
ACTH independant: Ectopic ACTH and
Adrenal tumors: No suppression
o ACTH levels
Normal to slightly high in Cushing's disease
Very high in ectopic ACTH secretion by
tumors
Undetectable levels in Adrenal tumors
o CRH stimulation test

MRI, High resolution CT scan, Contrast enhanced

CT scan of Pituitary or Adrenal gland
Normal pituitary fossa does not rule out
adenoma
Treatment
o Surgery (Pituitary or adrenal or ectpic tumor)
o Radiation
o Inhibition of adrenalcortical secretion: Mitotane

Hypothalamus Pituitary inter relations

Hypothalamus
o Hypothalamic peptides stimulate secretion of anterior
pituitary hormones
o Dopamine inhibits prolactin secretion
o Under neural regulation by variety of
neurotransmitters
o Regulated by closed -loop feedback system
o TRH, GnRF, CRF, GRF are releasing hormones
Anterior pituitary
o Adenohypophysis
o Derived from Rathke's pouch
o Somatomammotropins
Growth hormone
Prolactin / lactogenic
Chorionic somatomamotropin
o Corticotrophin (ACTH)
Stimulate secretion of glucocorticoid by
adrenal cortex

Pituitary glycoprotein hormones

Thyroid stimulating hormone (TSH)
Follicle stimulating hormone (FSH)
Regulate ovulation and secretion of
steroid by ovary
Leuteinizing hormone (LH)
Regulate ovulation and secretion of
steroid by ovary
Posterior pituitary
o Neurohypophysis
o Anatomical extension of hypothalamus
o Derived from diencephalon
o Located in sella tursica
o In the base of brain
Tests of anterior pituitary function
o ACTH
ACTH / undetectable in normal basal state
Deficiency: Stimulation by induced
hypoglycemia / of hypothalamus
CRF not available for clinical use
Hypothalamic problem
Positive CRF test
Negative response to
hypoglycemia
Pituitary problem
Negative CRF test
Negative response to
hypoglycemia
ACTH excess
Suppression with dexamethasone
o TSH
Deficiency: TRH stimulation: TSH levels
increase up to 15
Pituitary problem: Flat response

o
o

Hypothalamic problem: Normal

response

Excess

Flat response to TRH

Gonadotropins
Deficiency
GnRH stimulation
Clomiphere stimulation
Hypothalamic dysfunction
Normal response to GnRH
stimulation
Response to Clomiphere
stimulation
Pituitary dysfunction
Excess
Prolactin
Growth hormone
Measurable
Deficiency: stimulation by hypoglycemia, Ldopa, GRF
Excess: Glucose loading

TSH

Symptoms of adrenal cortical deficiency

Symptoms of hypothyroidism
Gonadotropin
Amenorrhea
Diminished libido
Loss of pubic and axillary hair
Atrophy of breast and Testis
Diagnosis
o Differentiate from polyglandular deficiency states
o Deficiency of major target organ products
o Absence of compensatory increases of tropic
hormones of pituitary
o Establish abnormality in the hypothalamic-pituitaryaxis
o Use of stimulation studies
o Use of hypothalamic releasing factors to distinguish
between Hypothalamic and pituitary dysfunction
Treatment
o Replacement of specific hormones
Caution in thyroid replacement. Concomitant
or preceding replacement of glucocorticoids
o Treat etiology
o

Anterior pituitary hypofunction

Hypothalamic defect
Pituitary gland defect
Common Etiology
o Tumors
o Granulomas
o Vascular necrosis
o Surgery
o Radiation
o Compression by a space occupying lesion
Clinical features
o Growth hormone

ACTH

Short stature
Delayed puberty

Anterior pituitary hyperfunction

Usually benign slow growing tumors

o Neurological symptoms (Headache)
o Visual defects (bitemporal hemianopsia)
o Pituitary insufficiency
o Excessive secretion of any of the anterior pituitary
hormones

Prolactin / Galactorrhea
Growth hormone / Acromegaly, Gigantism (in
young)
ACTH / Cushing's syndrome
Diagnosis
Clinical picture
Excess of the hormone
Inability to suppress by physiological
maneuvers
MRI and high resolution CT for evaluation of
tumor
Treatment options
Correct deficiencies
Surgery
Radiation
Bromocriptine

Disorders of posterior pituitary

Oxytocin / Release of breast milk, promote uterine

contraction in labor

Anitdiuretic hormone (ADH) / Regulates water metabolism

o Response to serum osmolality, hypovolemia and
hypotension
o Normal serum osmolality 285
o Acts on distal nephron to induce an increased water
permeability
o Excess: Water intoxication. Syndrome of
inappropriate ADH secretion
o Deficiency: Diabetes insipidus
Central vs Nephrogenic
Central : due to hypothalamic rather than
pituitary problem

AVP is stored in pituitary but synthesized in

the hypothalamus
Polyuria (>3 L/day) and polydypsia
Dilute urine (sp gr <1010 or osmolality <300)
Need to distinguish from psychogenic
polydypsia
Water deprivation test followed by pitressin
Treatment
Chlorpropamide
ADH replacement by nasal insufflations

Hypothyroidism
List common symptoms of hypothyroidism.
Answer

Weakness
Fatigue
Memory impairment
Cold intolerance
Constipation
Loss of hair
Hoarseness
Deafness
Menstrual irregularity

What are the physical findings of a patient with

hypothyroidism?

