Hyperprolactinemia 3

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Hyperprolactinemia 3

  1. 1. Selected Pituitary Disorders March 18, 2008
  2. 3. What is “a pituitary”? <ul><li>Pituita: Mucus </li></ul><ul><li>Former Belief That Pituitary Gland Secretes Mucus </li></ul>
  3. 4. Pituitary Hormones Anterior Pituitary Testosterone Estradiol FSH & LH Growth Hormone ACTH Cortisol TSH T 3 T 4 Prolactin Posterior Pituitary IGF-1 Oxytocin ADH
  4. 5. Importance  and ß Subunits <ul><li>TSH, LH, FSH and hCG: </li></ul><ul><li>Share a common  Subunit </li></ul><ul><li>ß Subunits Differ, Conferring Specificity to the Hormone </li></ul>
  5. 7. Selected Pituitary Disorders <ul><li>Pituitary Adenomas </li></ul><ul><li>Hypopituitarism </li></ul><ul><li>Pituitary Apoplexy </li></ul>
  6. 9. Clinical Manifestations of Pituitary Adenomas <ul><li>Mass Effect </li></ul><ul><li>Hormonal Overproduction </li></ul><ul><li>Hypopituitarism </li></ul>
  7. 10. Mass Effects Of Sellar Lesions <ul><li>Headache </li></ul><ul><li>Visual Field Defects </li></ul><ul><li>Cranial Nerve Palsies (3,4,6) </li></ul>
  8. 11. Bitemporal Hemianopsia Due To Pituitary Tumor Visual Fields Pituitary Tumor Compression Of Optic Nerve Medial Fibers By Tumor Impairs Peripheral Vision
  9. 12. Mass Effects of Sellar Lesions <ul><li>Headache </li></ul><ul><li>Visual Field Defects </li></ul><ul><li>Cranial Nerve Palsies (3,4,6) </li></ul><ul><li>Hypopituitarism </li></ul><ul><li>Diabetes Insipidus </li></ul><ul><li>Rare Effects </li></ul><ul><ul><li>Temperature Dysregulation </li></ul></ul><ul><ul><li>Dysregulation Of Food Intake </li></ul></ul>
  10. 13. Clinical Manifestations of Pituitary Adenomas <ul><li>Mass Effect </li></ul><ul><li>Hormonal Overproduction </li></ul><ul><li>Hypopituitarism </li></ul>
  11. 14. Goals Of Therapy For Pituitary Adenomas <ul><li>Reduction/Elimination Of Tumor Mass </li></ul><ul><li>Correction Of Visual Field Defects </li></ul><ul><li>Hormonal Cure </li></ul><ul><li>Preservation Of Pituitary Function </li></ul><ul><li>Prevention Of Recurrence </li></ul>
  12. 15. Pituitary Adenomas <ul><li>Prolactinoma </li></ul><ul><li>Non-Functioning Adenoma </li></ul><ul><li>GH-Producing Tumors </li></ul><ul><li>ACTH-Producing Tumors </li></ul><ul><li>TSH-Producing Tumors </li></ul>
  13. 16. Pituitary Prolactin Pituitary Stalk Hypothalamus Dopamine _ TRH + Physiology of Prolactin Secretion + Stress Suckling Sleep Etc.. First, Normal Physiology
  14. 17. Causes of Hyperprolactinemia <ul><li>Physiologic: Pregnancy, Nursing, Exercise, Physical & Psychological Stress, Sleep </li></ul><ul><li>Pharmacolgic: Estrogen, Metoclopramide, Verapmil, SSRI, Methyldopa, Opioids </li></ul>
  15. 18. If Taking A Medication That Raises Prolactin…… <ul><li>Stop ( IF POSSIBLE ) and Recheck </li></ul><ul><li>If Unable To Stop The Medication -> -> Check MRI of Sella Anyway </li></ul>
  16. 19. Causes of Hyperprolactinemia <ul><li>Physiologic: Pregnancy, Nursing, Exercise, Physical & Psychological Stress, Sleep </li></ul><ul><li>Pharmacolgic: Estrogen, Metoclopramide, Verapmil, SSRI, Methyldopa, Opioids </li></ul><ul><li>Others: Primary Hypothyroidism, Chest Wall Lesions, Chronic Renal Failure </li></ul><ul><li>Idiopathic </li></ul><ul><li>Tumors: Prolactinoma, Other Tumors Causing Pituitary Stalk Compression </li></ul>
  17. 20. In General….. <ul><li>The Prolactin Level Correlates With The Size of The Prolactinoma, </li></ul><ul><li>But Always Remember </li></ul><ul><li>Stalk Compression </li></ul>
  18. 21. Pituitary Prolactin Pituitary Stalk Hypothalamus Dopamine _ TRH + Pituitary Stalk Compression
  19. 22. Prolactin= 40 Pituitary Stalk Compression
  20. 23. In General….. <ul><li>The Prolactin Level Correlates With The Size of The Prolactinoma, </li></ul><ul><li>But Always Remember </li></ul><ul><li>Stalk Compression </li></ul><ul><li>The Hook Effect </li></ul>
  21. 24. Hook Effect Capture Antibody Prolactin Signal Antibody
  22. 25. Prolactin= 40; On Dilution, 2400ng/ml Hook Effect
  23. 26. Back to Prolactinomas….
