Seminars for the 5th year international students
Prof. MUDr. Jiří Horák
Pituitary and Hypothalamic Disorders
Physiology
Growth Hormone
is a 191-amino acid peptide. Secretion is stimulated by two hypothalamic
growth hormone-releasing hormones and inhibited by the hypothalamic
tetradecapeptide somatostatin. GH binds to receptors in the liver and
induces insulin-like growth factor 1, which mediates most of the growthpromoting effects of the growth hormone.
Prolactin has 198 amino acids. Its secretion is under inhibitory control
by hypothalamic dopamine. TRH and vasoactive intestinal polypeptide
(VIP) are prolactin-releasing factors. Prolactin levels increase during
pregnancy, enhancing breast development. Postpartum prolactin
stimulates milk production.
Evaluation of prolactin reserve: prolactin levels increase 3 to 5fold 15 to
30 minutes after TRH administration (200 µg i.v.)
Thyroid-stimulating hormone (TSH)
28,000 dalton glycoprotein hormone. TSH secretion is stimulated by the
hypothalamic tripeptide TRH. Negative feedback inhibition of TSH
secretion by peripheral thyroid hormones.
Adrenocorticotropic Hormone (ACTH)
A 39-amino acid peptide. Hypothalamic corticotropin-releasing hormone
(CRH) stimulates ACTH secretion. Cortisol exerts a negative feedback
effect on ACTH and CRH.
Gonadotropins (LH and FSH)
Hypothalamic GnRH regulates LH and FSH secretion. Gonadal steroids
exert both positive and negative feedback effects on gonadotroph
secretion. LH stimulates gonadal steroid secretion by testicular Leydig
cells and by the ovarian follicles. In females, the ovulatory LH surge
results in rupture of the follicle and then luteinization. In males, FSH
stimulates Sertoli cell spermatogenesis, and in females, follicular
development.
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Seminars for the 5th year international students
Prof. MUDr. Jiří Horák
Pituitary adenomas
Clin: headache, visual loss (typically bitemporal hemianopia), syndromes
of hypopituitary hormone hypersecretion and hyposecretion, and
incidentally discovered sellar enlargement.
Hypothalamic dysfunction
In children and young adults, craniopharyngioma is the most frequent
cause of hypothalamic dysfunction.
Clin: visual loss, symptoms of raised intracranial pressure {headache and
vomiting), hypopituitarism including growth failure, and diabetes
insipidus.
Hypothalamic disturbances: disorders of thirst (dehydration or polydipsia
and polyuria), appetite (hyperphagia and obesity), temperature regulation,
behaviour, and consciousness (somnolence and emotional lability).
Craniopharyngeoma is treated primarily with surgical resection and then
radiotherapy.
Hypopituitarism
results from diminished secretion of one or more pituitary hormones.
Pituitary insufficiency is usually a slow, insidious disorder.
Growth Hormone Deficiency
during infancy and childhood growth retardation, short stature, and
fasting hypoglycemia.
In adults: increased abdominal adiposity, reduced strength and exercise
capacity, cold intolerance, impaired psycho-social well-being. Adult GH
deficiency is usually accompanied by other symptoms of
panhypopituitarism.
TSH deficiency
causes thyroid gland involution and hypofunction.
Clin: lethargy, constipation, cold intolerance, bradycardia, weight gain,
dry skin, poor appetite, and delayed reflex relaxation time.
