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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