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Disorders of pituitary gland (( THE MASTER )) BY M.SASI
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
Disorders of Pituitary Gland
Pituitary Gland
The main endocrine gland.
Called the “master” gland.
Acts as the control center for the endocrine system which controls all
the hormones produced by other glands in the body.
Some of the neurons within the hypothalamus - neurosecretory
neurons - secrete hormones that strictly control secretion of hormones
from the anterior pituitary.
The hypothalamic hormones are referred to as releasing hormones and
inhibiting hormones, reflecting their influence on anterior pituitary
hormones.
Negative feed back is the rule between hormones and the master.
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
PITUITARY HYPERFUNCTION
(HYPERPITUITARISM)
Hyperpituitarism - excessive production of adenohypophyseal hormones .
Causes
Pituitary adenoma
Carcinoma (rare)
Hypothalamic disorder-excess stimulation of the pituitary (rare)
Order of frequency with which hormone secretion occurs in pituitary tumour is
prolactin (relatively common) GH ACTH gonadotrophin TSH
PITUITARY HYPERFUNCTION
(HYPERPITUITARISM)
Prolactin excess Hyperprolactinaemia
GH excess Acromegaly/ gigantism
ACTH excess Cushing’s disease
TSH excess (rare) Secondary
hyperthyroidism
Gonadotrophin excess menstrual disorders and
infertillity
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
Hypothalamic releasing and inhibiting hormones are carried directly to the
anterior pituitary gland via hypothalamic-hypophyseal portal veins.
Specific hypothalamic hormones
bind to receptors on specific
anterior pituitary cells,
modulating the release of the
hormones they produce.
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
The pituitary gland has two distinct parts, the anterior and the posterior lobes,
each of which releases different hormones.
Location and size
Suspended from hypothalamus by stalk (infundibulum)
Housed in sella turcica of sphenoid bone
1.3 cm diameter
Contiguous to vascular and
neurologic structures
1. Cavernous sinuses
2. Cranial nerves
3. Optic chiasma
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
Adenohypophysis(anterior pituitary)
Neurohypophysis (posterior pituitary)
The portion of the adenohypophysis known as the pars tuberalis contains cords
of epithelial cells and is filled with hypophyseal portal vessels.
• It reportedly contains gonadotropes and thyrotropes, plus other
secretory cells of unknown function.
• The pars intermedia is closely associated with pars nervosa and separated
from the pars distalis by the hypophyseal cleft. Melanocyte-stimulating
hormone is the predominant hormone secreted by the pars intermedia.
• Acidophils: contain the polypeptide hormones:
1. Somatotropes which produce growth hormone
2. Lactotropes which produce prolactin
• Basophils: contain the glycoprotein hormones:
1. Thyrotropes which produce thyroid stimulating hormone
2. Gonadotropes which produce luteinizing hormone or follicle-
stimulating hormone
3. Corticotropes which produce adrenocorticotrophic hormone
• Chromophobes
These are cells that have minimal or no hormonal content.
May be acidophils or basophils that have degranulated and thereby are
depleted of hormone
May also represents stem cells that have not yet differentiated into
hormone-producing cells.
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
NOTES:
• Although classification of cells as acidophils or basophils is useful in some
situations, specific identification of anterior pituitary cells requires
immunostaining for the hormone in question.
• In addition to differential staining characteristics, the size of secretory
granules varies among different types of cells in the anterior pituitary.
Somatotropes and lactotropes tend to have the largest size granules.
Control of Pituitary:
Feedback from Target
Organs
Negative
feedback
target
organ
hormone
levels
inhibits
release of
tropic
hormones
Positive feedback
stretching of uterus
Oxytocin release,
causes more stretching
of uterus, until delivery
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
Anterior Pituitary “Master gland”
Major blood source: hypothalamic-pituitary portal plexus
Allows transmission of hypothalamic peptide pulses without
significant systemic dilution.
Consequently, pituitary cells are exposed to sharp spikes of
releasing factors and in turn release their hormones as
discrete pulses.
Anterior Pituitary “Master gland”
Secreted in a pulsatile manner
Elicits specific responses in peripheral target tissues
Feedback control at the level of the hypothalamus and pituitary to
modulate pituitary function exerted by the hormonal products of
the peripheral target glands
Tumors cause characteristic hormone excess syndromes
Hormone deficiency
may be inherited or acquired
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
Pituitary Tumors
1. Is the tumor causing local mass effect?
2. Is hypopituitarism present?
3. Is there evidence of hormone excess?
• Clinical presentation: Mass effect
A.Superior extension
May compromise optic pathways – leading to impaired visual
acuity and visual field defects
May produce hypothalamic syndrome – disturbed thirst,
satiety, sleep, and temperature regulation
B.Lateral extension
May compress cranial nerves III, IV, V, and VI – diplopia
C. Inferior extension
May lead to cerebrospinal fluid rhinorrhea
Diagnosis
Check levels of all hormones produced
Check levels of target organ products
Treatment
Surgical excision, radiation, or medical therapy
Generally, first-line treatment surgical excision
Drug therapy available for some functional tumors
Simple observation
Option if the tumor is small, does not have local mass
effect, and is nonfunctional
Not associated with clinical features that affect quality
of life
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
Hyperpituitarism and Pituitary Adenomas
Pituitary tumor causes symptoms by any of three mechanisms:
1. By producing too much of one or more hormones.
2. By compressing the pituitary gland, and thus making it produce too
little of one or more hormones.
3. By compressing the optic nerves or (less commonly) the nerves
controlling eye movements, and thus causing either loss of part or
all of the visual field, or diplopia as may extend to cavernous sinus.
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
Epidemiology
Etiology is unknown
Not associated with environmental factors
10-15% of all primary brain tumors
20-25% of pituitary glands at autopsy found to have adenomas
70% of adenomas are endocrinogically secreting
25% of those with MEN-I develop pituitary adenomas
Natural History
Pituitary adenomas have long natural history
Vary in size and direction of spread
Microadenomas < 10 mm – may cause focal bulging
Macroadenomas > 10 mm – cause problems due to mass effect
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
Endocrine-Active Pituitary Adenomas
Prolactin – Amenorrhea, galactorrhea, impotence
Growth hormone – Gigantism and acromegaly
Corticotropin – Cushing’s disease, Nelson’s syndrome post adrenalectomy
TSH - Hyperthyroidism
Non-functioning Adenomas
25-30 % of patients do not have classical
hypersecretory syndromes
May grow to a large size before they are
detected
Present due to mass effect
Visual deficits
HA
Hormone deficiency
Prolactinoma:
• Prolactin (PRL) is a polypeptide protein hormone secreted by the
lactotroph cells in the anterior pituitary gland .
• Suppressed by hypothalamic dopamine to act on Lactotroph D2
receptors .
• Prolactin (PRL) is the hormone for stimulation & maintenance of milk
production in the breast .
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
Epidemiology
• Most common functional pituitary adenomas .
• Prolactinoma account for 40 % of pituitary tumor .
• Ninety percent are intrasellar adenomas that rarely increase in size.
• The rest are macroadenomas (10 mm) that usually come to clinical
attention because of local mass effects.
• Microprolactinomas are more frequent in women .
