Hyperprolactinemia 3

Selected Pituitary Disorders March 18, 2008

What is “a pituitary”? Pituita: Mucus Former Belief That Pituitary Gland Secretes Mucus

Pituitary Hormones Anterior Pituitary Testosterone Estradiol FSH & LH Growth Hormone ACTH Cortisol TSH T 3 T 4 Prolactin Posterior Pituitary IGF-1 Oxytocin ADH

Importance  and ß Subunits TSH, LH, FSH and hCG: Share a common  Subunit ß Subunits Differ, Conferring Specificity to the Hormone

Selected Pituitary Disorders Pituitary Adenomas Hypopituitarism Pituitary Apoplexy

Clinical Manifestations of Pituitary Adenomas Mass Effect Hormonal Overproduction Hypopituitarism

Mass Effects Of Sellar Lesions Headache Visual Field Defects Cranial Nerve Palsies (3,4,6)

Bitemporal Hemianopsia Due To Pituitary Tumor Visual Fields Pituitary Tumor Compression Of Optic Nerve Medial Fibers By Tumor Impairs Peripheral Vision

Mass Effects of Sellar Lesions Headache Visual Field Defects Cranial Nerve Palsies (3,4,6) Hypopituitarism Diabetes Insipidus Rare Effects Temperature Dysregulation Dysregulation Of Food Intake

Goals Of Therapy For Pituitary Adenomas Reduction/Elimination Of Tumor Mass Correction Of Visual Field Defects Hormonal Cure Preservation Of Pituitary Function Prevention Of Recurrence

Pituitary Adenomas Prolactinoma Non-Functioning Adenoma GH-Producing Tumors ACTH-Producing Tumors TSH-Producing Tumors

Pituitary Prolactin Pituitary Stalk Hypothalamus Dopamine _ TRH + Physiology of Prolactin Secretion + Stress Suckling Sleep Etc.. First, Normal Physiology

Causes of Hyperprolactinemia Physiologic: Pregnancy, Nursing, Exercise, Physical & Psychological Stress, Sleep Pharmacolgic: Estrogen, Metoclopramide, Verapmil, SSRI, Methyldopa, Opioids

If Taking A Medication That Raises Prolactin…… Stop ( IF POSSIBLE ) and Recheck If Unable To Stop The Medication -> -> Check MRI of Sella Anyway

Causes of Hyperprolactinemia Physiologic: Pregnancy, Nursing, Exercise, Physical & Psychological Stress, Sleep Pharmacolgic: Estrogen, Metoclopramide, Verapmil, SSRI, Methyldopa, Opioids Others: Primary Hypothyroidism, Chest Wall Lesions, Chronic Renal Failure Idiopathic Tumors: Prolactinoma, Other Tumors Causing Pituitary Stalk Compression

In General….. The Prolactin Level Correlates With The Size of The Prolactinoma, But Always Remember Stalk Compression

Pituitary Prolactin Pituitary Stalk Hypothalamus Dopamine _ TRH + Pituitary Stalk Compression

Prolactin= 40 Pituitary Stalk Compression

In General….. The Prolactin Level Correlates With The Size of The Prolactinoma, But Always Remember Stalk Compression The Hook Effect

Hook Effect Capture Antibody Prolactin Signal Antibody

Prolactin= 40; On Dilution, 2400ng/ml Hook Effect

Hyperprolactinemia Prolactin Level Correlates With Tumor Size Prolactin Level > 200 ng/ml Strongly Indicates A Prolactinoma

Hyperprolactinemia Hypogonadism Women: Amenorrhea, Oligomennorrhea, Galactorrhea, Infertility Men: Infertility and Erectile Dysfunction

Symptoms In Patients With Hyperprolactinemia Women (n = 1409) Amenorrhea 94% Galactorrhea 85% Men (n = 444) Impotence 78% Galactorrhea 11% Headaches 29% Hypopituitarism 34% Visual Field Defects 37%

Diagnosis And Testing History (Meds, Oligomenorrhea, Galactorrhea) Physical Examination (Visual Fields, Breast Discharge) Laboratory Pregnancy Test TSH, Free T4 Creatinine MRI Visual Fields (If MRI Shows Chiasmal Compression)

