Patient #Patient # 11

• 50 year old male• Chief complaints:

– Fatigue– sweating of hands and

feet– Increasing shoe size– Joint pains– Headache

Patient #1 (2)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 SymptomsAcromegaly - 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

AcromegalyAcromegaly

Frontal Bossing

Chin Protrusion

Acromegaly: Large HandsAcromegaly: Large Hands

Bone and Soft Tissue ManifestationsBone and Soft Tissue Manifestationsof Acromegalyof Acromegaly

A patient with marked macroglossia. This can cause severesleep apnea which can be associated with cardiac arrhythmiasand sudden death.

AcromegalyAcromegaly

Acromegaly: Skin TagsAcromegaly: Skin Tags

Acromegaly: Slow changes over yearsAcromegaly: Slow changes over years

Acromegaly: Slow changes over yearsAcromegaly: Slow changes over years

Initial Test to Diagnose Acromegaly?Initial Test to Diagnose Acromegaly?

Diurnal Variation in Pulsitile Growth Diurnal Variation in Pulsitile Growth Hormone SecretionHormone Secretion

Regulation of GH SecretionRegulation of GH Secretion

SS

GRH

GH

IGF-1+

TRH

InhibitionStimulation

Glucose

Dopamine

Alpha adrenergicOpiatesGABA

Screening Growth Hormone Levels in Screening Growth Hormone Levels in AcromegalyAcromegaly

GH

Upper“Normal”

Fasting

ControlAcromeg.

Post Prandial

ControlAcromeg.

Additional Tests to Diagnose Additional Tests to Diagnose AcromegalyAcromegaly

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 AcromegalyDefinitive Test for Acromegaly

• Oral Glucose Tolerance Test (OGTT)

Oral Glucose Tolerance TestOral Glucose Tolerance Test

0 30 60 120090Time (minutes)

GH

Upper“Normal”

Acromegaly

Control

Acromegaly: DiagnosisAcromegaly: Diagnosis

Clinical suspicion of acromegaly

1-2hr postprandial GH, IGF1 and IGFBP3

2 hr OGTT with GH levels

Acromegaly Excluded

Normal Abnormal

NormalAbnormal

Acromegaly diagnosed

Growth-Hormone ExcessGrowth-Hormone Excess

EtiologyEtiology

• 98%: GH-producing pituitary tumor• 2%: Ectopic GHRH secretion

– Small cell lung cancer– Bronchial or intestinal carcinoid tumors– Pancreatic islet cell tumor– Pheochromocytoma

Acromegaly: DiagnosisAcromegaly: Diagnosis

Clinical suspicion of acromegaly

1-2hr postprandial GH, IGF1 and IGFBP3

2 hr OGTT with GH levels

Pituitary MRI

Octreoscan

Site-specific CT/MRI

Acromegaly Excluded

Normal Abnormal

NormalAbnormal

Normal

TREATMENT

Abnormal

Pituitary Tumor

Optic Chiasm

Pituitary Macroadenoma Pituitary Macroadenoma (Sagittal MRI Scan)(Sagittal MRI Scan)

Normal Visual FieldsNormal Visual Fields

O.S. O.D.

90705090 70 50

Bitemporal hemianopsia Bitemporal hemianopsia due to Pituitary Tumordue to Pituitary Tumor

O.S. O.D.

90 70 50 3090705030

Visual Field Defects Caused by Visual Field Defects Caused by Pituitary TumorPituitary Tumor

From Sandoz slide set

Acromegaly (1)Acromegaly (1)

• Prevalence: 40-50 / 106

• Incidence: 3-4 / 106 • Mean age of onset: 32 years• Mean age at diagnosis: 42 years• Prognosis: 2x increased mortality if

not treated• Cure rate: Greatly reduced if tumor

invades cavernous sinus

Acromegaly -- TreatmentAcromegaly -- Treatment

Acromegaly: Treatment optionsAcromegaly: Treatment options

Transsphenoidal Surg. Radiotherapy Somatostatin Dopaminergic

Micro Macro Analog (Cabergoline)

GH <1 mcg/l Normal IGF1 82% 47% 75% (20 years) 50-65% 10-20%

Recurrence 5-10% * Late response inconv. & cost Low efficacy

Complications

Hypopit. 15% >50% None None

Other DI- 2-3% Neuro deficits Gallstones Nausea, hypotens.