• Macroprolactinomas are more frequent in men .
• Gender : female more than male 10 :1
• Age : 20-50 years .
• Some growth hormone producing tumors also cosecrete PROLACTIN.
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
CLINICAL MAINFESTATION:
1. Affect of increased hormone secretion
2. Mass effect
3. Affect on surrounding hormones
A. HORMONAL EFFECT :
• GnRH release is decreased in direct response to elevated prolactin,
leading to decreased production of LH and FSH
Women :
• Amenorrhea – this symptom causes women to present earlier.
• Infertility
• Oligomenorrhea, rarely galactorrhea
• Dryness in vagina may also occur and this makes intercourse a
painful experience
• Loss of libido
Although many women with hyperprolactinemia will have galactorrhea
and/ or amenorrhea .The absence these the two signs do not excluded
the diagnosis
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
Men
• Men with prolactinomas frequently present with headache, visual loss, or
neurological deficit but also have hypogonadism and infertility.
• Male patient presents with macroadenoma as an elder patient who
gradually becomes impotent may refer this to his age.
• This will lead to late presentation which is also applies to post
menopause female .
• Impotence – often ignored
• decreased libido, sexual desire
• Infertility
• Gynecomastia , hair growth decreased, shaving decreased
• Rarely galactorrhea
• Larger tumors
• Signs of mass effect
• Hyperprolactinemia may lead to bone loss in both men and women due
to the inhibitory effect of prolactin on sex steroids.
B. MASS EFFECT : headache ,CSF rhinorrhea , compression of optic chiasma
& cranial nerve.
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
DIAGNOSIS:
• Clinically : by excluded 2o
cause of High prolactin .
• HYPOTHYRODISM and PREGNANCY are 1st
to be excluded.
1) Physiological ( pregnancy ,stress ,nipple suckle )
2) Hypothalamic - pituitary disease ( tumor, trauma, infiltrative )
3) Others : hypothyroidism, chest injury, CRF .
4) Drugs .
a) Drugs which decrease dopamine stores
i) Phenothiazines
ii) Amitriptyline
iii) Metoclopramide
b) Factors inhibiting dopamine outflow
i) Estrogen
ii) Pregnancy
iii) Exogenous sources
5) Biochemical : by serum PRL concentration
* Normal range for serum prolactin is 5 - 20 ng/mL .
* Serum prolactin values above 200 ng/mL usually indicate the presence of a
lactotroph adenoma
Prolactin levels correlate with tumor size in the macroadenomas.
Suspect another tumor if prolactin low with a large tumor.
• Hook effect : can be observed in macroprolactinomas.
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
The extremely high PRL levels cause antibody saturation , the resulting in an
artifactually low reported value .
This can be eliminated by dilution of serum samples.
* Other s: FSH ,LH ,GH ,TSH, FT4 , RFT, LFT (2RY DEFICIENCY).
Antihypertensive agents
Methyldopa (Aldomet)
Reserpine (Hydromox,
Serpasil, others)
Verapamil (Calan, Isoptin)
Opiates
Codeine
Morphine
Antipsychotics agent
Phenothiazine drugs
Haloperidol (Haldol)
Risperidone (Risperdal)
Antidepressant agents
Clomipramine (Anafranil)
Desipramine (Norpramin)
Gastrointestinal drugs
Cimetidine (Antiacid)
Metoclopramide (Antaemetic)
Drugs
Diagnosis
A. Assess hypersecretion
• Basal, fasting morning PRL levels (normally <20 ug/L)
– Multiple measurements may be necessary
• Pulsatile hormone secretion
• levels vary widely in some individuals with
hyperprolactinemia .
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
B.Imaging : MRI Of Head
• Is the most sensitive test for detecting and measuring prolactinomas.
MRI scans may be repeated periodically to assess tumor progression and
the effects of therapy. Computer tomography (CT scan) also provides an
image of the pituitary, but it is less sensitive than the MRI for detection of
a prolactinoma.
• Should be performed in a patient with any degree of hyperprolactinemia
to look for a mass lesion in the hypothalamic-pituitary region and look
for damage to surrounding tissues.
TREATMENT:
The goals of therapy are to normalize prolactin, fertility, reduce tumor size, and
ameliorate the symptoms of hypogonadism & correct any vision abnormalities.
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
The indications for treatment :
1) Neurologic symptoms .
2) Hypogonadism or other symptoms .
1.The corner stone treatment of prolactinomas are medical treatment .
DOPAMINE AGONISTS
Dopamine agonists decrease prolactin secretion and reduce the size of
the lactotroph adenoma in more than 90 % of patients.
Decrease symptoms within days .
Decrease in serum prolactin within 2-3 weeks .
Decrease in size within 6 weeks ... ( 6 month ) .
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
1. Bromocriptine : dopamine agonist, It is given at least twice a day .
1.25 -2.5 mg PO at bedtime or with dinner ( max. 15 mg / d )
– Safe in pregnancy// Will restore menses
Bromocriptine normalizes prolactin and decreases tumor size in 80–90%
of patients with microadenomas and in 70% with large tumors.
2.Cabergoline : administered once or twice a week .
0.25 mg twice /wk or 0.5 mg once/wk .
2. Cabergoline is more effective and better tolerated than bromocriptine and is
also effective in treatment of tumors resistant to other dopamine agonists.
Cessation of therapy leads to recurrence of hyperprolactinemia and tumor
reexpansion .
Adverse effects
Common Less common
Nausea
Postural hypotension
Mental fogginess
valvular heart disease
Nasal stuffiness,
Depression,
Raynaud phenomenon,
Constipation
2.Surgical
TRANSSPHENOIDAL SURGERY
The indications for surgery :
1) Patients who do not respond to medical treatment or those who show
progression after an initial response to medical treatment .
2) Women who have a microadenoma, desire pregnancy, and cannot
tolerate medical treatment.
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
3) RADIATION THERAPY
The indications for radiation :
Radiation is primarily used to prevent regrowth of residual tumor in a
patient with a very large macroadenoma after transsphenoidal debulking
4) ORAL CONTRACEPTIVE
The indications for Estrogen- progestin : can be considered as therapy in
women with symptomatic microprolactinomas IF :
women cannot tolerate or
Do not respond to dopamine agonists or
Do not want to become pregnant.
Follow Up
After one month of therapy, the patient should be evaluated for side
effects and serum prolactin should be measured , So :
If the serum PRL is normal and no S/E So (continued).
If the serum PRL not decreased to normal but no S/E , the dose should be
increased gradually to as much as 1.5 mg of Cabergoline 2 or 3 times /
week or 5 mg of Bromocriptine 2 times / day. Whatever dose results in a
normal serum prolactin value should be continued .
If the prolactin has been normal for two or more years and no adenoma
is seen on MRI , discontinuation of the drug is the rule.
NOTE:
• How frequently to image the pituitary after therapy ?
【measure prolactin yearly and do not repeat an MRI unless there is a
marked increase in prolactin (more than 250 μg/liter) or clinical signs of
tumor expansion such as headaches or visual loss】.
• Because macroadenomas possess a higher growth potential,
more frequent radiographic monitoring is necessary.