  24. 27. Hyperprolactinemia <ul><li>Prolactin Level Correlates With Tumor Size </li></ul><ul><li>Prolactin Level > 200 ng/ml Strongly Indicates A Prolactinoma </li></ul>
  25. 28. Hyperprolactinemia <ul><li>Hypogonadism </li></ul><ul><li>Women: Amenorrhea, Oligomennorrhea, Galactorrhea, Infertility </li></ul><ul><li>Men: Infertility and Erectile Dysfunction </li></ul>
  26. 29. Symptoms In Patients With Hyperprolactinemia <ul><li>Women (n = 1409) </li></ul><ul><ul><li>Amenorrhea 94% </li></ul></ul><ul><ul><li>Galactorrhea 85% </li></ul></ul><ul><li>Men (n = 444) </li></ul><ul><ul><li>Impotence 78% </li></ul></ul><ul><ul><li>Galactorrhea 11% </li></ul></ul><ul><ul><li>Headaches 29% </li></ul></ul><ul><ul><li>Hypopituitarism 34% </li></ul></ul><ul><ul><li>Visual Field Defects 37% </li></ul></ul>
  27. 30. Diagnosis And Testing <ul><li>History (Meds, Oligomenorrhea, Galactorrhea) </li></ul><ul><li>Physical Examination (Visual Fields, Breast Discharge) </li></ul><ul><li>Laboratory </li></ul><ul><ul><li>Pregnancy Test </li></ul></ul><ul><ul><li>TSH, Free T4 </li></ul></ul><ul><ul><li>Creatinine </li></ul></ul><ul><li>MRI </li></ul><ul><li>Visual Fields (If MRI Shows Chiasmal Compression) </li></ul>
  28. 31. Prolactinoma: Treatment <ul><li>Selected Patients Can Be Observed </li></ul><ul><li>If Microadenoma Growing, Therapy Is Mandatory </li></ul><ul><li>Other Indications For Therapy: Symptoms of Decreased Libido, Menstrual Dysfunction, Galactorrhea, Infertility, Premature Osteoporosis </li></ul>
  29. 32. Prolactinoma: Treatment <ul><li>Most Treated Medically With Dopamine Receptor Agonists </li></ul><ul><li>Surgery/Radiation Only For Those Dopamine Receptor Agonist Resistant Or Intolerant </li></ul>
  30. 33. Goals Of Dopamine Agonist Therapy <ul><li>Normalize Prolactin Level And Relieve Associated Symptoms </li></ul><ul><li>Reduce Or Stabilize Tumor Size, Preserve Or Restore Pituitary Function </li></ul><ul><li>Prevent Disease Recurrence Or Progression </li></ul>
  31. 34. Micro-, Macroadenomas, And Idiopathic Hyperprolactinemia Treated With Dopamine Agonists 1 Fossati, Friesen, Bergh, Badano, Crosignani, Horowitz, Molitch, Liuzzi, van der Heijden, Brue, Webster, Pascal-V, Pinzone, DiSarno, Sabuncu; 2 Horowitz, Kleinberg, L’Hermite, Freda 3 Ferrari, Ferrari, Webster, Pascal-V, Muratori, Verhelst, Pinzone, DiSarno, Sabuncu 89% 544 612 Cabergoline 3 87% 85 98 Pergolide 2 76% 757 997 Bromocriptine 1 % Normal PRL Normal PRL Total Dopamine Agonist
  32. 35. Tumor Reduction With Dopamine Agonist
  33. 36. What About DA Agonists and Cardiac Valve Regurgitation? <ul><li>11,400 Patients Long Acting DA Agonists For Parkinson's Disease </li></ul><ul><li>31 Validated Cases Of New Valvular Regurgitation </li></ul><ul><li>Dose Dependent: > 3 mg Daily Associated With a 50-Fold Incidence Rate Ratio </li></ul><ul><li>Average Dose For Prolactinomas 1-2mg Weekly </li></ul><ul><li>Mechanism: Interaction of Carbegoline With Cardiac 5-HT 2  Receptor </li></ul>Schade R et al NEJM 356: 29, 2007
  34. 37. Prolactinomas: Indications for Surgery <ul><li>Visual Field Defects Unresponsive To Medical Therapy </li></ul><ul><li>Macroadenomas Unresponsive To Medical Therapy </li></ul><ul><li>Tumor Growth On Medical Therapy </li></ul><ul><li>Intolerance To Dopamine Agonist Therapy </li></ul><ul><li>Pituitary Apoplexy (Rare) </li></ul><ul><li>Cerebrospinal Rhinorrhea Due To Erosion Into Sphenoid Sinus (Rare) </li></ul>