Answer

Dry coarse skin

Periorbital edema
Coarse thin skin
Thick tongue
Slow speech
Deep voice
Delayed Achilles' tendon reflex time
Bradycardia

Schmidt's syndrome / Hashimotto's and pernicious

anemia and diabetes mellitus
Idiopathic
Post therapy for hyperthyroidism
o Radioactive iodine therapy / History of radioactive
iodine therapy
o Subtotal thyroidectomy / History of thyroidectomy
External beam radiotherapy / history of neck radiation for
lymphoma or head and neck cancer
Lithium, amiodarone
Iodide deficiency / underdeveloped countries

What are the common etiologies for primary hypothyroidism?

Answer

How does physical examination of the thyroid gland help in the

differential diagnosis of hypothyroidism?

Primary hypothyroidism

Answer

Hashimotto's thyroiditis
Idiopathic
Post therapy for hyperthyroidism
External beam radiotherapy
Lithium, Amiodarone
Iodide deficiency

What historical information will help you in identifying the

etiology for primary hypothyroidism?
Answer

Hashimotto's thyroiditis
o Family history or the presence in the patient of other
autoimmune endocrine disease

Hashimotto's thyroiditis
o enlarged thyroid
Idiopathic
o atrophic thyroid
Post therapy for hyperthyroidism
o depends on etiology
External beam radiotherapy
o radiation changes over thyroid (pigmentation,
induration)
Lithium, Amiodarone
o goiter
Iodide deficiency
o goiter

What are the common etiologies for secondary

hypothyroidism?

Answer

Answer

Hypothalamic dysfunction
Pituitary dysfunction

What are the common etiologies for secondary hypothyroidism

due to hypothalamic dysfunction?
Answer

Therapeutic irradiation
Hypothalamic tumors
o germinoma
o meningioma
o hamartoma

Pituitary dysfunction /secondary adrenal insufficiency,

hypogonadism, growth hormone deficiency
o Pituitary tumor
o Post partum pituitary necrosis
o Sarcoidosis
o Metastatic carcinoma involving pituitary,
hypothalamus or stalk
o Rathke's cleft cyst, craniopharyngioma, carotid artery
aneurysm compressing pituitary

What are the signs and symptoms that would suggest pituitary
tumor?
Answer

What are the symptoms and signs that would alert you to the
possibility of hypothalamic lesion?
Answer

Diabetes insipidus
Narcolepsy
Excessive appetite
Marked anorexia
Hyperthermia
Marked hypothermia

What are the common etiologies for secondary hypothyroidism

due to pituitary dysfunction?

Space-occupying mass of pituitary

Headache
Bitemporal hemianopsia
3rd, 4th, or 6th nerve defects
Seizures
Rhinorrhea
Meningitis

What would make you suspect postpartum pituitary necrosis

as the etiology for pituitary dysfunction?
Answer

History of shock or massive hemorrhage at time of delivery

Inability to breast feed

Amenorrhea afterwards

Primary: Exaggerated TSH response. TSH levels increase

up to 15
Pituitary: Flat TSH response
Hypothalamus: Normal TSH response

Which tests would help confirm the diagnosis of

hypothyroidism?
Which tests helpful in the diagnosis of identifying a pituitary
mass?

Answer

Total T4: Low

Free T4: Low
TSH
Free T3: of no value

Answer

Which lab test helps you to distinguish primary from

secondary hypothyroidism?

MRI with gadolinium enhancement to document the

presence of a mass
Testing for other tumor markers (alpha subunits)

What are the common non-specific lab abnormalities of

hypothyroidism?

Answer
Answer

TSH
o
o

increased / primary
decreased / secondary
Baseline and dynamic anterior pituitary hormone testing for
deficiencies and overproduction

CPK
Anemia
Bradycardia, low voltage and non specific ST T wave
changes
Hypoxia with hypercapnea

How do you distinguish hypothalamic from pituitary

dysfunction as the etiology for secondary hypothyroidism?

What are the treatment options for primary hypothyroidism?