【 repeat an MRI 2–3 yr after achievement of normal prolactin and
reduction in tumor size to confirm tumor suppression and to ensure that
prolactin levels are a reliable indicator of tumor size】.
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
ESSENTIALS OF DIAGNOSIS
Excessive growth of hands, feet, jaw, and internal organs; or gigantism before
closure of epiphyses.
Amenorrhea, headaches, visual field loss, weakness.
Soft, doughy, sweaty handshake.
Elevated IGF-I.
Serum GH not suppressed following oral glucose.
Acromegally is an anterior pituitary disorder characterized by:
• Enlargement, thickening, and broadening of bones
• Particularly extremities of the body
Epidemiology:
Estimated incidence is 3-4 cases/ million /year.
No clear relationship exists between incidence and race.
Acromegaly occurs with equal frequency in males and females.
Median age at diagnosis is 40 years in males and 45 years in females .
Problems in childhood or adolescence
Gigantism = oversecretion; dwarfism = hyposecretion
Sweating is a usual compliant.
SYMPTOMS AND SIGNS includes:
1. Excessive growth of soft tissues and bones
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
A. Thick, coarse, oily skin; enlarged lips, nose and tongue,
Supraorbital ridges, Broadening of nose.
B. Thickening wrinkles on forehead (bossing)
C. Protrusion of Lower jaw (prognathism)
D. Deepening of the voice due to enlarged sinuses and vocal
cords; snoring due to upper airway obstruction
E. Abnormal growth of the hands-spade like/feet
F. Excessive sweating and skin odor; fatigue and weakness;
headaches; impaired vision;
G. Enlargement of body organs, including the liver, spleen,
kidneys and heart.
H. Face with these features called as acromegalic or guerilla face
I. Multiple skin tags
J. Colon polyps----3-6 more likely than general population
K. Increased skin and GIT tumors.
L. Bone changes alter facial features including the spacing of
teeth
M.arthritis
Thyroid , parathyroid and adrenal glands shows hyperactivity
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
3. Pressure symptoms:
Decreased visual field and a acuity
May involve the cavernous sinus with ophthamoplegia
May extend to the hypothalamus with disturbance of
temperature blood pressure Control, appetite disturbance
,sleep and behavioral changes.
4. 2ry hormonal deficiency ((hypopituitrism)):
As the adenoma is increasing in size, it will compress over the hypothalamic
pituitary stalk leading to decreased supply of the secretor hormones with
reduction of sex hormones , thyroid hormones and cortisol.
TSH: causes fatigue, low energy, and weight gain.
Prolactin: causes inability to breastfeed after delivery.
ACTH: fatigue , low blood pressure, low sugar, and upset stomach.
Gonadotropins (FSH and LH): cause infertility, decrease in sex drive,
impotence, and irregular menstrual cycles.
Acromegaly
Co-morbidities
Hypertension
and heart disease
Cerebrovascular events
and headache
Sleep
apnea
50%
Arthritis
irreversible
Insulin-resistant
diabetes
40% DM or
Glucose
in tolerance
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
Causes of Acromegaly
• Hypersecretion of GH after fusion of epiphysis with shaft of bone
• Adenomatous tumor- Slow growing pituitary tumour (99%)
Diagnosis:
• The diagnosis of acromegaly is optimally based on both clinical and
biochemical evidence .
Lab Studies include:
1. glucose non suppressibility test.
Two baseline GH levels are obtained prior to ingestion of 75 or 100 g of
oral glucose, and additional GH measurements are made at 30, 60, 90,
and 120 minutes following the oral glucose load.
Patients with active acromegaly are unable to suppress GH concentration
below 1µg/L (immunradiometric assay) or below2µg/L (older
radioimmunoassay) after a 75-g oral glucose load
2. IGF-I measurement:
It is useful to gauge integrated GH secretion, to screen for acromegaly ,
and to monitor the efficacy of therapy.
How do you screen for acromegaly?
Check for high IGF-I levels (>3 U/ml)
3. Measurement of IGF-binding protein-3 (IGFBP-3):
The main binding protein for circulating IGF-1, is increased in acromegaly. It
might be useful in the diagnosis of acromegaly and may also be helpful in
following the activity of the disease during treatment .
• GHRH concentration can be obtained if clinically indicated.
• Random GH measurements which are often not diagnostic
because of the episodic secretion of GH, its short half-life,
and the overlap between GH concentration in acromegalic
patients and healthy subject
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
Imaging Studies:
• Imaging studies are only carried out after a firm biochemical diagnosis of
acromegaly.
• Imaging of the sella turcica should be performed first.
• Skull x-ray may show ballooning of pituitary fossa in cases of pituitary
macroadenoma
• MRI is more sensitive than CT scan.
• MRI shows a pituitary tumor in 90% of acromegalic patients.
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
Treatment:
Objectives of Treatment for Acromegaly
• Control and reverse symptoms and signs
• Suppress GH and IGF-1 to control morbidity and mortality
• Decrease pituitary tumor size
• Control tumor mass effects
• Preserve normal pituitary hormone secretion
A multimodality approach usually requires surgery as the first treatment line
followed by medical therapy for residual disease
Radiation treatment is reserved for refractory cases
Treatment
Surgery
Radiotherapy (not widely used)
Stereotactic Gamma Knife
Dopamine Agonists ( Cabergoline)
Somatastatin Analogue (Octreotide
LAR, Lanreotide Autogel)
GH receptor Antagonist
(Pegvisomant)
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
Surgical treatment:
• Even though surgery ( Transsphenoidal hypophysectomy ) might not cure a
significant number of patients , it is employed as the first line therapy.
• A remission rate of 80-85% can be expected for microadenomas and 50-
65% for macroadenomas.
• Sweating and carpal tunnel syndrome are improved within 24hours.
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
CUSHING’S DISEASE
Cause
• Hypersecretion of glucocorticoids mainly cortisol
• Either pituitary origin or adrenal origin OR ectopic ACTH
Cushing’s Cushing’s
disease syndrome
Pituitary origin
• Increased secretion of ACTH leads to hyperplasia of adrenal cortex
therefore, hypersecretion of glucocorticoids takes place.
• ACTH is increased by
• Tumor in pituitary cells ( basophilic cells)
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
• Malignant tumor of nonendocrine origin like cancer of lungs or
abdominal viscera
• Hypothalamic disorder causing hypersecretion of corticotropin
releasing hormone
• Cushings syndrome is a disease due to chronic exposure of tissues to
excess (supra-physiological doses) glucocorticoid (GC) hormones from
endogenous or exogenous source.
Causes / types:
• ACTH-dependant
• Non-ACTH-depentant
• Pseudo-Cushings syndrome
Signs and symptoms
1. Disproportionate distribution of body fat results:
• Moon face: Fat accumulation and retention of water and salt.
• Torso: Fat accumulation in chest and abdomen but slim legs and
arms(muscle wasting muscle atrophy and weakness-proximal ).
• Buffalo hump: Fat deposit on the back of neck and shoulder.
• Pot belly: Fat accumulation in upper abdomen.
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
2. Purple striae : Reddish purple stripes on abdomen due to:
Loss of collagen fibers due to protein depletion thin, weakened
integumentary tissues purple striae; rupture of small vessels.
