Download GH Stimulation Tests

Patient # 1
• 50 year old male
• Chief complaints:
– Fatigue
– sweating of hands and
feet
– Increasing shoe size
– Joint pains
– Headache
Patient #1 (2)
• Pertinent family
history
– No family history of
• Pituitary tumors
• Hypercalcemia
• Pancreatic tumors
• Past medical history
– s/p carpal tunnel
surgery
• Physical findings
Acromegaly - Signs and Symptoms
• GH Excess
– Enlargement of hands and
feet
– Thick skin
– Skin tags
– Sweating
– Sleep Apnea
– Carpal Tunnel Syndrome
– Glucose intolerance
– Osteoarthritis
– Colonic Polyps
• Tumor-related
– Headache
– Visual field defect
– Loss of pituitary
function
• Gonadotrophins
• TRH - hypothyroid
• ACTH - Addison’s
Acromegaly
Frontal Bossing
Chin Protrusion
Acromegaly: Large Hands
Bone and Soft Tissue Manifestations
of Acromegaly
Acromegaly
A patient with marked macroglossia. This can cause severe
sleep apnea which can be associated with cardiac arrhythmias
and sudden death.
Acromegaly: Skin Tags
Acromegaly: Slow changes over years
Acromegaly: Slow changes over years
Initial Test to Diagnose Acromegaly?
Diurnal Variation in Pulsitile Growth
Hormone Secretion
Regulation of GH Secretion
Dopamine
Glucose
TRH
SS
GRH
GH
Stimulation
Inhibition
+
IGF-1
Alpha adrenergic
Opiates
GABA
Screening Growth Hormone Levels in
Acromegaly
Fasting
Post Prandial
GH
Upper
“Normal”
Acromeg.
Control
Acromeg.
Control
Additional Tests to Diagnose
Acromegaly
1. IGF-1 (Insulin-like Growth Factor 1)
2. IGF-BP3 (IGF binding protein 3)
• Advantages:
–
–
•
Single blood level
No diurnal variation
Disadvantages
–
Some overlap with normal
Definitive Test for Acromegaly
• Oral Glucose Tolerance Test (OGTT)
Oral Glucose Tolerance Test
Acromegaly
GH
Upper
“Normal”
Control
0
30
60
90
Time (minutes)
1200
Acromegaly: Diagnosis
Clinical suspicion of acromegaly
1-2hr postprandial GH, IGF1 and IGFBP3
Normal
Abnormal
Acromegaly Excluded
Normal
2 hr OGTT with GH levels
Abnormal
Acromegaly diagnosed
Growth-Hormone Excess
Etiology
• 98%: GH-producing pituitary tumor
• 2%: Ectopic GHRH secretion
–
–
–
–
Small cell lung cancer
Bronchial or intestinal carcinoid tumors
Pancreatic islet cell tumor
Pheochromocytoma
Acromegaly: Diagnosis
Clinical suspicion of acromegaly
1-2hr postprandial GH, IGF1 and IGFBP3
Normal
Abnormal
Acromegaly Excluded
Normal
2 hr OGTT with GH levels
Abnormal
Pituitary MRI
Octreoscan Normal
Site-specific CT/MRI
Abnormal
TREATMENT
Pituitary Macroadenoma
(Sagittal MRI Scan)
Optic Chiasm
Pituitary Tumor
Normal Visual Fields
90
70
O.S.
50
50
70
90
O.D.
Bitemporal hemianopsia
due to Pituitary Tumor
90
70
50
30
30
O.S.
50
70
O.D.
90
Visual Field Defects Caused by
Pituitary Tumor
From Sandoz slide set
Acromegaly (1)
•
•
•
•
•
Prevalence:
Incidence:
Mean age of onset:
Mean age at diagnosis:
Prognosis:
• Cure rate:
40-50 / 106
3-4 / 106
32 years
42 years
2x increased mortality if
not treated
Greatly reduced if tumor
invades cavernous sinus
Acromegaly -- Treatment
Acromegaly: Treatment options
Transsphenoidal Surg.