  35. 38. Results of Transsphenoidal Surgery for Prolactinomas Soule SG et al. Clin Endo 1996;44:711 Swearingen B et al. Clin Neurosurg 1997;45:48 Hofle G et al. Exp Clin Endo Diabetes 1996;106:211 Turner HE et al. Eur J Endo 1999;140:43 Tyrrell JB et al. Neurosurgery 1999;44:254 Laws ER, Thapar K. Endo Clin N Amer 1999;28:119 10-40% 60-80% Long-Term Normalization 10-20% 10-20% Recurrence Rate 20-50% 80-90% PRL Normalization Macroadenomas Microadenomas
  36. 39. Prolactinomas and Pregnancy <ul><li>Prolactin Levels And Pituitary Size Increase During Normal Pregnancy From Lactotroph Hyperplasia </li></ul>
  37. 40. Prolactin Levels During Pregnancy
  38. 41. Management of Prolactinomas During Pregnancy <ul><li>Stop Dopamine Receptor Agonist When Pregnancy Test Positive </li></ul><ul><li>Follow Patient Symptomatically Every 3 Months </li></ul><ul><li>If Headaches or Visual Complaints, Repeat MRI (Non-Contrast) & Visual Fields Tests </li></ul><ul><li>Reinstitute Bromocriptine If Evidence Of Tumor Enlargement </li></ul><ul><li>Monitoring Prolactin Levels During Pregnancy Not Indicated </li></ul>
  39. 42. Pituitary Adenomas <ul><li>Prolactinoma </li></ul><ul><li>Non-Functioning Adenoma </li></ul><ul><li>GH-Producing Tumors </li></ul><ul><li>ACTH-Producing Tumors </li></ul><ul><li>TSH-Producing Tumors </li></ul>
  40. 43. Gonadotroph Adenoma <ul><li>75% Of “Non-Functioning” Adenomas Secrete Gonadotropins </li></ul><ul><li>Increase LH, FSH,  and ß Subunits </li></ul><ul><li>Symptoms Come From Mass Effect </li></ul>
  41. 44. Signs & Symptoms in Patients with Clinically Nonfunctioning Macroadenomas 5% CSF Rhinorrhea 5% 8% Apoplexy 5% 12% Ophthalmoplegia 54% Visual Acuity Decrease 44% 36% 56% Headaches 58% 61% 75% Hypopituitarism 66% 68% 78% Visual Field Defects Toronto (n=153) Rochester (n=100) Montreal (n=126)
  42. 45. Non-Functioning Pituitary Adenomas <ul><li>Clinical Manifestations: </li></ul><ul><ul><ul><li>Mass Effect </li></ul></ul></ul><ul><ul><ul><li>Hypopituitarism </li></ul></ul></ul><ul><li>Treatment: Surgery If Tumor Is Causing Compressive Symptoms Or Hypopituitarism </li></ul>For Macroadenomas, Measure PRL At 1:100 Dilution To Exclude Prolactinoma
  43. 48. Percentage of Transsphenoidal Operations in 3 Medical Centers Resulting In Each Complication: Ciric et al., Neurosurgery 1997;40:225 7.6% - 19% Diabetes Insipidus 7.2% 14.9% 20.6% Hypopituitarism 0.5% 0.8% 2.4% Loss of Vision 0.4% 0.6% 1.4% Carotid injury 1.5% 2.8% 4.2% CSF Leak 0.5% 0.8% 1.9% Meningitis 0.2% 0.6% 1.2% Death >500 ops 200-500 ops. <200 ops. COMPLICATION
  44. 49. Non-Functioning Pituitary Adenomas <ul><li>Clinical Manifestations: </li></ul><ul><ul><ul><li>Mass Effect </li></ul></ul></ul><ul><ul><ul><li>Hypopituitarism </li></ul></ul></ul><ul><li>Treatment: Surgery If Tumor Is Causing Compressive Symptoms Or Hypopituitarism </li></ul><ul><li>Follow Up Radiation </li></ul>For Macroadenomas, Measure PRL At 1:100 Dilution To Exclude Prolactinoma
  45. 50. Radiotherapy <ul><li>Conventional </li></ul><ul><ul><li>Multi-Fractional </li></ul></ul><ul><li>Stereotactic </li></ul><ul><ul><li>Single Fraction </li></ul></ul><ul><ul><li>Less Radiation To Surrounding Tissue </li></ul></ul>Gamma Knife LINAC Proton Beam