Stretching of abdominal wall by excess subcutaneous fat
Rupture of sub dermal tissues due to stretching.
- Skin- thin, atrophic skin , easily damaged, with skin breaks And ulceration
4. Thinning of subcutaneous tissues, bruises, echymoses.
5. Darkening of skin on neck (aconthosis)
6. Pigmentation of skin - due to very high levels of ACTH - manifestation in:
mucous membranes, hair, and skin .
7. Facial redness (facial plethora)
8. Weakening of muscle-proximal myopathy.
9. Facial hair growth ( Hirsutism )- acne, oligomenorrhea ,changes of ovulation
due to adrenal androgens level in women
10. Bone resorption leads to osteoporosis
11. Hyperglycemia due to gluconeogeneis leads adrenal diabetes and glycosuria
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
12. Hypertension vascular sensitivity to catecholamines.
13 Suppression of the immune system susceptibility to infections
14. Poor healing
15. hyperglycemia, glycosuria, hypokalemia, metabolic alkalosis
Epidemiology
Majority of cases are Exogenous due to therapeutic use of glucocorticoids /
ACTH
Endogenous CS :
Annual incidence has been estimated to be 13 cases / million (USA) :
70 % Cushing`s disease (CD)
15 % Ectopic ACTH secretion
15 % Primary adrenal tumor
Sex : F : M ratio for pituitary or adrenal CS 5 : 1
Ectopic CS : more common in males-lung cancer
Age : Peak incidence of pituitary or adrenal CS : 25-40 years
Ectopic ACTH CS usually occurs later in life
Mortality / Morbidity
1. Primarily related to glucorticoid (GC) excess
ie : HTN, DM, perforated viscera , immune suppression, psychiatric problems, …
2. . Pituitary tumors may increase morbidity and mortality
3. . Adrenocortical carcinoma 5-y survival < 30%.
4. . Exogenous GC suppress HPA axis which carries risk of adrenal crisis
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
Differential Diagnosis
Pseudo-Cushing`s Syndrome
. Major depression
. Alcoholism
Hypercortisolism without Cushing`s syndrome
. Obesity
. Psychiatric illness / anorexia nervosa
. Stress : acute illness, trauma, …etc
. States of elevated (cortisol binding globulin) CBG :
. Pregnancy
. Estrogen therapy
. Hyperthyroidism
. Familial generalized glucocorticoid resistance
Diagnosis of Cushing`s Syndrome
Principals
1. Biochemical Confirmation
2. Localization by Imaging
Steps of Diagnostic Workup
1. Screening tests
2. Confirmation of diagnosis of CS
3. Knowing the Cause of CS
4. Imaging
Steps to do:
DEXAMETHAZONE single night dose
DEXAMTHEAZONE 2 days
Urinary free cortisol
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
Screening Tests in the evaluation of Cushing’s syndrome
Specificity
(%)
Sensitivity
(%)
InterpretationMeasurementsProtocolTest
70 - 8098Normal, < 5
mcg/dl
8 A.M. plasma
cortisol.
Dex, 1 mg PO at
11 P.M.
1 mg overnight
DST
9895-100Values 2 – 3 fold
higher than the
upper limit of
normal suggest
Cushing syndrom
Cortisol, creatinine.24-hr urine
collection
24-hr urine free
cortisol
( UFC)
74 - 10056 - 69Urine free cortisol
>36 mcg/day or
urine 17-OHCS >4
mg/day suggests
Cushing syndrom
24-hr urine
collection for
cortisol, 17-OHCS,
creatinine during
last 24 hrs of dex
administration
Dex, 0.5 mg PO
q6h 48 hrs (last
dose 6 A.M.)
2-day low-dose
urine DST
(UFC)
10090Normal < 1.4
mcg/dL
Plasma cortisol 2
hrs after last dose of
dexa
Dex, 0.5 mg PO
q6h 48 hrs (last
dose 6 A.M.)
2-day low-dose
serum DST
Specifici
ty (%)
Sensitivit
y (%)
InterpretationMeasurementsProtocolTest
100100Cortisol > 1.4
mcg/dl
suggests
Cushing’s
Plasma cortisol
15 mins after
CRH injection
Same as
LDDST with
first dose dex
given at noon
and CRH, 1
mcg/kg IV at 8
A.M. after last
dose of dex.
CRH / dex
10092Value < 1.3
ng/mL exc.
Cushing’s
Salivary cortisol11 P.M sampleLate-night
salivary
cortisol
10096Cortisol > 7.5
mcg/dL
suggests
Cushing’s
Midnight
plasma cortisol
Indwelling
catheter.
Hospitalization
recommended
Midnight
plasma
cortisol
Screening tests – cont.
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
Specificity
(%)
Sensitivity
(%)
InterpretationProtocolTest
10083PituitaryCushing’s will
havesuppression ofurine
17-OH by >64% or a >90%
reductionin urine free
cortisol
Collest24-hr urine for 17-OH or
urinefree cortisol andcreatinine;
give dex, 2 mg POq6h 48 hrs; re-
collecturine during last 24 hrs of
dexadministration.
2– day
HDDST
10092PituitaryCushing’s will
havesuppression of
cortisolby 50% compared
tobaseline.
Measureplasma cortisol at 8A.M.;
givedex 8 mg PO at11 P.M.;
redraw plasma cortisol next
morningat 8A.M.
8mg dex
10093Increase ofACTH (mean of
+15and +30 mins values)
by35% over baseline
(meanof -5 and -1 min)
suggestspituitary
Cushing,s
CHR,1 mcg/kg IV bolus at 8 A.M.
(giventhroughindwellingcatheter
placed2 hrs beforebolus );draw
plasmaACTH at -5, -1 min before
CRHand +15, +30 mins after CRH
CRH
10095- 100PituitaryCushing’s if
basalpetrosal : peripheral
>2 or post-CRH petrosal:
peripheral > 3
Simultaneousbilateral inferior
petrosalsampling andperipheral
samplingforACTH beforeand
afterCRH, 100 mcg IV
IPSS
Differentiating Cushing`s disease from Ectopic ACTH
38. 38
DR. MAGDI AWAD SASI PITUITARY DISORDERS
PlasmaACTH 2
ACTH<10pg/mL
ACTH-IndependentCauses
ACTH10-20pg/mL
Indeterminate
ACTH>20pg/mL
ACTH-DependentCauses
BiochemicalTests
IPSS withCRH
Central: PeripheralACTHGradient
< 2 2-3 > 3
CushingsDisease Indeterminate EctopicACTH
CRHStimulation Test
ACTHResponse
> 34% < 34%
CushingsDisease Indeterminate
DexamethasoneSuppression Test
UFCor 17-OHCSResponse
Present Absent
Cushing’sdisease Indeterminate
MetyraponeStimulationTest
17-OHCSor Compound S Response
Present Absent
Cushing’sdisease Indeterminate
Bilaterally Small Glands
PPNAD
Exogenous steroids
Unilateral Mass
Contralateral Gland Small
Adrenal adenoma
Adrenal carcinoma
Bilateral Masses
Idiopathic massive macronodularadrenal disease
Massive macronodularadrenal disease/
abnormal receptors
McCune-Albright syndrome
Bilateral adenomas
(Consideriodocholesterolscan to determine
functional state of masses)
(ReconsiderACTH-dependentforms)
AdrenalCTScan ACTH<20 pg/mL ACTH>20 pg/mL
Remeasure ACTH, or
measure ACTH after CRH
40. 40
DR. MAGDI AWAD SASI PITUITARY DISORDERS
Imaging studies for Cushing`s syndrome should be performed after the
biochemical evaluation has been done
1. Pituitary:
1.5-T hr MRI with 3mm contiguous slices before and after gadolinum contrast
2. Adrenal: CT/MRI Iodo cholestrol scan
3. Chest , Abdomen, Neck, Pelvis CT / MRI
4. Octeriotide scintigraphy
5. Selective venous sampling of site suspected of ectopic ACTH production
6. PET imaging with isotopes eg CII 5HTP
TREATMENT:
SURGERY
MEDICATION
RADIOTHERAPY
Treatment of Cushing`s syndrome is directed by the primary cause.