Dg: low TSH + low T4 and T3
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Seminars for the 5th year international students
Prof. MUDr. Jiří Horák
Etiology of hypopituitarism
type of disorder
congenital
septo-optic dysplasia
Prader-Willi syndrome
Lawrence-Moon-Biedle syndrome
isolated anterior pituitary hormone
or RF deficiency
tumors
pituitary
secretory adenomas
nonsecretory adenomas
hypothalamic
craniopharyngioma
hamartoma
pinealoma
dermoid
epidermoid
glioma
lymphoma
immunological
meningioma
autoimmune lymphocytic hypophysitis
infiltrative
hemochromatosis
Langerhans cell histiocytosis
sarcoidosis
metastatic carcinoma
infectious
amyloidosis
tuberculosis
mycoses
syphilis
physical trauma
cranial trauma and hemorrhage
ionizing radiation
stalk section
surgery
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Seminars for the 5th year international students
Prof. MUDr. Jiří Horák
vascular
postpartum pituitary necrosis (Sheehan's
syndrome)
pituitary apoplexy
carotid aneurysm
Gonadotropin deficiency
Central hypogonadism in childhood results in failure to enter normal
puberty. Females have delayed breast development, scant pubic and
axillary hair, and primary amenorrhea. In boys, the phallus and testes
remain small, and body hair is sparse.
Sex steroids are required for closure of the epiphyses of the long bones.
Clin: tall adolescents with eunuchoid proportions. In adult women,
hypogonadism presents as breast atrophy, loss of pubic and axillary hair,
and secondary amenorrhea. Hypogonadal adult males develop testicular
atrophy, decreased libido, impotence, and loss of body hair.
ADH (vasopressin) deficiency
occurs with posterior pituitary dysfunction and leads to DI with polyuria,
polydipsia, and nocturia.
Dg of pituitary hormone deficiency
Quadruple Bolus Test for Anterior Pituitary Reserve
hypothalamic releasing hormone
pituitary hormone
TRH 200 µg
TSH, prolactin
CRF 1 µg/kg
ACTH
GHRH 1 µg/kg
GH
gonadotropin RH 100 µg
FSH, LH
Th of panhypopituitarism
replacement of thyroxine, glucocorticoids, and sex steroids. Children with
short stature should receive GH replacement therapy. Testosterone
therapy in males restores libido and potency, beard growth, and muscle
strength.
Estrogen replacement therapy in females maintains secondary sex
characteristics and prevents hot flashes. Human menopausal
gonadotropins and human chorionic gonadotropin given i.m. or
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Seminars for the 5th year international students
Prof. MUDr. Jiří Horák
gonadotropin RH administered by infusion pumps may be given to induce
ovulation.
In patients with combined TSH and ACTH deficiency, glucocorticoids
should be replaced prior to thyroxine, as thyroxine may precipitate acute
adrenal failure.
Empty Sella Syndrome
occurs when the arachnoid membranes herniate through an incompetent
diaphragma sella and extend into the sella turcica, partially filling it with
cerebrospinal fluid and compressing the pituitary gland. Primary empty
sella syndrome is the most common cause of an enlarged sella turcica.
This results from a congenital weakness in the diaphragma sella.
Secondary empty sella syndrome can occur following pituitary surgery or
radiation therapy or in Sheehan's syndrome. Empty sella syndrome is
usually asymptomatic and detected incidentally on routine imaging of the
head. Endocrine function is usually normal; partial hypopituitarism may
be present.
Dg: MRI - fluid in sella turcica
Pituitary tumours
Prolactinomas are the most common secretory pituitary tumours.
Secretory pituitary tumours: signs and symptoms due to hypersecretion of
the particular pituitary trophic hormone.
GH adenomas: acromegaly, prolactinomas: amenorrhoea + galactorrhea
in females and sexual dysfunction in males, ACTH-secreting adenomas:
Cushing disease.
Large pituitary adenomas (secretory or nonsecretory) can result in signs
and symptoms due to pressure on surrounding structures. Headache is a
frequent symptom. Extension of the tumour into the suprasellar space 
compression of the optic chiasm bitemporal hemianopia. Lateral
extension into the cavernous sinus can result in ophthalmoplegia,
diplopia, or ptosis due to dysfunction of the third, fourth, fifth, and sixth
cranial nerves. Compression of surrounding normal pituitary tissue due to
an enlarging tumor mass can cause hyposecretion of one or several
pituitary trophic hormones.