Micro
GH <1 mcg/l
Normal IGF1 82%
Radiotherapy
Somatostatin
Dopaminergic
Analog
(Cabergoline)
75% (20 years)
50-65%
10-20%
Late response
inconv. & cost
Low efficacy
15%
>50%
None
None
DI- 2-3%
Neuro deficits
Gallstones
Nausea,
hypotens.
Macro
47%
Recurrence 5-10% *
Complications
Hypopit.
Other
* At 10 years, Longer-term recurrence probably higher
Regulation of GH Secretion
Dopamine
Glucose
TRH
SS
GRH
GH
Stimulation
Inhibition
+
IGF-1
Alpha adrenergic
Opiates
GABA
Pegvisomant - GH receptor antagonist
Normalization of GH
Normalization of IGF1
Tumor growth
Long-term effect
90%
80-90%
Rare
Unknown
Acromegaly: Treatment Algorithm
Pituitary Adenoma
Invasive
< 1 cm
>1 cm
Consider preoperative
somatostatin analog
Transphenoidal surgery
Post-prand.
GH <1 mcg/l
IGF-1 normal
Annual Follow-up
Adapted from
Melmed ESAP, 1999
Post prand GH >1 mcg/l
And/or IGF-1 elevated
somatostatin analog or dopaminergic
Progressive therapy
if post-prand.
somatostatin analog, GHR
GH >1 mcg/l
antagonist or dopaminergic
and IGF-1 not
normal
Combination therapy
Radiation Therapy
Patient #3
• 35 year old woman
• Chief complaint
– Amenorrhea for 6 months
– Galactorrhea
– Otherwise healthy
• Past medical history
• Family History
• Physical findings
Patient #3
• Prolactin -- 5000 pmol/l (nl < 900 pmol/l)
• CT - consistent with microadenoma
Differential Diagnosis of
Hyperprolactinemia
• Medications
– Alpha-methyldopa, reserpine
– Phenothiazines, butyrophenones,
– benzamides (metoclopramide, sulpride)
Estrogens
– H2-receptor blockers (cimetidine)
– Opiates
• Hypothyroidism
• Decreased dopamine delivery to pituitary
– Pituitary, suprasellar and hypothalamic lesions
– Radiation damage to the hypothalamus
Differential Diagnosis of
Hyperprolactinemia
• Prolactin levels > 11,000 pmol/l is usually indicative of
macroprolactinoma.
• Stalk compression, medications, hypothyroidism and
stress usually result in prolactin levels < 2,000 and
virtually always less than 6,500 pmol/l.
• Microprolactinomas, mass lesions compressing the
pituitary stalk frequently present with similar prolactin
levels.
Hyperprolactinemia: Clinical
Presentation
Women:
Amenorhea
57-90 %
Oligomenorrhea 10-28 %
Regular menses 9-15 %
Galactorrhea
30-80 %
Headache
40 %
Visual field defect<25 %
Hirsutism
19 %
Men:
Decreased libido
Impotence
Headache
Visual field defect
Galactorrhea
Gynecomastia
75-100 %
68-100 %
70 %
36-70 %
10-30 %
4-50 %
Prolactinoma: Results of Treatment
Response
Recurrence
Surgery
Microprolactinoma
Macroprolactinoma
Radiotherapy
Medical Therapy
Microprolactinoma
Macroprolactinoma
60-80%
10-30%
50%
~100%
Normalization of PRL after ~10 years
>90%
50-80%
Clinical Evaluation of Hyperprolactinemia
Increased fasting, resting prolactin levels
< 6,500 pmol/l
Exclude:
Stress
Renal failure
Medications
Hypothyroidism
"Non-functioning"
macroadenoma
Surgery and/or
Radiation
> 6,500 pmol/l
CT or MRI
Microprolactinoma
CT or MRI
Macroprolactinoma
Dopaminergic Therapy
Patient #3: A.L. - History
• 58 year old male
• Presenting symptoms (3 months):
–
–
–
–
–
–
Decreased vision
Weight loss
Nausea
Dizziness
Impotence
Occasional diarrhea
• Physical examination:
– Bitemporal hemianopsia
– Atrophic testes
A.L. - Laboratory Data
• Blood count, electrolytes, liver and kidney
functions - Normal
• Endocrine tests:
–
–
–
–
–
–
–
–
Prolactin - 50,400 pmol/l (N <450)
T4 - 46 nmol/l (N 60 - 160)
T3 - 2.0 nmol/l (N 1.2 - 3)
TRH test: TSH increased from 1.2 to 7.2 mU/l
with delayed curve
ACTH test: Cortisol 108 to 617 µmol/l
@ 60 minutes (Normal basal 200-700)
Testosterone - <0.9 nM/l (Nl 7-30)
LH - 4.1 U/l (3-15)
FSH - 1.2 U/l (1-10)
AL- Pre-treatment MRI
Pituitary
Macroadenoma
Optic
Chiasm
A.L. - Pre-treatment Visual Fields
24/3/89
90
70
50
30
30
O.S.