  46. 51. Adverse Effects of Conventional Radiotherapy For Pituitary Adenomas <ul><li>Hypopituitarism: Up to 80% </li></ul><ul><ul><li>GH > LH/FSH > ACTH > TSH </li></ul></ul><ul><li>Second Brain Tumors: 2-3% at 20 years </li></ul><ul><li>Stroke: Increased 2-Fold </li></ul><ul><li>Cognitive Dysfunction: Rare </li></ul>
  47. 52. Pituitary Adenomas <ul><li>Prolactinoma </li></ul><ul><li>Non-Functioning Adenoma </li></ul><ul><li>GH-Producing Tumors </li></ul><ul><li>ACTH-Producing Tumors </li></ul><ul><li>TSH-Producing Tumors </li></ul>
  48. 53. Growth Hormone (GH)-Producing Tumors Pituitary Liver IGF-1 GH
  49. 54. Growth Hormone (GH)-Producing Tumors: Clinical Manifestations <ul><ul><li>Soft Tissue Enlargement </li></ul></ul><ul><ul><li>Bony Enlargement </li></ul></ul>
  50. 56. Enlargement Of Soft Tissue In Acromegaly Large Nose, Large Lips, Furrowed Brow, Increased Supraorbital Ridges, And Growth Of Skin Lesions
  51. 57. Growth Hormone (GH)-Producing Tumors: Clinical Manifestations <ul><ul><li>Soft Tissue Enlargement </li></ul></ul><ul><ul><li>Bony Enlargement </li></ul></ul><ul><ul><li>Degenerative Joint Disease </li></ul></ul><ul><ul><li>Glucose Intolerance </li></ul></ul><ul><ul><li>Hypertension </li></ul></ul><ul><ul><li>Sleep Apnea </li></ul></ul><ul><ul><li>Propensity To Carcinoma (Colon) </li></ul></ul>
  52. 58. Prevalence of Adenomatous Colonic Polyps in Acromegaly Delhougne et al., JCEM 1996;80:3223 0 5 10 15 20 25 30 35 40 Total <55 >55 Men Women % with Polyps Acromegaly (n=103) Controls (n-138)
  53. 59. Acromegaly & Mortality <ul><li>Poor Prognosis Associated With: </li></ul><ul><li>Cardiac Disease </li></ul><ul><li>Hypertension </li></ul><ul><li>Long Duration Of Symptoms Before Dx </li></ul><ul><li>Older Age At Diagnosis </li></ul>Life Expectancy  10 Years Probability Of Survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 Length of Survival (years) 5 10 15 20 25 Matched Population Acromegaly <ul><li>151 Patients </li></ul><ul><li>Mean Age At Diagnosis 41 </li></ul><ul><li>7 Years Of Disease Before Diagnosis </li></ul>Rajasoorya et al Clin End 1994:41;95
  54. 60. Screening For Acromegaly <ul><li>Best Test: IGF-1 Level </li></ul>
  55. 61. Biochemical Diagnosis of Acromegaly
  56. 62. Diagnostic Testing For Acromegaly <ul><li>Elevated Serum IGF-1 Level </li></ul><ul><li>Inability To Suppress GH Levels During An Oral </li></ul><ul><li> Glucose Tolerance Test (OGTT) </li></ul><ul><ul><li>GH < 0.4 ng/ml By IRMA </li></ul></ul><ul><ul><li>GH < 1 ng/ml By Conventional RIA </li></ul></ul><ul><li>MRI To Identify Location, Size Of Tumor </li></ul><ul><ul><li>60% Macroadenomas </li></ul></ul><ul><li>Visual Fields If Tumor Found To Be Abutting Chiasm </li></ul><ul><li>GHRH Measurement If No Clear Tumor On MRI </li></ul><ul><li>Or If At Surgery The Pathology Is Hyperplasia </li></ul><ul><li>Evaluate For Hypopituitarism If Macroadenoma </li></ul>
  57. 63. Growth Hormone (GH)-Producing Tumors <ul><li>Treatment: </li></ul><ul><li>Surgery, Irradiation, Medication </li></ul>
  58. 64. Cox model predicted survival Long-Term Mortality After Transsphenoidal Surgery Years after surgery Normal IGF-I Elevated IGF-I 0.8 0.4 0.2 1.0 0.6 Patient in remission Patient not in remission 0 5 10 15 20 Swearingen, B. et al. J Clin Endocrinol Metab 1998;83:3419
  59. 65. TREATMENT <ul><li>Transphenoidal Surgery </li></ul><ul><li>Irradiation </li></ul><ul><li>Medications </li></ul>
  60. 66. Effects of Gamma Knife Radiotherapy in Acromegaly Landolt et al., J Neurosurg 1998;88:1002