Destructive pituitary lesions result in hormone loss in the following
pattern: GH - LH/FSH - TSH - ACTH - prolactin.
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Seminars for the 5th year international students
Prof. MUDr. Jiří Horák
Prolactinomas
Hyperprolactinemia in women: hypogonadism  estrogen deficiency.
Gonadotropin levels are normal, and sex steroids are decreased. Prolactin
inhibits pulsatility in gonadotropin secretion  anovulation. In
hyperprolactinemic males, testosterone levels are usually suppressed.
Clin: in women, amenorrhea, galactorrhea, and infertility. Estrogen
deficiency may cause osteopenia, vaginal dryness, hot flashes, and
irritability. Prolactin stimulates adrenal androgen production  weight
gain and hirsutism.
Males usually present with loss of libido and impotence due to
hypogonadism.
Dg: basal serum prolactin level > 200 ng/ml; MRI.
Th: bromocriptine (a dopamine agonist) at a dosage of 2.5 to 15 mg/day
orally in divided doses restores gonadal function and fertility in a
majority of patients. Bromocriptine may cause tumour shrinkage. Surgery
is indicated in patients with visual field abnormalities or neurologic
symptoms. Trans-sphenoidal microsurgery is the procedure of choice.
Acromegaly and gigantism
In childhood, hypersecretion of GH leads to gigantism, in adults
acromegaly (local overgrowth of bone in the acral areas).
Clin: acral enlargement - widening of the hand and feet and coarsening of
the facial features. The mandible grows downward and forward 
prognathism and widely spaced teeth. Ring, glove, and shoe size increase.
Dg: insulin-like growth factor-1 mediates the classical acral changes that
occur with acromegaly. IGF-1 levels are elevated.
GH levels 2 hours after an oral glucose load of 100g. In healthy persons,
GH levels are suppressed to < 2 ng/ml.
MRI or CT of the pituitary
Th: trans-sphenoidal microsurgery is the treatment of choice.
Radiotherapy has a high incidence of hypopituitarims.
Medical management: bromocriptine (effective only in a minority of
patients) and octreotide (a long-acting somatostatin analogue - very
effective). It is administered as a s.c. injection three times daily.
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Prof. MUDr. Jiří Horák
Clinical features of acromegaly
type of change
change
manifestation
somatic
acral changes
enlarged hands and feet
musculoskeletal
arthralgias
changes
prognathism
carpal tunnel syndrome
proximal myopathy
skin changes
sweating
colon changes
polyps
carcinoma
cardiovascular
cardiomegaly
visceromegaly
hypertension
tongue
thyroid
liver
endocrine
reproduction
menstrual abnormalities
problems
galactorrhea
decreased libido
carbohydrate
impaired glucose tolerance
metabolism
diabetes mellitus
lipid metabolism hypertriglyceridemia
Gonadotropin-Secreting Pituitary Tumours
Mainly in males, are rare. Secrete usually FSH only.
Clin:
 signs of local pressure (visual impairment);
 hypogonadism
Th: surgical removal ± subsequent radiotherapy
Thyrotropin-Secreting Pituitary Tumour
Extremely rare
Dg: increased TSH + increased T4
Th: surgery + radiotherapy
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Seminars for the 5th year international students
Prof. MUDr. Jiří Horák
The Posterior Pituitary Gland
ADH is a 1084-dalton nonapeptide. It binds to receptors on the renal
tubule, increasing the water permeability of the luminal membrane of the
collecting duct epithelium, thus facilitating reabsorption of water.
Maximal ADH effect results in a small volume of concentrated urine with
osmolarity as high as 1200 mOsm/kg. Deficiency of ADH results in a
large volume of very dilute urine (as low as 100 mOsm/kg).
ADH also binds to peripheral arteriolar receptors, causing
vasoconstriction and increase in blood pressure; however, it also causes
bradycardia and inhibition of sympathetic nerve activity.