In general, therapy should reduce the cortisol secretion to normal.
The optimal approach to treatment of CS is resection of abnormal tissue.
When surgery cannot be done or is not successful , control of hypercortisolism
may be attempted with medication.
Pituitary radiation may be useful if surgery fails for Cushing`s disease.
The treatment for exogenous CS is gradual reduction of dose or withdrawal of
glucocorticoid .
The treatment of choice for CD is transsphenoidal surgery by an experienced
surgeon.
41. 41
DR. MAGDI AWAD SASI PITUITARY DISORDERS
The goal of surgery is to remove the adenoma , preserving as much pituitary
function as possible.
A. MRI-guided pituitary surgery, a new procedure, may be indicated
B. With experienced surgeon, initial cure ranges from 66% to 89%, but may be
much lower in les experienced hands or after repeat surgery
C . The more extensive the mass and the resulting resection, the greater the risk
for loss of pituitary function
D. Transcranial resection for macroadenoma or tumors invading the cavernous
sinus. Success rate : 50 %-70 %
E. Permenant post-op complications (5%) : DI, partial / complete
hypopituitarism, injury to local tissues
F. After surgery most patients who achieve long-term remission are
hypocortisolemic and require replacement therapy until the HPA axis is
normalized , usually within the first postoperative yr
G. The recurrence rate after initial surgery is 10% or less
. Pituitary irradiation is used when TS surgery is not successful or not possible ,
late effects include hypopituitarism
. Bilateral adrenalectomy is an option if TS surgery , pituitary irradiation, and
medical treatment fail to normalize cortisol
. Nelson`s syndrome may develop in some patients treated with bilateral
adrenalectomy without pituitary irradiation.
Assessing Response to Surgery
. Most patients who had surgery develop adrenal insufficiency postoperatively
and are typically on high dose of hydrocortisone which should be tapered
gradually , over 3-4 days
. Morning daily cortisol and UFC are obtained daily for 3 days without HC.
42. 42
DR. MAGDI AWAD SASI PITUITARY DISORDERS
. Post operative hypercortisolemic ===indicate surgical failure.
. Eucortisolemic patients with morning values 6-9 ug/dl are at risk of
recurrence compared with hypocortisolemic patients .
. There should be return to dexamethasone suppressebility
Medical treatment of CS((all forms))
. Compounds that modulate ACTH release from pituitary :
. Retanserin . Cyproheptadine
. Bromocriptine . Octeriotide
. Compounds that inhibit stroidogenesis :
. Mitotane, ketoconazol, metyrapone, trilostane,etomidate
. Compounds that act on cortisol receptor :
. Mifeprestone
. Combination therapy may be used
43. 43
DR. MAGDI AWAD SASI PITUITARY DISORDERS
Hyperthyroidism
Synthesis and release of thyroid hormones is influenced by TSH from the
pituitary.
Two kinds of hormones are produce in the thyroid gland triiodothyronine
(T3) and thyroxine (T4).
Concern the regulation of the metabolic and oxidation rates in all the
tissues of the body except the brain.
Hypothalamus - the highest control of thyroid function.
Hyperfunction
Hyperthyroidism - over-activity of the thyroid gland results in excessive
secretion of T3 and T4.
Hyperthyroidism is a disorder that occurs when the thyroid gland makes
more thyroid hormone than the body needs.
44. 44
DR. MAGDI AWAD SASI PITUITARY DISORDERS
Thyroid hormones circulate throughout the body in the bloodstream and
act on virtually every tissue and cell in the body. Hyperthyroidism causes
many of the body’s functions to speed up.
Thyrotoxicosis is due to diffused toxic goiter (Grave’s disease) or nodular
toxic goiter, with single or multiple nodules (adenomas) of the thyroid
responsible for the excessive T3 and T4 secretion.
Symptoms
The patient will have symptoms of toxic thyroid gland. Hyperthyroidism has
many symptoms that can vary from person to person
CNS--heat intolerance, nervousness or irritability, heat intolerance, fatigue or
muscle weakness bilateral progressive proximal myopathy, sweating, trouble
sleeping , hand tremors, mood swings (common in young)
CVS-- rapid and irregular heartbeat, palpitation , dyspnea , chest pain.(elder)
GIT--weight loss, increased apetite, diarrhea, epigastric pain
TSOMA is a rare adenoma .
DIAGNOSIS:
Many symptoms of hyperthyroidism are the same as those of other diseases, so
hyperthyroidism usually cannot be diagnosed based on symptoms alone. With
suspected hyperthyroidism, a medical history and physical exam mandatory .
1.TSH test
2.T3
3.T4
Increased levels of TSH in toxic patient gives a clue to the diagnosis.
45. 45
DR. MAGDI AWAD SASI PITUITARY DISORDERS
PART 2= DEACREASED HORMONE PRODUCTION
HYPOPITUITRISM
(Anterior Pituitary Insufficiency)
Partial/ complete hypopituitrism
The pituitary gland is effected by something and may be deficient in one single
hormone, several hormones, or have complete pituitary failure(PAN).
Hypopituitarism is a rare disorder where there is a loss of function in the
pituitary and the failure to secrete hormones that affect many of the
body's functions.
There are may symptoms which are not specific leading to delay of
diagnosis and you should look for patients who at risk of pituitary
dysfunction like radiotherapy , trauma ,postdelivery shock due to
bleeding -sheehans syndrome , TB etc.
Who and when?
Can affect both males and females.
Can occur at any time in life.
Can be congenital .
Hypopituitarism can also be acquired (a condition that develops later in
life) and may be caused by:
Radiation to the head
Tumors in the brain
Other disorders, such as tuberculosis or sarcoidosis which infiltrate the
gland, can result in a reduction in function.