  61. 67. TREATMENT <ul><li>Transphenoidal Surgery </li></ul><ul><li>Irradiation </li></ul><ul><li>Medications: </li></ul><ul><li>Dopamine Agonists: 30-40% Secrete Prolactin </li></ul><ul><li>Octreotide </li></ul><ul><li>Pegvisomant </li></ul>
  62. 68. Efficacy of Somatostatin Analogues In Treatment of Acromegaly Newman, Endocrinol Metab Clin N Amer 1999;28:171 Freda, J Clin Endocrinol Metab 2002;87:3013 11% 5% 17% (33/194) 48% (199/417) Lanreotide 35% 8% 43% (22/51) 66% (204/309) Octreotide LAR 21% 25% 46% (53/116) 53% (220/417) Octreotide SC 20-50% Shrinkage <20% Shrinkage Total with Shrinkage (%) IGF-I Normalization Somatostatin Agonist
  63. 69. TREATMENT <ul><li>Transphenoidal Surgery </li></ul><ul><li>Irradiation </li></ul><ul><li>Medications: </li></ul><ul><li>Dopamine Agonists: 30-40% Secrete Prolactin </li></ul><ul><li>Octreotide </li></ul><ul><li>Pegvisomant </li></ul>
  64. 70. Mechanism of GH Binding And Signal Transduction IGF-I Dimerization GH has two binding sites, each of which binds identical cell surface receptor When both sites bind, dimerizing the receptors, signal transduction occurs
  65. 71. Growth Hormone Receptor Antagonist: Pegvisomant Site-1 Binding to GH Receptor Enhanced Site-2 binding disrupted Functional Dimerization Prevented; Signal Transduction and IGF-I Production Do Not Occur
  66. 72. Percentage of Patients Achieving a Normal Serum IGF-I with Pegvisomant 20 40 60 80 100 placebo 10 mg 15 mg 20 mg % * * * * P <0.0001 v. placebo 54 7 89 81 Trainer et al NEJM 2000:342;1171-1177
  67. 73. Pituitary Adenomas <ul><li>Prolactinoma </li></ul><ul><li>Non-Functioning Adenoma </li></ul><ul><li>GH-Producing Tumors </li></ul><ul><li>ACTH-Producing Tumors </li></ul><ul><li>TSH-Producing Tumors </li></ul>
  68. 74. Cushing’s Disease
  69. 75. Hypothalamic-Pituitary Adrenal Axis ACTH Cortisol Cortisol Hypothalamus Pituitary Adrenal = Stimulation = Inhibition CRH ACTH Cortisol
  70. 76. Clinical Signs <ul><li>Gross Obesity Of Trunk With Wasting Of Limbs </li></ul><ul><li>Facial Rounding And Plethora </li></ul><ul><li>Hirsutism With Frontal Balding </li></ul><ul><li>Muscle Weakness </li></ul><ul><li>Vertebral Fractures </li></ul><ul><li>Hypertension And Diabetes Mellitus </li></ul><ul><li>Lethargy </li></ul><ul><li>Depression </li></ul><ul><li>Acne </li></ul><ul><li>Easy Bruising </li></ul><ul><li>Loss Of Libido And Menstrual Irregularity </li></ul>
  71. 78. Cushing’s Syndrome Clinical Features <ul><li>Before Cushing’s </li></ul><ul><li>Cushing’s Syndrome Syndrome </li></ul>
  72. 79. Pseudo-Cushings <ul><li>Depression </li></ul><ul><li>Alcoholism </li></ul>
  73. 80. Always Remember: <ul><li>Hormone Pairs  Get The ACTH Level!!! </li></ul>
  74. 81. Etiology: Need The ACTH Level <ul><li>ACTH-Dependent </li></ul><ul><ul><li>Cushings Disease </li></ul></ul><ul><ul><li>Ectopic ACTH </li></ul></ul><ul><ul><li>Ectopic CRH </li></ul></ul><ul><li>ACTH-Independent </li></ul><ul><ul><li>Adrenal Adenoma </li></ul></ul><ul><ul><li>Adrenal Carcinoma </li></ul></ul><ul><ul><li>Adrenal Hyperplasia </li></ul></ul><ul><ul><li>Exogenous Steroids </li></ul></ul>
  75. 82. ACTH Levels In Cushing’s Disease Compared To The Normal Range 70 18 81 Cushing's Disease Adrenal Tumor Ectopic ACTH 0 150 100 50 200 250 300 500 700 900 1000-2000 2000-4000 4000-12000 Plasma ACTH Concentrations at 900 Plasma ACTH (ng/l) Trainer, PJ in Besser/Thorner, eds. Clinical Endocrinology ,3rd Ed., 1999:Mosby-Wolfe, pg. 8.7.