Deficiency of ADH or insensitivity of the kidney to ADH  diabetes
insipidus manifested as polyuria and polydipsia. Inappropriate secretion
of ADH  the syndrome of inappropriate ADH secretion (SIADH)  a
hyponatremic state.
Oxytocin is a 1007-dalton nonapeptide that causes uterine smooth muscle
contraction. It is released by nipple stimulation and facilitates milk
ejection by causing mammary duct myoepithelial cell contraction in
response to nipple stimulation.
Diabetes Insipidus
Central (neurogenic) or renal (nephrogenic).
Patients are polyuric, secreting large volumes of diluted urine
dehydration  thirst  polydipsia.
Causes of Diabetes Insipidus
Causes of Central Diabetes Insipidus
 idiopathic
 familial
 hypophysectomy
 infiltration of hypothalamus and posterior pituitary

Langerhans cell histiocytosis

granulomas
 infection
 tumors
 autoimmune
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Seminars for the 5th year international students
Prof. MUDr. Jiří Horák
Causes of nephrogenic diabetes insipidus
 idiopathic
 familial
 chronic renal disease (pyelonephritis, polycystosis)
 hypokalemia
 hypercalcemia
 sickle cell anemia
 drugs
lithium
fluoride
demeclocycline
colchicine
DD: primary polydipsia  decreased ADH secretion  water diuresis.
Random simultaneous samples of plasma and urine for sodium and
osmolarity: in diabetes insipidus, urine osmolarity < plasma osmolarity.
Plasma osmolarity may be elevated, depending on the patient's state of
hydration. In primary polydipsia, both plasma and urine are dilute.
The water deprivation test: the patient is denied fluids for 12 to 18 hours,
and body weight, blood pressure, urine volume, urine specific gravity,
and plasma and urine osmolarity are measured every 2 hours. If the body
weight falls more than 3%, the study should be terminated. A normal
response is a decrease in urine output to 0.5 ml/min, as well as an
increase in urine concentration to greater than that of plasma. Patients
with DI maintain a high urine output, which continues to be dilute
(specific gravity < 1.005 {200 mOsm/kg of water}). Patients with
primary polydipsia increase their urine osmolarity to values > plasma
osmolarity. Water deprivation is continued until the urine osmolarity
plateaus (an hourly increase of < 30 mOsm/kg for three successive
hours). At that point, 5 µg of vasopressin is administered s.c., and the
urine osmolarity is measured after 1 hour. Patients with complete central
DI increase urine osmolarity above plasma osmolarity, whereas in
nephrogenic DI the urine osmolarity increases less than 50%. Patients
with primary polydipsia have increases < 10%.
Th: central DI - desmopressin acetate (DDAVP), a synthetic analog of
ADH, is administered intranasally. Adequacy of replacement is
monitored by serum osmolarity and sodium.
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Seminars for the 5th year international students
Prof. MUDr. Jiří Horák
Nephrogenic DI
As far as possible, the underlying disease process should be reversed.
Diuretics with dietary salt restriction can be used.
SIADH
Plasma ADH concentrations are inappropriately high for plasma
osmolarity, resulting in water retention leading to hyponatremia and
decreased plasma osmolarity (< 280 mOsm/kg). Urine osmolarity is
higher than the plasma osmolarity.
Disorders Associated with SIADH
type of disorder
disorder
pulmonary disorders
malignant (oat cell carcinoma)
CNS disorders
benign (TBC, pneumonia, abscess)
meningitis
brain abscess
head trauma
adverse drug effects
clofibrate
chlorpropamide
cyclophosphamide
phenothiazine
carbamazepine
tumours (ectopic
lymphoma
production of ADH)
sarcoma
carcinoma of pancreas or duodenum
Th: the underlying condition should be treated. Fluid restriction is the
cornerstone of treatment.
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