* At 10 years, Longer-term recurrence probably higher

Regulation of GH SecretionRegulation of GH Secretion

SS

GRH

GH

IGF-1+

TRH

InhibitionStimulation

Glucose

Dopamine

Alpha adrenergicOpiatesGABA

Pegvisomant - GH receptor antagonistPegvisomant - GH receptor antagonist

Normalization of GH 90%Normalization of IGF1 80-90%

Tumor growth Rare

Long-term effect Unknown

Acromegaly: Treatment AlgorithmAcromegaly: Treatment Algorithm

Pituitary Adenoma

< 1 cm >1 cmConsider preoperative somatostatin analog

Progressive therapyif post-prand.GH >1 mcg/land IGF-1 notnormal

Post-prand.GH <1 mcg/lIGF-1 normal

Post prand GH >1 mcg/lAnd/or IGF-1 elevated

somatostatin analog or dopaminergic

Radiation Therapy

Transphenoidal surgery

Annual Follow-up

Adapted fromMelmed ESAP, 1999

somatostatin analog, GHR antagonist or dopaminergic

Combination therapy

Invasive

Patient #3Patient #3

• 35 year old woman

• Chief complaint– Amenorrhea for 6 months– Galactorrhea– Otherwise healthy

• Past medical history

• Family History

• Physical findings

Patient #3Patient #3

• Prolactin -- 5000 pmol/l (nl < 900 pmol/l)

• CT - consistent with microadenoma

Differential Diagnosis of Differential Diagnosis of HyperprolactinemiaHyperprolactinemia

• 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 Differential Diagnosis of HyperprolactinemiaHyperprolactinemia

• 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 Hyperprolactinemia: Clinical Presentation 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 75-

100 %Impotence 68-

100 %Headache 70 %Visual field defect 36-70

%Galactorrhea 10-30

%Gynecomastia 4-50

%

Prolactinoma: Results of TreatmentProlactinoma: Results of Treatment

ResponseRecurrence

SurgeryMicroprolactinoma 60-80% 50%

Macroprolactinoma 10-30% ~100%

Radiotherapy Normalization of PRL after ~10 years

Medical TherapyMicroprolactinoma >90%Macroprolactinoma 50-80%

Clinical Evaluation of HyperprolactinemiaClinical Evaluation of Hyperprolactinemia

< 6,500 pmol/l > 6,500 pmol/l

CT or MRICT or MRI

"Non-functioning"macroadenoma

Macro-prolactinoma

Dopaminergic TherapyDopaminergic TherapySurgery and/orRadiation

Surgery and/orRadiation

CT or MRICT or MRI

Exclude: Stress Renal failure Medications Hypothyroidism

Increased fasting, resting prolactin levels

Micro-prolactinoma

Patient #3: A.L. - HistoryPatient #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 DataA.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 MRIAL- Pre-treatment MRI

PituitaryMacroadenoma

OpticChiasm

A.L. - A.L. - Pre-treatment Visual FieldsPre-treatment Visual Fields

O.S. O.D.

24/3/89

90 70 50 3090705030

A.L. - TreatmentA.L. - Treatment

• Diagnosis:– Macroprolactinoma– Hypopituitarism:

• Thyroid axis• Adrenal axis• Gonadotrophin axis

• Treatment:– Postpone surgery– Bromocriptine in increasing doses– Cortisol, thyroid and testosterone

replacement

Ap

ril-

89

Ap

ril-

90

Dec

-91

Au

g-8

9

Jan

- 9

3

0

5

10

15

20

25

30

0

20,000

40,000

60,000

80,000

Bromocriptine (mg/d)

Prolactin (pmol/l)

Pro

lac

tin

pm

ol/l

Bro

mo

crip

tin

e D

os

e (m

g/d

)

A.L. - Prolactin Levels During TreatmentA.L. - Prolactin Levels During Treatment

A.L. - Post-treatment Visual FieldsA.L. - Post-treatment Visual Fields

O.S. O.D.