Prolactinoma: Treatment Selected Patients Can Be Observed If Microadenoma Growing, Therapy Is Mandatory Other Indications For Therapy: Symptoms of Decreased Libido, Menstrual Dysfunction, Galactorrhea, Infertility, Premature Osteoporosis

Prolactinoma: Treatment Most Treated Medically With Dopamine Receptor Agonists Surgery/Radiation Only For Those Dopamine Receptor Agonist Resistant Or Intolerant

Goals Of Dopamine Agonist Therapy Normalize Prolactin Level And Relieve Associated Symptoms Reduce Or Stabilize Tumor Size, Preserve Or Restore Pituitary Function Prevent Disease Recurrence Or Progression

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

Tumor Reduction With Dopamine Agonist

What About DA Agonists and Cardiac Valve Regurgitation? 11,400 Patients Long Acting DA Agonists For Parkinson's Disease 31 Validated Cases Of New Valvular Regurgitation Dose Dependent: > 3 mg Daily Associated With a 50-Fold Incidence Rate Ratio Average Dose For Prolactinomas 1-2mg Weekly Mechanism: Interaction of Carbegoline With Cardiac 5-HT 2  Receptor Schade R et al NEJM 356: 29, 2007

Prolactinomas: Indications for Surgery Visual Field Defects Unresponsive To Medical Therapy Macroadenomas Unresponsive To Medical Therapy Tumor Growth On Medical Therapy Intolerance To Dopamine Agonist Therapy Pituitary Apoplexy (Rare) Cerebrospinal Rhinorrhea Due To Erosion Into Sphenoid Sinus (Rare)

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

Prolactinomas and Pregnancy Prolactin Levels And Pituitary Size Increase During Normal Pregnancy From Lactotroph Hyperplasia

Prolactin Levels During Pregnancy

Management of Prolactinomas During Pregnancy Stop Dopamine Receptor Agonist When Pregnancy Test Positive Follow Patient Symptomatically Every 3 Months If Headaches or Visual Complaints, Repeat MRI (Non-Contrast) & Visual Fields Tests Reinstitute Bromocriptine If Evidence Of Tumor Enlargement Monitoring Prolactin Levels During Pregnancy Not Indicated

Gonadotroph Adenoma 75% Of “Non-Functioning” Adenomas Secrete Gonadotropins Increase LH, FSH,  and ß Subunits Symptoms Come From Mass Effect

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)

Non-Functioning Pituitary Adenomas Clinical Manifestations: Mass Effect Hypopituitarism Treatment: Surgery If Tumor Is Causing Compressive Symptoms Or Hypopituitarism For Macroadenomas, Measure PRL At 1:100 Dilution To Exclude Prolactinoma

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

Non-Functioning Pituitary Adenomas Clinical Manifestations: Mass Effect Hypopituitarism Treatment: Surgery If Tumor Is Causing Compressive Symptoms Or Hypopituitarism Follow Up Radiation For Macroadenomas, Measure PRL At 1:100 Dilution To Exclude Prolactinoma

Radiotherapy Conventional Multi-Fractional Stereotactic Single Fraction Less Radiation To Surrounding Tissue Gamma Knife LINAC Proton Beam

Adverse Effects of Conventional Radiotherapy For Pituitary Adenomas Hypopituitarism: Up to 80% GH > LH/FSH > ACTH > TSH Second Brain Tumors: 2-3% at 20 years Stroke: Increased 2-Fold Cognitive Dysfunction: Rare

Growth Hormone (GH)-Producing Tumors Pituitary Liver IGF-1 GH

Growth Hormone (GH)-Producing Tumors: Clinical Manifestations Soft Tissue Enlargement Bony Enlargement

Enlargement Of Soft Tissue In Acromegaly Large Nose, Large Lips, Furrowed Brow, Increased Supraorbital Ridges, And Growth Of Skin Lesions

Growth Hormone (GH)-Producing Tumors: Clinical Manifestations Soft Tissue Enlargement Bony Enlargement Degenerative Joint Disease Glucose Intolerance Hypertension Sleep Apnea Propensity To Carcinoma (Colon)