  76. 83. Always Remember: <ul><li>Hormone Pairs  Get The ACTH Level!!! </li></ul><ul><li>Circadian Rhythm </li></ul>
  77. 84. Biochemical Assessment <ul><li>Circadian Rhythm Assessment: </li></ul><ul><ul><li>Midnight Salivary Cortisol </li></ul></ul>
  78. 85. To Exclude Cushing’s…. <ul><li>Role of Midnight Salivary Cortisol: </li></ul><ul><li>Easy To Obtain </li></ul><ul><li>Normal Evening Nadir Preserved in Obese and Depressed Patients, But Not Patients With Cushing's </li></ul><ul><li>93% Sensitivity and 100% Specificity </li></ul><ul><li>Appropriate Assay-Specific Normative </li></ul>
  79. 86. Evaluation Of Cushing’s Syndrome <ul><li>Confirm Initial Clinical Suspicion With: </li></ul><ul><li>Overnight 1 mg Dexamethasone Suppression Test </li></ul><ul><li>24 Hour Urinary Free Cortisol </li></ul><ul><li>Midnight Salivary Cortisol </li></ul><ul><li>ACTH Elevated </li></ul><ul><li>MRI Sella </li></ul><ul><li>Low, Then High Dose Dex </li></ul><ul><li>Suppression </li></ul><ul><li>Consider Inferior Petrosal </li></ul><ul><li>Sinus Sampling </li></ul><ul><li>ACTH Suppressed </li></ul><ul><li>Adrenal CT or MRI </li></ul><ul><li>If Equivocal, Adrenal </li></ul><ul><li>Vein Sampling </li></ul>
  80. 87. Understanding Dexamethasone Testing Mini-Dexamethasone 1 mg at 11pm & Measure Serum Cortisol At 8am Screening Test For Cushing’s Syndrome Low Dose Dexamethasone 0.5 mg Every 6 Hours For 48 Hours Measuring Urine Free Cortisol & Serum Cortisol Before & After DEX High Dose Dexamethasone 2.0 mg Every 6 Hours For 48 Hrs Measuring Urine Free Cortisol & Serum Cortisol Before & After DEX = Stimulation = Inhibition ACTH Cortisol Cortisol CRH
  81. 88. Evaluation Of Cushing’s Syndrome <ul><li>Confirm Initial Clinical Suspicion With: </li></ul><ul><li>Overnight 1 mg Dexamethasone Suppression Test </li></ul><ul><li>24 Hour Urinary Free Cortisol </li></ul><ul><li>Midnight Salivary Cortisol </li></ul><ul><li>ACTH Elevated </li></ul><ul><li>MRI Sella </li></ul><ul><li>Low, Then High Dose Dex </li></ul><ul><li>Suppression </li></ul><ul><li>Consider Inferior Petrosal </li></ul><ul><li>Sinus Sampling </li></ul><ul><li>ACTH Suppressed </li></ul><ul><li>Adrenal CT or MRI </li></ul><ul><li>If Equivocal, Adrenal </li></ul><ul><li>Vein Sampling </li></ul>
  82. 90. IPSS Interpretation <ul><li>Cushing’s Disease If: </li></ul><ul><li>1. Basal IPS:P ACTH Ratio >2 </li></ul><ul><li>2. CRH Stimulated ACTH Ratio >3 </li></ul>
  83. 91. ACTH-Producing Tumors <ul><li>Diagnosis: Hypercortisolism </li></ul><ul><li>Make Sure The Source Is Pituitary </li></ul><ul><li>Treatment: Surgery </li></ul>
  84. 92. Cushing’s Disease: Transsphenoidal Surgery <ul><li>Result Intrasellar Extrasellar </li></ul><ul><li> Adenoma Adenoma </li></ul><ul><li> (n=168) (n=48) </li></ul><ul><li>Remission 86% 46% </li></ul><ul><li>Persistence 13% 39% </li></ul><ul><li>Recurrence 1% 15% </li></ul>Malmpalam et al., 1990
  85. 93. Treatment of Cushing’s Disease With Ketoconazole Pre Post Pre Post Percent Normalized 94% 100% Pre Post Pre Post 0 200 400 600 800 1000 1200 1400 1600 Urinary Free Cortisol (nmol/24h) Sonino et al Tabarin et al
  86. 94. Monitoring of Response <ul><li>Clinical Monitoring </li></ul><ul><li>ACTH Not Reliable </li></ul><ul><li>24 Hour Cortisol Excretion  Between-Individual Variability </li></ul>
