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
Site-specific CT/MRI
Normal
Abnormal
TREATMENT
Pituitary Macroadenoma
(Sagittal MRI Scan)
Optic Chiasm
Pituitary Tumor
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%
Recurrence
Radiotherapy
Macro
47%
75% (20 years)
Somatostatin
Dopaminergic
Analog
(Cabergoline)
50-65%
10-20%
5-10%*Late responseinconv. & cost Low efficacy
Complications
Hypopit.
Other
15%
>50%
None
None
DI- 2-3%
Neuro deficits
Gallstones
Nausea,
hypotens.
* At 10 years, Longer-term recurrence probably higher
Pegvisomant - GH receptor antagonist
Normalization of GH
Normalization of IGF1
Tumor growth
Long-term effect
0%
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.
GH >1 mcg/l
and IGF-1 not
normal
somatostatin analog, GHR
antagonist or dopaminergic
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
‫• אשה בת ‪35‬‬
‫• מתלוננת על‬
‫– אמנוריאה ‪ 6‬חודשים‬
‫– גלקטוריאה‬
‫– פרט לכך בריאה‬
‫• בדיקה גופנית‪ :‬הפרשת חלב ספונטנית דו"צ‬
‫‪Patient #3‬‬
‫• ‪ – MRI‬מיקרואדנומה ‪ 6‬מ"מ‬
‫• פרולקטין ‪( 6000‬תקין עד ‪)900‬‬
‫‪Hyperprolactinemia - etiology‬‬
‫• גידול בהיפופיזה המפריש פרולקטין‬
‫– מיקרואדנומה – )‪(<1 cm‬‬
‫– מאקרואדנומה ‪(>1 cm) -‬‬
‫– גידולים מעורבים (‪ 30%‬מהגידולים המפרישים ‪)GH‬‬
‫• אי ספיקת כליות כרונית‬
‫– ירידה בפינוי הפרולקטין‬
‫• גירוי תחושתי בבית החזה‬
‫– כוויות‪ ,‬ניתוחים‪ ,‬טראומה וכו‬
‫• סטרס פיזי או נפשי‬
‫– ביתא אנדורפין מדכא הפרשת דופמין‬
Hyperprolactinemia - etiology
‫• תרופות‬
– Alpha-methyldopa, reserpine
– Phenothiazines, butyrophenones, benzamides (metoclopramide,
sulpride)
– Estrogens
– H2-receptor blockers (cimetidine)
– Opiates
‫• היפותירואידיזם‬
‫ מעבר דופמין להיפופיזה‬/ ‫• הפרעה בהפרשת‬
‫ היפופיזריות או סופרהסלריות‬,‫– לזיות היפותלמיות‬
‫– נזק קרינתי להיפותלמוס‬
‫‪Hyperprolactinemia - etiology‬‬
‫• רמות פרולקטין מעל ‪ 11,000‬מעידות לרוב על‬
‫מאקרופרולקטינומה‬
‫• לחץ על ה ‪ ,stalk‬תרופות‪ ,‬היפותירואידיזם וסטרס‬
‫לרוב גורמים לפרולקטין מתחת ל ‪ 2,000‬ותמיד מתחת‬
‫ל ‪pmol/l 6,500‬‬
‫• מיקרופרולקטינומות ומסות הלוחצות על ה ‪ stalk‬לרוב‬
‫מתייצגות עם רמות פרולקטין דומות‬
‫‪Effects of hyperprolactinemia‬‬
‫•‬
‫•‬
‫•‬
‫•‬
‫היפותלמוס ‪ :‬עיכוב בייצור ‪GnRH‬‬
‫בלוטות חלב בשד ‪ :‬גירוי להפרשת חלב‬
‫שחלות‪/‬אשכים ‪ :‬תגובתיות ירודה‬
‫לגונדוטרופינים‬
‫עצם ‪ :‬הורדת צפיפות העצם באפקט לא ישיר‬
Prolactinoma: Results of Treatment
Response
Recurrence
Surgery
Microprolactinoma
60-80%
50%
Macroprolactinoma
10-30%
~100%
Radiotherapy
Medical Therapy
Normalization of PRL after ~10 years
Microprolactinoma
>90%
Macroprolactinoma
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
Treatment of Prolactinomas
• Dopamine agonist therapy will normalize
prolactin and lead to tumor regression in most
patients with macro- and microprolactinomas
• The primary limiting factors are side-effects which
occur in as many as 40% of patients. However,
cessation of therapy is necessary in only 5-10% of
patients.
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 mIU/l (N <250)
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
O.S.
O.D.
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 mIU/l
Prolactin (pmol/l)
Bromocriptine Dose (mg/d)
80,000
A.L. - Post-treatment Visual Fields
26/10/89
O.S.
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:
– 100 - 500 mIU/l (N < 250) 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
Dopamine Agonists:
Alternatives to Oral Bromocriptine
Name
Advantage
Disadvantage
Bromocriptine
Gold Standard
Long experience
Side-effects
Depot Bromocript.
Very long-acting
Less side-effects
Parenteral
Vaginal Bromocript. Less side-effects
Short half-life
Lisuride
Complementary
to Bromocript.
Side-effects
Pergolide
Long-acting
(once daily)
Side-effects
Cancer in rodents
Cabergoline
Long-acting
(once weekly)
well tolerated
GH (ng/dl)
Y.L. : Long-term Follow-up
GH (ng/dl)
Y.L. : Long-term Follow-up
Prolactin - Diurnal Variation
SW
I+II
WAKE
Plasma Prolactin (pmol/l)
REM
600
400
200
Sleep
08
14
20
02
24 Hour Clock Time
08
Control of Prolactin Secretion
Hypothalamus
+
PRFs
(TRH)
Dopamine
(Other PIFs?)
-
+
Lactotropes
-
Estrogen
Thyroid Hormone
Prolactin
Breast milk synthesis
Prolactin Effect on
Gonadotrophin Secretion
Inhibits
Hypothalamus
GnRH
Dopamine
Stimulates
+
Pituitary
Hyperprolactinemia
Gonadotrophs
LH
Gonads
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
Adenyl cyclase
ATP
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