50
70
O.D.
90
A.L. - Treatment
• Diagnosis:
– Macroprolactinoma
– Hypopituitarism:
• Thyroid axis
• Adrenal axis
• Gonadotrophin axis
• Treatment:
– Postpone surgery
– Bromocriptine in increasing doses
– Cortisol, thyroid and testosterone
replacement
A.L. - Prolactin Levels During Treatment
30
Bromocriptine (mg/d)
25
60,000
20
40,000
15
10
20,000
5
0
Jan - 93
Dec-91
April-90
Aug-89
0
April-89
Prolactin pmol/l
Prolactin (pmol/l)
Bromocriptine Dose (mg/d)
80,000
A.L. - Post-treatment Visual Fields
26/10/89
90
70
50
O.S.
50
70
90
O.D.
AL- MRI Post-treatment
Optic chiasm
A.L. - Long-term Follow-up
• CT, MRI:
– Complete tumor regression - empty sella
• Complete normalization of visual fields
• Pituitary functions:
– Complete normalization of all axes
• Prolactin levels:
– 130 - 650 pmol/l (N < 450) on 1.25 - 0.625
mg/d bromocriptine
Pt# 4
• 55 year old male
–
–
–
–
Coma
Blood pressure normal, no edema
Hyponatremia
Normokalemia
–
–
–
–
–
Viral syndrome 2 days before entry
Weight loss
Nausea
Progressive impotence, weakness and fatigue
Not taking any medications
• Past medial history
• Liver/Kidney function normal
• Chest x-ray normal
Patient #4 (2)
• Additional tests:
– Urine sodium -- 50 mEq/l
• Presumptive Diagnosis
Syndrome of Inappropriate ADH
(SIADH)
• Clinical findings:
– Hyponatremia
– Euvolemia (mild volume expansion)
– Normokalemia
• Diagnosis:
– Hyponatremia
– Inappropriately elevated urine sodium
– No volume depletion or severe volume expansion
• Etiology:
–
–
–
–
–
Glucocorticoid deficiency
Hypothyroidism
Pulmonary lesions
CNS lesions
Drugs (Chlorpropamide and others)
SIADH - Water and Sodium Balance
• Increased ADH activity
– Decreased free water clearance
– Increased total body water
• Hyponatremia
• Increased ECF volume
• Increased ECF volume
–
–
–
–
Increased GFR
Decrease proximal nephron Na+ reabsorption
Increased sodium loss
Minimizing increased ECF volume
• No edema
– Worsening hyponatremia
Pituitary MRI
Loss of Pituitary Function
• Functional abnormalities
–
–
–
–
–
–
ACTH
Thyroid
Gonadotrophins
GH
Prolactin
Anti-diuretic hormone
• Structural abnormalities
– Visual field disturbance
– Cranial nerve dysfunction
– CNS leak
Loss of Pituitary Function: Etiology
• Congenital
• Pituitary tumors
– Functional
– Non-functional
• Non-pituitary tumors
– Craniopharyngioma
– Metastases
• Trauma
– Surgical
– Head trauma
• Inflammation
– Autoimmune
hypophysitis
– Granulomatous disease
• histiocytosis X
• Sarcoid
• Tuberculosis
– Rathke’s pouch rupture
Hormone Replacement Therapy in
Panhypopituitary Patient
• Adrenal Cortex:
– Emergency (Stress)
• Hydrocortisone
50-100 mg IV every 8 h.