  87. 95. Pituitary Adenomas <ul><li>Prolactinoma </li></ul><ul><li>Non-Functioning Adenoma </li></ul><ul><li>GH-Producing Tumors </li></ul><ul><li>ACTH-Producing Tumors </li></ul><ul><li>TSH-Producing Tumors </li></ul>
  88. 96. Hypothalamic-Pituitary-Thyroid Axis TR Heart Liver Bone CNS Target Tissues TRH Hypothalamus Pituitary T 4 T 3 T 4  T 3 Liver, Muscle T 4 T 3 TSH Thyroid Gland
  89. 97. TSH Producing Adenoma <ul><li>100 Cases Reported </li></ul><ul><li>85% Macroadenoma </li></ul>
  90. 98. TSH-Producing Tumors <ul><li>Clinical Manifestations: Hyperthyroidism </li></ul><ul><li>Diagnosis: </li></ul><ul><li>Elevated Free T4 Levels With </li></ul><ul><li>Elevated Or Inappropriately Normal TSH Levels </li></ul><ul><li>Important To Distinguish From Thyroid Hormone Resistance </li></ul>
  91. 99. TSH-Secreting Adenoma vs RTH Normal No suppression Response to T 3 suppression No Yes High  subunit No Yes Lesion on MRI Yes No Familial cases RTH TSH-oma Feature
  92. 100. TSH-Producing Tumors <ul><li>Clinical Manifestations: Hyperthyroidism </li></ul><ul><li>Diagnosis: </li></ul><ul><li>Elevated Free T4 Levels With </li></ul><ul><li>Elevated Or Inappropriately Normal TSH Levels </li></ul><ul><li>Treatment: Surgery And Radiation </li></ul>
  93. 101. Ablative Treatment For TSH-Secreting Pituitary Adenomas Beck-Peccoz & Persani, 2002 32 36 32 Total (192) 23 42 35 Surgery + XRT (57) 17 50 33 Irradiation (6) 34 33 33 Surgery (129) Unchanged (%) Improved (%) Cured (%) Treatment (No. of Pts.)
  94. 102. TSH-Producing Tumors <ul><li>Clinical Manifestations: Hyperthyroidism </li></ul><ul><li>Diagnosis: </li></ul><ul><li>Elevated Free T4 Levels With </li></ul><ul><li>Elevated Or Inappropriately Normal TSH Levels </li></ul><ul><li>Treatment: Surgery And Radiation </li></ul><ul><li>Role Of Octreotide </li></ul>
  95. 103. Medical Management of TSH-Secreting Adenomas <ul><li>Monthly Octreotide-LAR Effective In Controlling Hyperthyroidism In Both Untreated Patients And Those Treated With Surgery +/- Radiotherapy </li></ul><ul><li>Few Side Effects: Minor GI Upset </li></ul><ul><li>Tumor Shrinkage Rarely Occurred </li></ul>
  96. 104. Summary of Pituitary Tumors Making The Diagnosis <ul><ul><li>Prolactinoma: Elevated Prolactin </li></ul></ul><ul><ul><li>Non Functioning Pituitary Tumors: Mass With Elevated FSH/LH And Prolactin </li></ul></ul><ul><ul><li>GH-Producing Tumor: Elevated IGF-1; Confirm With Glucose Suppression Test </li></ul></ul><ul><ul><li>ACTH-Producing Tumor: Elevated Cortisol; Failure to Suppress With Dex </li></ul></ul><ul><ul><li>TSH-Producing Tumor: Elevated T4 Levels; Normal Or High TSH Levels </li></ul></ul>
  97. 105. Summary of Pituitary Tumors Treatment <ul><ul><li>Prolactinoma: ALWAYS Start With Dopamine Agonist </li></ul></ul><ul><ul><li>Other Hormone-Producing Tumors: Surgery </li></ul></ul>
  98. 106. Pituitary Incidentaloma <ul><li>10-20% Of Normal Individuals </li></ul><ul><li>Incidental Finding On CT And MRI </li></ul><ul><li>Tumor, Old Infarct, Rathke Pouch, Aneurysm, Cranipharyngiom, Meningioma, Glioma, Dysgerminoma, Sarcoidoisis, Hamartoma, Lymphocytic Infiltration </li></ul>
  99. 107. Incidentaloma <ul><li>40% Stain For Prolactin </li></ul><ul><li>Check: Prolactin, T 4 , TSH, IGF-1, LH FSH, </li></ul><ul><li> Submit, And Dex Suppression Test </li></ul><ul><li>Image Every 6-12 Months </li></ul><ul><li>Growing Lesion Merits Surgical Resection </li></ul>