46. 46
DR. MAGDI AWAD SASI PITUITARY DISORDERS
Causes of hypopituitarism
Tumours (tu’)
Pituitarytumor
Adenoma,craniopharyngioma
Cerebraltumor
Hypothalamicdisorders
Tumor
Functionaldisturbance-
Eg -Anorexia nervosa
IsolatedGH and GnH secretion
due to impairedsecretionof
hypothalamicreleasing
hormones
Miscellaneous
Sarcoidosis(inflammation of
L.N)
Histocytosis X(abnormal
increasein the numberof
immunecells )
Haemochromatosis
Vascular ds
Necrosis(Sheehan’s synd)
Infarction
Severehypotension
Cranial arteritis
Trauma
Infection
Meningitis esp TB, syphilis
Iatrogenic
Surgery
Irradiation
Prolongedrx with
glucocorticoidor thyroid
hormones-isolatedACTH or
TSH suppression
3 most common causes:
secretory adenoma of ant pituitary
Sheehan’s syndrome (postpartum pituitary necrosis)
Empty sella syndrome (pituitary gland become shrinks or becomes
flattened)
47. 47
DR. MAGDI AWAD SASI PITUITARY DISORDERS
GENERAL RULES IN HYPOPITUITIRSM:
Partial hypopituitarism is more frequent than PANHYPOPITUITRISM.
Symptoms/signs do not manifest until > 75% of ant lobe is destroyed.
GH secretion is an early feature of pituitary failure which effects is
dramatic in children but less significant in adults.
LH/ FSH are affected before ACTH.
The hormones which are mandatory for survival are the last to be lost.
Hypothyroidism is an uncommon presenting feature of pituitary failure.
The presentation differs depending on:
-age
-sex
-severity of the deficiency
-number of hormones involved
-underlying cause of the hypopituitarism
Hormone Features of deficiency
GH Children: growth retardation, weakening of bone strength
Adults: ↓muscle bulk, feeling unwell
Tendency to hypoglycaemia.
Prolactin
Gonadotrophins
Failure of lactation
Children: delayed puberty
Female: oligomenorrhoea, infertility,atrophy of breast &testis
Male: Impotence,azoospermia,testicular atrophy
Both sexes: loss of libido, loss of body hair
ACTH Weight loss ,Hypotension, fatigue and low energy
48. 48
DR. MAGDI AWAD SASI PITUITARY DISORDERS
TSH
Vasopressin
Hypoglycaemia ,Hypotension, decrease skin pigmentation
Weight gain, cold intolerence,fatique
Thirst, polyuria
49. 49
DR. MAGDI AWAD SASI PITUITARY DISORDERS
Measurement of anterior pituitary hormones:
Measured in serum by immunoassay
Pulsatility of secretion of some of these hormones makes inappropriate to
rely on single measurements for diagnostic purposes
Dynamic tests/ functional tests are important tools in investigating
pituitary functions and other endocrine organs.
INSULIN INDUCING HYPOGLYCEMIA(ITT)
Isolated deficiencies of anterior pituitary hormones due to pathologies
other than genetic – do exist!
If present – may point to underlying pathology
1. Isolated gonadotrophin deficiency-Haemochromatosis
2. Isolated ACTH deficiency -Lymphocytic hypophysitis
Timing of onset of hypopituitarism
• Childhood
GHD - growth
FSH/LH – puberty
• Adult
Normal height/secondary sex characteristics
Investigation for Hypopituitarism:
• Gonadotrophin status
– FSH,LH,T/E2
– GnRH test x
– TSH, FT4
50. 50
DR. MAGDI AWAD SASI PITUITARY DISORDERS
– TRH test x
– Prolactin
– INSULIN TOLERANCE TEST
GH stimulation tests
• ITT/Arginine/Glucagon
• Arginine + GHRH
• GHRH + GHRP
Diabetes Insipidus
• 24 hour urine output > 3 litres
• 8 hour fluid deprivation test
Radiology – MRI Scan
Microadenoma vs Macrodenoma
o Risk of hypopituitarism
Stalk interruption
Type and site of lesion
Evolution
Basic principle of dynamic tests:
Hypofunction - stimulation tests
Hyperfunction-suppression tests
Treatment
Hormone replacement therapy, including glucocorticoids, thyroid
hormone, sex steroids, growth hormone and vasopressin, is usually free
of complications.
51. 51
DR. MAGDI AWAD SASI PITUITARY DISORDERS
• Hormone replacement therapy
– usually free of complications
• Treatment regimens that mimic physiologic hormone production
– allow for maintenance of satisfactory clinical homeostasis
Trophic Hormone Deficit Hormone Replacement
ACTH Hydrocortisone (10-20 mg A.M.; 10 mg P.M.)
Cortisone acetate (25 mg A.M.; 12.5 mg P.M.)
Prednisone (5 mg A.M.; 2.5 mg P.M.)
TSH L-Thyroxine (0.075-0.15 mg daily)
FSH/LH Males
Testosterone enanthate (200 mg IM every 2 wks)
Testosterone skin patch (5 mg/d)
Females
Conjugated estrogen (0.65-1.25 mg qd for 25days)
Progesterone (5-10 mg qd) on days 16-25
Estradiol skin patch (0.5 mg, every other day)
For fertility: Menopausal gonadotropins, human
chorionic gonadotropins
GH Adults: Somatotropin (0.3-1.0 mg SC qd)
Children: Somatotropin [0.02-0.05 (mg/kg per day)]
Vasopressin Intranasal desmopressin (5-20 ug twice daily)
Oral 300-600 ug qd
52. 52
DR. MAGDI AWAD SASI PITUITARY DISORDERS
Prognosis/Prevention
• Patients can lead a normal life
• Hypopituitarism is permanent so it requires a lifelong treatment
• Patients will have to alter their lives depending on the primary
cause of the disorder.
• There is no known prevention except for the prevention of damage
to the pituitary/hypothalamic area from injury.
DON’T FORGET:
• Remember that the cause may be functional
– Treatment should be aimed at the underlying cause
• Hypopituitarism may present
1) Acutely with cortisol deficiency
2) After withdrawal of prolonged glucocorticoid therapy that has
caused suppression of the HPA axis.
3) Post surgical procedure//Post trauma -Hemorrhage
• Exacerbation of cortisol deficiency in a pt w unrecognized ACTH deficiency
1. Medical/surgical illness
2. Thyroid hormone replacement therapy
Glucocorticoid replacement require careful dose adjustments during
stressful events.
Consider cortisol deficiency
In a patient who has received a large dose of radiation particularly if
1) sodium
2) TSH deficient
3) symptoms worsen with thyroxine therapy
53. 53
DR. MAGDI AWAD SASI PITUITARY DISORDERS
4) SPECIFIC CONDITIONS OF HORMONAL DEFICIENCY:
A.Pituitary Apoplexy
Hemorrhagic infarction of a pituitary adenoma/tumor.
Considered a neurosurgical emergency.
Presentation:
Variable onset of severe headache
Nausea and vomiting
Meningismus
Vertigo
+/ - Visual defects
+/ - Altered consciousness
Symptoms may occur immediately or may develop over 1-2 days .
Risk factors:
1) Diabetes
2) Radiation treatment
3) Warfarin use
Usually resolve completely
Transient or permanent hypopituitarism is possible
• undiagnosed acute adrenal insufficiency
Diagnose with CT/MRI
Differentiate from leaking aneurysm
Treatment:
• Surgical - Transsphenoid decompression
– Visual defects and altered consciousness
54. 54
DR. MAGDI AWAD SASI PITUITARY DISORDERS
Medical therapy – if symptoms are mild
• Corticosteroids
B. Empty Sella Syndrome
Often an incidental MRI finding
Usually have normal pituitary function
• Implying that the surrounding rim of pituitary tissue is fully
functional
Hypopituitarism may develop insidiously
Pituitary masses may undergo clinically silent infarction with
development of a partial or totally empty sella by cerebrospinal
fluid (CSF) filling the dural herniation.