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)

Acromegaly & Mortality Poor Prognosis Associated With: Cardiac Disease Hypertension Long Duration Of Symptoms Before Dx Older Age At Diagnosis 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 151 Patients Mean Age At Diagnosis 41 7 Years Of Disease Before Diagnosis Rajasoorya et al Clin End 1994:41;95

Screening For Acromegaly Best Test: IGF-1 Level

Biochemical Diagnosis of Acromegaly

Diagnostic Testing For Acromegaly Elevated Serum IGF-1 Level Inability To Suppress GH Levels During An Oral Glucose Tolerance Test (OGTT) GH < 0.4 ng/ml By IRMA GH < 1 ng/ml By Conventional RIA MRI To Identify Location, Size Of Tumor 60% Macroadenomas Visual Fields If Tumor Found To Be Abutting Chiasm GHRH Measurement If No Clear Tumor On MRI Or If At Surgery The Pathology Is Hyperplasia Evaluate For Hypopituitarism If Macroadenoma

Growth Hormone (GH)-Producing Tumors Treatment: Surgery, Irradiation, Medication

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

TREATMENT Transphenoidal Surgery Irradiation Medications

Effects of Gamma Knife Radiotherapy in Acromegaly Landolt et al., J Neurosurg 1998;88:1002

TREATMENT Transphenoidal Surgery Irradiation Medications: Dopamine Agonists: 30-40% Secrete Prolactin Octreotide Pegvisomant

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

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

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

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

Hypothalamic-Pituitary Adrenal Axis ACTH Cortisol Cortisol Hypothalamus Pituitary Adrenal = Stimulation = Inhibition CRH ACTH Cortisol

Clinical Signs Gross Obesity Of Trunk With Wasting Of Limbs Facial Rounding And Plethora Hirsutism With Frontal Balding Muscle Weakness Vertebral Fractures Hypertension And Diabetes Mellitus Lethargy Depression Acne Easy Bruising Loss Of Libido And Menstrual Irregularity

Cushing’s Syndrome Clinical Features Before Cushing’s Cushing’s Syndrome Syndrome

Pseudo-Cushings Depression Alcoholism

Always Remember: Hormone Pairs  Get The ACTH Level!!!

Etiology: Need The ACTH Level ACTH-Dependent Cushings Disease Ectopic ACTH Ectopic CRH ACTH-Independent Adrenal Adenoma Adrenal Carcinoma Adrenal Hyperplasia Exogenous Steroids

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.

Always Remember: Hormone Pairs  Get The ACTH Level!!! Circadian Rhythm

Biochemical Assessment Circadian Rhythm Assessment: Midnight Salivary Cortisol

To Exclude Cushing’s…. Role of Midnight Salivary Cortisol: Easy To Obtain Normal Evening Nadir Preserved in Obese and Depressed Patients, But Not Patients With Cushing's 93% Sensitivity and 100% Specificity Appropriate Assay-Specific Normative

Evaluation Of Cushing’s Syndrome Confirm Initial Clinical Suspicion With: Overnight 1 mg Dexamethasone Suppression Test 24 Hour Urinary Free Cortisol Midnight Salivary Cortisol ACTH Elevated MRI Sella Low, Then High Dose Dex Suppression Consider Inferior Petrosal Sinus Sampling ACTH Suppressed Adrenal CT or MRI If Equivocal, Adrenal Vein Sampling

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

IPSS Interpretation Cushing’s Disease If: 1. Basal IPS:P ACTH Ratio >2 2. CRH Stimulated ACTH Ratio >3

ACTH-Producing Tumors Diagnosis: Hypercortisolism Make Sure The Source Is Pituitary Treatment: Surgery

Cushing’s Disease: Transsphenoidal Surgery Result Intrasellar Extrasellar Adenoma Adenoma (n=168) (n=48) Remission 86% 46% Persistence 13% 39% Recurrence 1% 15% Malmpalam et al., 1990