  100. 108. Frequency of Pituitary Adenomas Found at Autopsy <ul><li>14,095 Unselected Pituitaries Examined At Autopsy In 27 Series </li></ul><ul><ul><li>1,511 ( 10.7% ) Had Pituitary Adenomas </li></ul></ul><ul><ul><ul><li>Range 1.5 – 33.0% </li></ul></ul></ul><ul><ul><ul><li>All But Three < 10 mm </li></ul></ul></ul><ul><ul><li>42.5% Stained Positively For Prolactin </li></ul></ul>
  101. 109. Natural History of Untreated Pituitary Incidentalomas *5 Of These 39 Had Tumor Enlargement Secondary To Hemorrhage Into The Tumor Reinecke et al., JAMA 1990;263:2772 Donovan & Corenblum, Arch Int Med 1995;155:181 Nishizawa et al., Neurosurgery 1998;43:1344 Feldkamp et al., Clin Endocrinol 1999;51:109 Eguchi et al., Prog 6 th Intl Pit Congress, 1999 Sanno et al., Eur J Endocrinol 2003;149:123 0.6 – 12 0.6 - 15.0 Yrs Followed 197 113 No Change 23 9 Decreased 39* (15%) 10 (8%) Enlarged 259 132 Total Macroadenomas Microadenomas
  102. 110. Flow Diagram for Pituitary Incidentalomas Evaluation of Pituitary Function Hyperfunctioning Clinically Nonfunctioning Prolactinoma Other < 1 cm > 1 cm Dopamine Surgery Visual Fields Agonist R/O Pituitary Hypofunction Repeat MRI at Repeat MRI at 1, 2, 5 yrs 0.5, 1, 2, 5 yrs No Change Tumor Growth Abnl Fields No Further Surgery Studies (?)
  103. 111. Selected Pituitary Disorders <ul><li>Pituitary Adenomas </li></ul><ul><li>Hypopituitarism </li></ul><ul><li>Pituitary Apoplexy </li></ul>
  104. 112. Hypopituitarism <ul><li>Clinical Manifestations: Non-Specfic Sx’s </li></ul><ul><li>Diagnosis </li></ul><ul><ul><li>Hypothalmic Pituitary Adrenal Axis: Cortisol, ACTH, Or Stimulation Tests (Insulin-Induced Hypoglycemia) </li></ul></ul><ul><ul><li>Thyroid Axis: Low Free T4 And Normal Low TSH </li></ul></ul><ul><ul><li>Growth Hormone: Low IGF-1 and GH After Insulin-Induced Hypoglycemia </li></ul></ul><ul><ul><li>Gonadal Axis: Low Testosterone Or Estradiol Levels With Inappropriately Normal Or Low Gonadotropins </li></ul></ul><ul><li>Treatment: Hormone Replacement </li></ul>
  105. 113. Causes of Hypopituitarism <ul><li>Pituitary Or Non-Pituitary Tumors </li></ul><ul><li>Post Pituitary Surgery </li></ul><ul><li>Radiation </li></ul><ul><li>Infarction </li></ul><ul><li>Trauma </li></ul><ul><li>Infiltrative Diseases </li></ul><ul><li>Infectious </li></ul>
  106. 114. Summary of Hypopituitarism <ul><li>Notice the Clinical Scenario (Trauma, Post Surgery, Bleeding etc…) </li></ul><ul><li>Notice the Clinical Manifestations </li></ul><ul><li>Make the Diagnosis </li></ul><ul><li>First Priority: Replace Glucocorticoid and Thyroid Hormone </li></ul>
  107. 115. Selected Pituitary Disorders <ul><li>Pituitary Adenomas </li></ul><ul><li>Hypopituitarism </li></ul><ul><li>Pituitary Apoplexy </li></ul>
  108. 116. Pituitary Apoplexy <ul><li>Sudden Hemorrhage Into The Pituitary Gland </li></ul><ul><li>Hemorrhage Often Occurs Into An Existing Adenoma </li></ul><ul><li>Headache, Diplopia Due To Pressure On The Oculomotor Nerves, And Hypopituitarism </li></ul><ul><li>All Pituitary Hormonal Deficiencies Can Occur, But Sudden Loss Of ACTH And Therefore Cortisol Can Cause Life-Threatening Hypotension </li></ul>
  109. 117. Questions??

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