Rarely, functional pituitary adenomas may arise within the rim of
pituitary tissue, and these are not always visible on MRI
C. Lymphocytic Hypophysitis
a. Etiology
i. Presumed to be autoimmune
b. Clinical Presentation
i. Women, during postpartum period
ii. Mass effect (sellar mass)
iii. Deficiency of one or more anterior pituitary hormones
1. ACTH deficiency is the most common
c. Diagnosis
i. MRI - may be indistinguishable from pituitary adenoma
55. 55
DR. MAGDI AWAD SASI PITUITARY DISORDERS
d. Treatment
i. Corticosteroids – often not effective
ii. Hormone replacement
D. Craniopharyngioma
Derived from Rathke's pouch.
Arise near the pituitary stalk
i. extension into the suprasellar cistern common
These tumors are often large, cystic, and locally invasive
Many are partially calcified
ii. characteristic appearance on skull x-ray and CT images
Majority of patients present before 20yr
Usually with signs of increased intracranial pressure, including headache,
vomiting, papilledema, and hydrocephalus
Associated symptoms include:
– Visual field abnormalities, personality changes and cognitive
deterioration, cranial nerve damage, sleep difficulties, and weight
gain.
• Children
– growth failure associated with either hypothyroidism or growth
hormone deficiency is the most common presentation
• Adults
i. sexual dysfunction is the most common problem
ii. erectile dysfunction
iii. amenorrhea
56. 56
DR. MAGDI AWAD SASI PITUITARY DISORDERS
• Anterior pituitary dysfunction and diabetes insipidus are common.
• Treatment :
– Transcranial or transsphenoidal surgical resection
followed by postoperative radiation of residual tumor
This approach can result in long-term survival and ultimate cure
most patients require lifelong pituitary hormone replacement.
• If the pituitary stalk is uninvolved and preserved at the time of surgery
– Incidence of subsequent anterior pituitary dysfunction is
significantly diminished.
57. 57
DR. MAGDI AWAD SASI PITUITARY DISORDERS
RARE DISEASES(POSTGRADUATE)
1.Dwarfism
• Pituitary disorder in children characterized by stunted growth
Cause of Dwarfism
• Reduction in the GH in infancy or early childhood
• Occurs because of following reasons:
Deficiency of GH releasing hormone from hypothalamus
Deficiency of Somatomedin – C
Atrophy of acidophilic cells in the adenohypophysis
Tumor of chromophobes : nonfunctioning tumor , compresses and
destroys the normal cells
Panhypopituitarism
58. 58
DR. MAGDI AWAD SASI PITUITARY DISORDERS
Signs and Symptoms
Stunted skeletal growth
Maximum height approximately 3 feet
Head becomes slightly larger in relation of body
Mental activity is normal without any deformity
Reproductive system is not affected due to lack of GH but in
Panhypopituitarism puberty is not obtained due to lack of
gonadotropic hormone
Laron Dwarfism
Genetical disorder
Called as GH insensitivity
Occurs due to presence of abnormal GH secretagogue receptors in liver
GHS becomes abnormal due to mutation in genes responsible for
receptor
Doesn’t depend on amount of GH secretion , hormone can’t stimulate
the growth due to abnormal GHS
Psychogenic Dwarfism((psychosocial dwarfism or Stress dwarfism)):
Due to extreme emotional deprivation or stress
Deficiency of GH
Dwarfism in Dystrophia adiposogenitalis((Frohlich syndrome))
• Rare childhood disorder
• Characterized by :
• Obesity
• Growth retardation
• Retarded development of genital organs
• Associated with tumors of hypothalamus – increased appetite and
decrease in gonadotropin hormone
59. 59
DR. MAGDI AWAD SASI PITUITARY DISORDERS
2.Acromicria
• Rare disease in adults characterized by the atrophy of the extremities of
the body
Causes of Acromicria
• Deficiency of GH in adults
• Secretion of GH decreases in
the following conditions:
Deficiency of GH
releasing hormone
Atrophy of acidophilic
cells in the anterior
pituitary
Tumor of
chromophobes
Panhypopituitarism
Signs and Symptoms
• Atrophy and thinning of extremities ( major symptoms )
• Associated with hypothyroidism
• Hyposecretion of adrenocortical hormone
• Person becomes lethargic and obese
• Loss of sexual function
60. 60
DR. MAGDI AWAD SASI PITUITARY DISORDERS
3.Simmond’s Disease((cachexia))
Rare pituitary disease
Occurs mostly in panhypopituitarism
Signs and Symptoms
Developing senile decay
Senile decay is due to deficiency of hormone from target glands of
anterior pituitary e.g. thyroid gland, adrenal cortex and the gonads
Loss of hair and loss of teeth
The skin on face becomes dry and wrinkled. ( most common )
4.Dystrophia Adiposogenitalis
Obesity and hypogonadism affecting mainly adolescent boys
Also known as Frohlich syndrome or hypothalamic eunuchism
Causes
Hypoactivity of both anterior and posterior pituitary
Tumor in pituitary gland and hypothalamic regions concerned with
food intake and gonadal development
Injury or atrophy of pituitary gland
Genetic inablility of hypothalamus to secrete luteinizing hormone
Symptoms
Obesity (common feature)
Sexual infantilism (failure to develop secondary sexual characters)
Dwarfism occurs if disease starts in growing age
Called as infantile or prepubertal type of Frohlich syndrome (in
children)
and adult type of Frohlich’s syndrome (in adults)
Other features are loss of vision and diabetes.
61. 61
DR. MAGDI AWAD SASI PITUITARY DISORDERS
5. Hypothalamic Dysfunction
Craniopharyngioma: most frequent cause in children and young adults.
Primary central nervous system tumors, pinealomas, dermoid and epidermoid
tumors seen in adulthood.
Posterior Pituitary hypofunction
Vasopressin
Main actions:
1.Promote tubular reabsorption of water.
2.Stimulate smooth muscle contraction.
By giving vasopressin in pharmacological dose
i. Coronary vasoconstriction.
ii. Contraction of smooth muscles in the gut.
iii. Pallor.
Mechanism of action:
The disulphide linkage of the peptide may be the means of the attachement to
the target organ.
So, blockade-------loss of action of hormone.
Each day , 70-50ml/H2O isomotic with plasma are filtered by the glomeruli.
85% of the filtered water is reabsorbed passively by the proximal tubule along
with the active reabsorption of solutes (Na&CL) without aid of vasopressin.
So , the urine remains remains isosomatic with plasma.
62. 62
DR. MAGDI AWAD SASI PITUITARY DISORDERS
The long U shaped loop of henle form counter –current concentrating system.
The ascending limb –actively transports sodium to the interstitial fluid of the
renal medulla , reendering this region hypertonic and the urine reaching the
distal tubule hypotonic and large volume.
ANTIDIURETICHORMONE production(ADH) cranial diabetes insipidus (DI)
Posterior Pituitary disorder characterized by excess loss of water through urine.