Answer

Answer

TRH stimulation:

Thyroid hormone replacement therapy with non-generic lthyroxin or a generic form that has undergone rigorous
quality controlled supervision of the manufacturing process.
With risk factors for coronary arterial disease, it would be
wise to start with a low dose of thyroid hormone and
increase the dose slowly.

What are the treatment options for secondary hypothyroidism?

Answer

Evaluate if secondary hypoadrenalism is present

If preset, treat simultaneously with the treatment of the
hypothyroidism
Also evaluate whether hypogonadism and/or growth
hormone deficiency is present and treat accordingly
Then treat the cause of the secondary hypothyroidism

What are the components of total serum thyroxin?

Describe euthyroid hypothyroxinemia / sick syndrome.

Answer

Clinical picture
Normal sized thyroid gland
Low serum TBG
Hypoalbuminemia / nephrotic syndrome, cirrhosis
Low serum total T4
Normal free T4
Normal TSH
Normal TSH response to TRH

What is sub clinical hypothyroidism?

Answer

Euthyroid
Normal serum T4 and T3
Elevated TSH

Answer
Hyperthyroidism

Free thyroxine 0.03%

Thyroxine binding albumin 10%
Thyroxine binding prealbumin 20%
Thyroxine binding globulin 70%

Alterations in these binding proteins can alter serum thyroxine

values and mistaken diagnosis of hypo or hyperthyroidism can be
made.

What are the symptoms of hyperthyroidism?

Answer
Symptoms: Potentiation of sympathetic system by excess thyroxine

Nervousness
Heat intolerance
Palpitations

Tremor
Weight loss in spite of voracious appetite
Weakness particularly proximal muscle group
Hyper defecation

What are the physical findings of hyperthyroidism?

Toxic adenoma

Factitious thyrotoxicosis

Toxic struma ovari

Thyroiditis

Answer

Thyroid enlargement
o pyramidal lobe
o bruit
Potentiation of sympathetic system by excess thyroxine
o lid lag
o warm moist skin
o fine tremor
o brisk reflexes
o tachycardia
Onycholysis / Plumber's nails
Mucopolysaccharide infiltration
o proptosis
o ophthalmopathy: diplopia
o pretibial myxedema
o clubbing/ thyroid acropachy

How does physical examination of the thyroid help in the

differential diagnosis of hyperthyroidism?
Answer

Graves disease
o

diffuse enlargement

bruit

Toxic multinodular goiter

o

multiple nodules

Toxic adenoma

What are the common etiologies for hyperthyroidism?

o
Answer

Factitious thyrotoxicosis

Grave's disease
o

single nodule

Toxic multinodular goiter

small thyroid

Toxic struma ovari

o

Thyroid auto antibodies are insensitive

TRH stimulation: flat TSH response in Grave's disease

small thyroid

Thyroiditis
o

Describe the lab findings in a patient with euthyroid

hyperthyroxinemia, related to alteration in TBG.

diffuse enlargement
Answer

What tests are useful to confirm hyperthyroidism?

Answer

Total T4: high

Free T4: High
Free T3: High
TSH: Decreased

High serum TBG

Estrogens hepatitis, 5-fluorouracil
High serum total T4
Normal free T4
Normal TSH

Describe the clinical and lab findings in a patient with

euthyroid hyperthyroxinemia, unrelated to TBG levels.
Answer

What are the tests useful to distinguish Grave's disease from

other causes?
Answer

RAIU/ Scintiscan
o increased uptake / symmetrical goiter / Graves
o heterogynous uptake / asymmetric / thyroiditis,
multinodular goiter
o hot nodule / toxic adenoma
o decreased / factitious and struma ovari and
thyroiditis
TRAb
TSI

Clinical picture
Acute non-thyroidal illness, psychiatric illness, drugs
Normal sized thyroid gland
High serum total T4
High free T4
Unrelated to TBG

What are the treatment options for hyperthyroidism?

Answer

Antithyroid drug therapy

Radioactive iodine therapy

Surgery
Symptomatic therapy with beta blockers

What are the treatment options based on the etiology?

Answer

Graves disease
o Induce euthyroid state with antithyroid drug therapy
first
o Radioactive iodine therapy
majority preferred form of treatment
o Surgery
for children
large goiter
Toxic multinodular goiter
o Induce euthyroid state with antithyroid drug therapy
first
o Radioactive iodine therapy
majority
o Surgery
large goiter
pressure complications from goiter
Toxic adenoma
o Radioactive iodine therapy or
o Surgery
Thyroiditis / symptomatic therapy only
Factitious thyrotoxicosis / treat the personality problem

How would you treat a pregnant patient with hyperthyroidism?

Answer

Treat with antithyroid drugs only

Surgery is rarely indicated
Radioactive iodine therapy should never be used
Close monitoring of newborn for thyroid function