26/10/89

90705090 70 50

AL- MRI Post-treatmentAL- MRI Post-treatment

Optic chiasm

A.L. - Long-term Follow-upA.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# 4Pt# 4

• 55 year old male– Coma– Blood pressure normal, no edema– Hyponatremia– Normokalemia

• Past medial history– Viral syndrome 2 days before entry – Weight loss– Nausea – Progressive impotence, weakness and fatigue– Not taking any medications

• Liver/Kidney function normal• Chest x-ray normal

Patient #4 (2)Patient #4 (2)

• Additional tests:– Urine sodium -- 50 mEq/l

• Presumptive Diagnosis

Syndrome of Inappropriate ADH Syndrome of Inappropriate ADH (SIADH)(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 BalanceSIADH - 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 MRIPituitary MRI

Loss of Pituitary FunctionLoss 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: EtiologyLoss 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 Hormone Replacement Therapy in Panhypopituitary PatientPanhypopituitary Patient

• Adrenal Cortex:– Emergency (Stress)

• Hydrocortisone 50-100 mg IV every 8 h.– Maintainance

• Dexamethasone 0.25 - 0.75 mg/d or• Prednisone 5-7.5 mg/d or• Hydrocortisone 15-30 mg/d or• Cortosone Acetate 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

Macroadenoma of PituitaryMacroadenoma 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

The EndThe EndThe EndoThe Endo

Differential Diagnosis of Differential Diagnosis of HyperprolactinemiaHyperprolactinemia

• 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 Schematic View of an ADH-Sensitive Collecting Tubule CellTubule Cell

ATP

cAMP

A

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.

ADH receptor

Adenyl cyclase

cAMP

ATP

kinase

B

C H2OH2O Cortisol and

Thyroid Hormone requiring

Renal Concentrating MechanismRenal Concentrating Mechanism

Cortex

Medulla

NaH2O

Dilute

400

800

1100

H2O

H2O

Concentrated

10+ Liters/day

ADH PresentNa

H2O

300

Modified from Schrier, Renal and Electrolyte Disorders,

Na

Renal Diluting MechanismRenal Diluting Mechanism

Cortex

Medulla

NaH2O

Dilute

400

500

600

H2O

Na

Dilute

10+ Liters/day

ADH AbsentNa

H2O

Modified from Schrier, Renal and Electrolyte Disorders,

Acromegaly: Treatment optionsAcromegaly: Treatment options

Transsphenoidal Surg. Radiotherapy Somatostatin Dopaminergic

Micro Macro Analog (Cabergoline)

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%

Disadvantages

Recurrence 5-10% * Late response inconv. & cost Low efficacy

Complications

Hypopit. 15% >50% None None

Other DI- 2-3% Neuro deficits Gallstones Nausea, hypotens.

* Actual long-term recurrence probably higher

.

GH

(µ

g/l)

0

10

20

30

40

9/86pre-op

3/87Octr.

1500 µg

6/87Octr.

1500 µg

7/87No

Treat.

3/88post-

op

89 90 91 92 93

Y. L. - AcromegalyFollow-up

Y.L. : Long-term Follow-upY.L. : Long-term Follow-upG

H (

ng/d

l)

.

GH

(µ

g/l)

0

10

20

30

40

9/86pre-op

3/87Octr.

1500 µg

6/87Octr.

1500 µg

7/87No

Treat.

3/88post-

op

89 90 91 92 93

Y. L. - AcromegalyFollow-up

.

GH

(µ

g/l)

0

10

20

30

40

9/86pre-op

3/87Octr.

1500 µg

6/87Octr.

1500 µg

7/87No

Treat.

3/88post-

op

89 90 91 92 93

Y. L. - AcromegalyFollow-up

.

GH

(µ

g/l)

0

10

20

30

40

9/86pre-op

3/87Octr.

1500 µg

6/87Octr.

1500 µg

7/87No

Treat.

3/88post-

op

89 90 91 92 93

Y. L. - AcromegalyFollow-up

.

GH

(µ

g/l)

0

10

20

30

40

9/86pre-op

3/87Octr.

1500 µg

6/87Octr.

1500 µg

7/87No

Treat.

3/88post-

op

89 90 91 92 93

Y. L. - AcromegalyFollow-up

Oral Glucose Tolerance TestOral Glucose Tolerance Test

0 30 60 120090Time (minutes)

GH

Upper“Normal”

L.Y.Acromegaly

Control