1. Patient #1 50 year old male Chief complaints: –Fatigue –sweating of hands and feet –Increasing shoe size –Joint pains –Headache

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

3. 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

4. Acromegaly Frontal Bossing Chin Protrusion

5. Acromegaly: Large Hands

6. Bone and Soft Tissue Manifestations of Acromegaly

7. A patient with marked macroglossia. This can cause severe sleep apnea which can be associated with cardiac arrhythmias and sudden death. Acromegaly

8. Acromegaly: Skin Tags

10. Acromegaly: Slow changes over years

12. Initial Test to Diagnose Acromegaly?

13. Diurnal Variation in Pulsitile Growth Hormone Secretion

14. Regulation of GH Secretion SS GRH GH IGF-1 + TRH Inhibition Stimulation Glucose Dopamine Alpha adrenergic Opiates GABA

15. Screening Growth Hormone Levels in Acromegaly GH Upper “Normal” Fasting Control Acromeg. Post Prandial Control Acromeg.

16. 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

17. Definitive Test for Acromegaly Oral Glucose Tolerance Test (OGTT)

18. Oral Glucose Tolerance Test 03060120090 Time (minutes) GH Upper “Normal” Acromegaly Control

19. Acromegaly: Diagnosis Clinical suspicion of acromegaly 1-2hr postprandial GH, IGF1 and IGFBP3 2 hr OGTT with GH levels Acromegaly Excluded NormalAbnormal Normal Abnormal Acromegaly diagnosed

20. 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

21. Acromegaly: 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 NormalAbnormal Normal Abnormal Normal TREATMENT Abnormal

22. Pituitary Tumor Optic Chiasm Pituitary Macroadenoma (Sagittal MRI Scan)

23. Normal Visual Fields O.S. O.D. 907050907050

24. Bitemporal hemianopsia due to Pituitary Tumor O.S. O.D. 90705030 90705030

25. Visual Field Defects Caused by Pituitary Tumor From Sandoz slide set

26. Acromegaly (1) Prevalence: 40-50 / 10 6 Incidence: 3-4 / 10 6 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

27. Acromegaly -- Treatment

28. Acromegaly: Treatment options Transsphenoidal Surg.RadiotherapySomatostatinDopaminergic MicroMacroAnalog(Cabergoline) GH <1 mcg/l Normal IGF182%47%75% (20 years)50-65%10-20% Recurrence 5-10%*Late responseinconv. & costLow efficacy Complications Hypopit.15%>50%NoneNone OtherDI- 2-3%Neuro deficitsGallstonesNausea, hypotens. * At 10 years, Longer-term recurrence probably higher

29. Regulation of GH Secretion SS GRH GH IGF-1 + TRH Inhibition Stimulation Glucose Dopamine Alpha adrenergic Opiates GABA

30. Pegvisomant - GH receptor antagonist Normalization of GH 90% Normalization of IGF180-90% Tumor growthRare Long-term effectUnknown

31. Acromegaly: Treatment Algorithm Pituitary Adenoma < 1 cm>1 cm Consider preoperative somatostatin analog Progressive therapy if post-prand. GH >1 mcg/l and IGF-1 not normal Post-prand. GH <1 mcg/l IGF-1 normal Post prand GH >1 mcg/l And/or IGF-1 elevated somatostatin analog or dopaminergic Radiation Therapy Transphenoidal surgery Annual Follow-up Adapted from Melmed ESAP, 1999 somatostatin analog, GHR antagonist or dopaminergic Combination therapy Invasive

32. Patient #3 35 year old woman Chief complaint –Amenorrhea for 6 months –Galactorrhea –Otherwise healthy Past medical history Family History Physical findings

33. Patient #3 Prolactin -- 5000 pmol/l (nl < 900 pmol/l) CT - consistent with microadenoma

34. 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

35. 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.