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

Monitoring of Response Clinical Monitoring ACTH Not Reliable 24 Hour Cortisol Excretion  Between-Individual Variability

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

TSH Producing Adenoma 100 Cases Reported 85% Macroadenoma

TSH-Producing Tumors Clinical Manifestations: Hyperthyroidism Diagnosis: Elevated Free T4 Levels With Elevated Or Inappropriately Normal TSH Levels Important To Distinguish From Thyroid Hormone Resistance

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

TSH-Producing Tumors Clinical Manifestations: Hyperthyroidism Diagnosis: Elevated Free T4 Levels With Elevated Or Inappropriately Normal TSH Levels Treatment: Surgery And Radiation

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.)

TSH-Producing Tumors Clinical Manifestations: Hyperthyroidism Diagnosis: Elevated Free T4 Levels With Elevated Or Inappropriately Normal TSH Levels Treatment: Surgery And Radiation Role Of Octreotide

Medical Management of TSH-Secreting Adenomas Monthly Octreotide-LAR Effective In Controlling Hyperthyroidism In Both Untreated Patients And Those Treated With Surgery +/- Radiotherapy Few Side Effects: Minor GI Upset Tumor Shrinkage Rarely Occurred

Summary of Pituitary Tumors Making The Diagnosis Prolactinoma: Elevated Prolactin Non Functioning Pituitary Tumors: Mass With Elevated FSH/LH And Prolactin GH-Producing Tumor: Elevated IGF-1; Confirm With Glucose Suppression Test ACTH-Producing Tumor: Elevated Cortisol; Failure to Suppress With Dex TSH-Producing Tumor: Elevated T4 Levels; Normal Or High TSH Levels

Summary of Pituitary Tumors Treatment Prolactinoma: ALWAYS Start With Dopamine Agonist Other Hormone-Producing Tumors: Surgery

Pituitary Incidentaloma 10-20% Of Normal Individuals Incidental Finding On CT And MRI Tumor, Old Infarct, Rathke Pouch, Aneurysm, Cranipharyngiom, Meningioma, Glioma, Dysgerminoma, Sarcoidoisis, Hamartoma, Lymphocytic Infiltration

Incidentaloma 40% Stain For Prolactin Check: Prolactin, T 4 , TSH, IGF-1, LH FSH,  Submit, And Dex Suppression Test Image Every 6-12 Months Growing Lesion Merits Surgical Resection

Frequency of Pituitary Adenomas Found at Autopsy 14,095 Unselected Pituitaries Examined At Autopsy In 27 Series 1,511 ( 10.7% ) Had Pituitary Adenomas Range 1.5 – 33.0% All But Three < 10 mm 42.5% Stained Positively For Prolactin

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

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 (?)

Hypopituitarism Clinical Manifestations: Non-Specfic Sx’s Diagnosis Hypothalmic Pituitary Adrenal Axis: Cortisol, ACTH, Or Stimulation Tests (Insulin-Induced Hypoglycemia) Thyroid Axis: Low Free T4 And Normal Low TSH Growth Hormone: Low IGF-1 and GH After Insulin-Induced Hypoglycemia Gonadal Axis: Low Testosterone Or Estradiol Levels With Inappropriately Normal Or Low Gonadotropins Treatment: Hormone Replacement

Causes of Hypopituitarism Pituitary Or Non-Pituitary Tumors Post Pituitary Surgery Radiation Infarction Trauma Infiltrative Diseases Infectious

Summary of Hypopituitarism Notice the Clinical Scenario (Trauma, Post Surgery, Bleeding etc…) Notice the Clinical Manifestations Make the Diagnosis First Priority: Replace Glucocorticoid and Thyroid Hormone

Pituitary Apoplexy Sudden Hemorrhage Into The Pituitary Gland Hemorrhage Often Occurs Into An Existing Adenoma Headache, Diplopia Due To Pressure On The Oculomotor Nerves, And Hypopituitarism All Pituitary Hormonal Deficiencies Can Occur, But Sudden Loss Of ACTH And Therefore Cortisol Can Cause Life-Threatening Hypotension

Hyperprolactinemia 3

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Hyperprolactinemia 3