– Maintainance
•
•
•
•
Dexamethasone
Prednisone
Hydrocortisone
Cortosone Acetate
0.25 - 0.75 mg/d
5-7.5 mg/d
15-30 mg/d
25-37.5 mg/d
• Thyroid:
– Levothyroxin
100-200 mcg/d
• Maintain T4 level in upper normal range
• Gonadal Steroids:
– Estrogen/Progesterone or Testosterone
• Desmopressin (DDAVP)
• Growth Hormone
or
or
or
Macroadenoma of Pituitary
• Treatment:
– Hormonal Replacement
– Surgical
• Most cases require surgery
• Dopaminergic for prolactinoma
– Radiation
•
•
•
•
Small effect
High probability of pituitary dysfunction
Low probability of secondary tumor
May have long-term subtle neurologic effects
– Medical
• Steroids for hypophysitis
• Specific treatment for granulomatous disease
TheEndo
End
The
Differential Diagnosis of
Hyperprolactinemia
• Prolactin producing pituitary tumor
– Microprolactinoma (<1 cm)
– Macroprolactinoma (>1 cm)
– Mixed tumors (30% of GH producing tumors)
• Chronic renal failure
– Decreased clearance and suppressibility
• Thoracic sensory nerve stimulation
– Chest wall burns, incisions, trauma etc.
• Mental and physical stress
– May be mediated through ß-endorphin
suppression of dopamine secretion
Schematic View of an ADH-Sensitive Collecting
Tubule Cell
ATP
Adenyl cyclase
ATP
kinase
cAMP
cAMP
ADH receptor
H2O
A
B
C
H2O
Cortisol and
Thyroid Hormone
requiring
ADH binds to the contraluminal surface, activating adenylyl cyclase and
generating cAMP. This causes cytoplasmic tubules containing water
channels, aquaporins (A), to fuse with the luminal membrane (B), allowing
free transport of water into the cell. C = particle aggregates in luminal
membrane.
Renal Concentrating Mechanism
Dilute
Cortex
10+ Liters/day
Na
H2O
300
400
Medulla
H2O
Na
H2O
800
ADH Present
H2O
1100
Modified from Schrier, Renal and Electrolyte Disorders,
Na
Concentrated
Renal Diluting Mechanism
Dilute
Cortex
10+ Liters/day
Na
H2O
400
Medulla
H2O
H2O
Na
500
ADH Absent
Na
600
Modified from Schrier, Renal and Electrolyte Disorders,
Dilute
Acromegaly: Treatment options
Transsphenoidal Surg.
Radiotherapy
Somatostatin
Dopaminergic
Analog
(Cabergoline)
Micro
Macro
GH <5 mcg/l
80%
50-60%
77% (15 years)
65%
20%
GH <2 mcg/l
70%
40%
no data
40%
no data
Nl IGF-1
50%
50%
no data
50%
10%
Late response
inconv. & cost
Low efficacy
15%
>50%
None
None
DI- 2-3%
Neuro deficits
Gallstones
Nausea,
hypotens.
Disadvantages
Recurrence 5-10% *
Complications
Hypopit.
Other
* Actual long-term recurrence probably higher
GH (ng/dl)
Y.L. : Long-term Follow-up
Oral Glucose Tolerance Test
Acromegaly
GH
L.Y.
Upper
“Normal”
Control
0
30
60
90
Time (minutes)
1200