36. Hyperprolactinemia: Clinical Presentation Women: Amenorhea57-90 % Oligomenorrhea10-28 % Regular menses9-15 % Galactorrhea30-80 % Headache40 % Visual field defect<25 % Hirsutism19 % Men: Decreased libido75-100 % Impotence68-100 % Headache70 % Visual field defect36-70 % Galactorrhea10-30 % Gynecomastia 4-50 %

37. Prolactinoma: Results of Treatment ResponseRecurrence Surgery Microprolactinoma 60-80%50% Macroprolactinoma 10-30% ~100% Radiotherapy Normalization of PRL after ~10 years Medical Therapy Microprolactinoma >90% Macroprolactinoma 50-80%

38. Clinical Evaluation of Hyperprolactinemia < 6,500 pmol/l> 6,500 pmol/l CT or MRI "Non-functioning" macroadenoma Macro- prolactinoma Dopaminergic Therapy Surgery and/or Radiation Surgery and/or Radiation CT or MRI Exclude: Stress Renal failure Medications Hypothyroidism Increased fasting, resting prolactin levels Micro- prolactinoma

39. 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

40. 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)

41. AL- Pre-treatment MRI Pituitary Macroadenoma Optic Chiasm

42. A.L. - Pre-treatment Visual Fields O.S. O.D. 24/3/89

43. A.L. - Treatment Diagnosis: –Macroprolactinoma –Hypopituitarism: Thyroid axis Adrenal axis Gonadotrophin axis Treatment: –Postpone surgery –Bromocriptine in increasing doses –Cortisol, thyroid and testosterone replacement

44. A.L. - Prolactin Levels During Treatment

45. A.L. - Post-treatment Visual Fields O.S. O.D. 26/10/89

46. AL- MRI Post-treatment Optic chiasm

47. 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

48. Pt# 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

49. Patient #4 (2) Additional tests: –Urine sodium -- 50 mEq/l Presumptive Diagnosis

50. 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)

51. SIADH - Water and Sodium Balance Increased ADH activity –Decreased free water clearance –Increased total body water Hyponatremia Increased ECF volume –Increased GFR –Decrease proximal nephron Na + reabsorption –Increased sodium loss –Minimizing increased ECF volume No edema –Worsening hyponatremia

52. Pituitary MRI

53. Loss of Pituitary Function Functional abnormalities –ACTH –Thyroid –Gonadotrophins –GH –Prolactin –Anti-diuretic hormone Structural abnormalities –Visual field disturbance –Cranial nerve dysfunction –CNS leak

54. 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

55. Hormone Replacement Therapy in Panhypopituitary Patient Adrenal Cortex: –Emergency (Stress) Hydrocortisone 50-100 mg IV every 8 h. –Maintainance Dexamethasone0.25 - 0.75 mg/dor Prednisone 5-7.5 mg/dor Hydrocortisone 15-30 mg/dor Cortosone Acetate25-37.5 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

56. 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

57. The End The Endo

58. 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

59. Schematic View of an ADH-Sensitive Collecting Tubule 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 H2OH2O Cortisol and Thyroid Hormone requiring

60. Renal Concentrating Mechanism Cortex Medulla Na H 2 O Dilute 400 800 1100 H2OH2O H2OH2O Concentrated 10+ Liters/day ADH Present Na H2OH2O 300 Modified from Schrier, Renal and Electrolyte Disorders, Na

61. Renal Diluting Mechanism Cortex Medulla Na H 2 O Dilute 400 500 600 H2OH2O Na Dilute 10+ Liters/day ADH Absent Na H2OH2O Modified from Schrier, Renal and Electrolyte Disorders,

62. Acromegaly: Treatment options Transsphenoidal Surg.RadiotherapySomatostatinDopaminergic MicroMacroAnalog(Cabergoline) GH <5 mcg/l80%50-60%77% (15 years)65%20% GH <2 mcg/l70%40%no data40%no data Nl IGF-150%50%no data50%10% Disadvantages Recurrence 5-10%*Late responseinconv. & costLow efficacy Complications Hypopit.15%>50%NoneNone OtherDI- 2-3%Neuro deficitsGallstonesNausea, hypotens. * Actual long-term recurrence probably higher

63. Y.L. : Long-term Follow-up GH (ng/dl)

64. Oral Glucose Tolerance Test 03060120090 Time (minutes) GH Upper “Normal” L.Y. Acromegaly Control