Implication
• Site of lesion is hypothalamic/ high stalk.
• occurs with posterior pituitary dysfunction.
• Pathology of lesion much more likely to be cranopharyngioma vs pituitary
adenoma.
• Presence of DI provides no information about anterior pituitary function
except that ACTH status must be normal for DI to be manifested.
• ADH deficiency results in a large volume of urine which is very dilute.
Types of DI:
Central (neurogenic) origin: failure of posterior pituitary to secrete
adequate amounts of ADH.
Nephrogenic origin: failure of kidney to respond to circulating ADH
Regardless of cause, patients secret Large volumes of dilute urine
causing cellular and extra-cellular dehydration resulting in excess
thirst(polydypsia and polyuria)
DI needs to be differentiated from:
63. 63
DR. MAGDI AWAD SASI PITUITARY DISORDERS
Primary polydypsia a compulsive psychoneurotic disorder
appearing as a thirst disorder. Pt drinks > 5L of water a day
Results in decreased ADH secretion and water causes
subsequent diuresis
plasma and urine are dilute as opposed to DI where urine
osmolarity is less than plasma osmolarity due to
inappropriate water diuresis
Causes of cranial DI
INFECTION- Meningitis, Abscess and Encephalitis.
ISCHEMIA- Vascular disorders
INFLAMMATION- Granulomatous disease
Tumors- craniopharyngioma, secondary tumors (metastatic CA), pituitary
tumors with suprasellar extension
Trauma. Lesion (injury) or degradation of supraoptic and paraventricular
nuclei of hypothalamus
Lesion in hypothalamo-hypophyseal tract
Atrophy of posterior pituitary
Surgery.
Inability of renal tubules to give response to ADH hormone. Called as
Nephrogenic diabetic insipidus
IDEOPATHIC.
Signs and Symptoms:
1.Polyuria
• Excretion of large quantity of dilute urine with increased frequency of
voiding is called polyuria.
• Daily output is 4 to 12 liters.
• Due to absence of ADH ,the epithelial cells of distal convoluted tubule in
the nephron and the collecting duct of the kidney becomes impermeable
to water.
64. 64
DR. MAGDI AWAD SASI PITUITARY DISORDERS
2.Polydipsia
• Intake of excess water.
• Because of polyuria ,thirst center in hypothalamus results in intake of
large quantity of water .
3.Dehydration
In some cases ,the thirst center in the hypothalamus is also affected by
the lesion.
Fatigue , dryness of mouth, dizziness ,palpitation.
Therefore water intake decreases in these patients and, the loss of
water through urine is not compensated.
DIAGNOSIS:
Primary test for cause of polyuria -
Water deprivation for 12- 18hrs
Body weight, BP ,urine volume, urine specific gravity,
plasma and osmolarity measured q 2hrs
24-h urine output collection
50 mL/kg per day (>3500 mL in a 70-kg man).
Normal response is decreased urine output, increased urine
concentration greater than plasma
Patient with DI maintain high dilute urine output.
pts with primary polydypsia have urine omsolarity greater than
plasma .
water deprivation continue until plasma lvl plateaus, then AVP is
given and urine osmolarity is checked in 1hr
Check osmolarity
>300 mosmol/L
65. 65
DR. MAGDI AWAD SASI PITUITARY DISORDERS
Due to a solute diuresis and the patient should be evaluated for
uncontrolled diabetes mellitus or other less common causes of
excessive solute excretion
<300 mosmol/L
Due to water diuresis and should be evaluated further to determine
which type of DI is present .
If does not result in urine concentration before body weight
decreases by 5% or plasma osmolarity/sodium exceed the
upper limit of normal
(osmolarity >300 mosmol/L, specific gravity >1.010)
Primary polydipsia or a partial defect in AVP secretion or
action are largely excluded
Severe pituitary or nephrogenic DI are the only remaining
possibilities
o pts w/ complete central DI; urine osmolarity increases to about plasma
osmolarity .
o pts w/ nephrogenic DI; osmolarity of urine increases less than 50%.
o pts w/primary poldypsia; osmolarity increases <10%.
Diagnosis: Neurogenic vs Nephrogenic
• Administer Desmopressin (DDAVP)
• 1 g ,0.03 ug/kg ,subcutaneously or intravenously
• Measure urine osmolality
– (30,60,120 min) ,1 to 2 h later
• An increase of >50% indicates severe pituitary DI
• Smaller or absent response is strongly suggestive of nephrogenic DI
TREATMENT:
Central DI
Desmopressin acetate (DDAVP) intranasal or orally
66. 66
DR. MAGDI AWAD SASI PITUITARY DISORDERS
serum osmolarity and sodium is monitored
Chlorpropamide (Diabinese)
Antidiuretic effect can be enhanced by cotreatment with a
thiazide diuretic
SE: hypoglycemia, disulfiram like reaction to ethanol
Contraindicated in Gestional DI
Nephrogenic DI tx
seek underlying cause
Not affected by treatment with DDAVP or chlorpropamide
May be reduced by treatment with a thiazide diuretic and/or
amiloride in conjunction with a low-sodium diet
Inhibitors of prostaglandin synthesis (e.g., indomethacin) are also
effective in some patients
maintain a state of mild sodium depletion w/reduction in solute
load on kidney by giving diuretics and salt restriction
Psychogenic or dipsogenic DI
There is no effective treatment
Syndrome of Inappropriate secretion of Antidiuretic Hormone (SIADH)
• Disease characterized by loss of sodium through urine due to
hypersecretion of ADH
67. 67
DR. MAGDI AWAD SASI PITUITARY DISORDERS
plasma ADH concentrations inappropriately high for plasma
osmolarity
leads to water retention and hyponatremia w/ decrease
plasma osmolarity
DX can only be made in absence of hyper-volumemia
(nephrotic syndrome, cardiac failure, cirrhosis) and w/
normal thyroid, adrenal and renal function
Signs and Symptoms
Depends on degree of hyponatremia and rate of fall of plasma
osmolarity
i. Loss of appetite
ii. Weight loss
iii. Nausea and vomiting
iv. Headache
v. Muscle weakness , spasm and cramps
vi. Fatigue
vii. Restlessness and irritability
• Anorexia, vomiting and confusion w/ sodium between 115 and
120mEq/l
• Na level <110mEq/l; disorientation, stupor, coma, seizures,
paralysis, and focal neurologic findings
several malignant and benign conditions are associated w/SIADH
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DR. MAGDI AWAD SASI PITUITARY DISORDERS
Disorders associated w/SIADH
Pulmonary: malignant- Oat cell carcinoma
benign- TB, pneumonia, abscess
CNS: meningitis, brain abscess, hd trauma
Adverse drug effects: Clofibrate,
Chlorpropamide, Cyclophosmamide,
Phenothiazine, Carbamazapine
Tumors (ectopic production of ADH):
lymphoma, Sarcoma, Carcinoma of pancreas or
duodenum 31
Syndrome of Inappropriate
ADH secretion
• Treatment
– Acute
• Fluid restriction
• Hypertonic saline
– Central myelinolysis
– Chronic
• Demeclocyline 150-300mg PO TID-
QID
–Reversible Nephrogenic DI