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Pituitary Insufficiency

Pituitary Insufficiency. William Harper, MD, FRCPC Endocrinology & Metabolism Assistant Professor of Medicine McMaster University. Pituitary Disorders. Mass effect Headaches CN II, III, IV, V 1 , V 2 , VI Pituitary hypersecretory Syndrome PRL, GH, ACTH, > > TSH

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Pituitary Insufficiency

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  1. Pituitary Insufficiency William Harper, MD, FRCPC Endocrinology & Metabolism Assistant Professor of Medicine McMaster University

  2. Pituitary Disorders • Mass effect • Headaches • CN II, III, IV, V1, V2, VI • Pituitary hypersecretory Syndrome • PRL, GH, ACTH, > > TSH • Anterior Pituitary Dysfunction • ACTH, TSH, LH/FSH > > GH • Posterior Pituitary Dysfunction • ADH

  3. Mass Effect: H/A, CN II, EOM, V1, V2 (LR6SO4)3 V1 V2

  4. H-P-A Axis

  5. High ACTH Cushing’s Ectopic ACTH Cushing’s Disease

  6. Establish hypercortisolism (Cushing’s syndrome) • “Screening” tests • 1 mg O/N DMST • DXM 1 mg po 11PM  8AM plasma cortisol • < 140 nM R/O Cushing’s Syndrome • SEN 98% SPEC 71-80% • < 50 nM SEN ~100% SPEC ? (Poor), still some cases missed! • 24 UFC • < 248 nM/d R/O Cushing’s Syndrome (SEN 95-100%) • 248-840 nM/d Equivocal • > 840 nM/d consistent with Cushing’s Syndrome (SPEC 98%)

  7. Establish hypercortisolism (Cushing’s syndrome) • “Confirmatory Tests” • 24 UFC • > 840 nM/d Establishes Cushing’s Syndrome on 2 or more collections AND clear clinical findings of Cushing’s makes diagnosis of Cushing’s with SPEC 98% • Otherwise, need an additional confirmatory test. • LDDST (Liddle Test) • 2 baseline 24h urine for cortisol and 17-OH steroids • DXM 0.5 mg q6h x 48h (8 doses) • During 2nd day on DXM repeat 24h urine collection • UFC > 100 nM/d or 17OHS > 11 uM/d indicates Cushing’s • Historical gold standard but SEN 56-69%, SPEC 74-100% • Plasma cortisol < 50 nM measured 2 or 6 hours after last dose has SEN 90-100% and SPEC 97-100%

  8. Clinical Suspicion Screen Test: 24 UFC or 1mg O/N DST (+/- evening plasma/salivary cortisol) Confirmatory Testing: Repeat 24 UFC +/- CRH/DXM Test (+/- evening plasma/salivary cortisol) ACTH < 1.1pM >2.2pM 1.1-2.2pM ACTH Independent CT abdo ACTH dependent 1st 8mg O/N DST or HDDST 2nd CRH Test if above test negative CRH Test No Stim Positive Stim No CRH stim No DXM suppression Stim by CRH or DXM suppresses Adrenal Surgery • Ectopic ACTH • CT thorax, abdo • Thyroid U/S • Octreotide Scan Pituitary MRI Conclusive (>0.8-1.0cm) Inconclusive IPSS >2 basal >3 CRH <1.5 basal <2 CRH Conclusive Pituitary Surgery Continue search for ectopic source Remove ectopic source

  9. Case • 49 year old female • Adie’s pupil x 2 years • L frontoparietal H/A • Neurologist ordered MRI • Enlarged Pituitary! • Subsequent Endo referral • TSH 31.7 mU/L, FT4 6 pM  Hypothyroid! • FSH 63 (menopausal)

  10. Pituitary Hyperplasia • Another cause of sellar mass! • Physiological enlargement of pituitary • Lactotroph Hyperplasia (pregnancy) • Pregnancy, most common • Thyrotroph, Gonadotroph Hyperplasia • Primary gland failure • Somatotroph, Corticotroph Hyperplasia • GHRH or CRH secreting neuroendocrine tumors

  11. Prolactinoma • Most common pituitary tumor • Dx: elevated PRL with size/level correlation (stalk-effect!) • Treatment: • Dopamine Agonist • Bromocriptine, Cabergoline, Pergolide, Quinagolide • TSSx • XRT • Treatment goals: • Macroadenoma: shrink tumor (mass effect, H/A) • Stop galactorrhea • Reestablish menses/fertility • OCP if fertility not wanted

  12. Prolactinoma: pregnancy • Microadenoma: • 1.6% symptomatic growth • Stop bromocriptine once conception achieved • Macroadenoma • 13-36% symptomatic growth during pregnancy • Continue bromocriptine througout pregnancy • Monitoring PRL useless • Formal VF tests q3mos • MRI if any change in vision

  13. Anterior Pituitary Dysfunction • Gold standard diagnosis = 3x bolus test • Insulin  ACTH, GH (Insulin Tolerance Test) • LHRH  LH, FSH • TRH  TSH, PRL • Done > 6 weeks post pituitary surgery • ITT contraindicated: elderly, cardiac disease • 8AM plasma cortisol • 1 mcg ACTH stimulation testing

  14. Diagnosis of AI • 8AM Plasma Cortisol (Pcortisol at 8AM or during “Stress”): < 83 nM  AI confirmed < 138 nM  suggests AI present (SEN 36%, SPEC~100%) > 552 nM  excludes AI (>552 nM @ anytime of day, SEN~100%) [with possible exception of critically-ill patients]

  15. Diagnosis of AI • Short Cortrosyn/ACTH test • Must be performed within a few days of starting exogenous glucocorticoid Rx or else H-P-A axis will be suppressed by steroid Rx • Exogenous glucocorticoid must be dexamethasone (isn’t picked up by the cortisol RIA)

  16. Short Cortrosyn Test • High (Standard) Dose: • 250 ug IV or IM, measure cortisol t = 0, 30, 60 min • Normal: any cortisol > 550 nM (even pre-injection t = 0) • Rules out 1˚ AI (SEN 100%) but only 90% SEN for 2˚ AI • Low Dose: • 1 ug IV (can’t be IM), measure cortisol t = 0, 30 min • t = 30 min cortisol > 500 nM rules out 1˚ or 2˚ AI (exception is 2˚ AI of recent onset < 2wk) • SEN 95% SPEC 96% ( > 600 nM SEN 100%, SPEC 83%) • 1 ug dose stimulates maximal adrenal cortex secretion 30 min after injection and in normal subjects results in a peak plasma ACTH concentration 2X that seen in an ITT

  17. Short Cortrosyn Test (cont’d) • Criteria requiring a minimum cortisol increment (i.e. 2x baseline or absolute rise of 250 nM) now considered invalid • High basal cortisol due to stress or normal diurnal variation may represent near maximal stimulation with an inability to increase secretion further in upwards of 20% of normal patients • Possible exception of critically-ill patients

  18. Distinguish 1˚from Central AI Plasma ACTH • Measure with basal cortisol during short ACTH test • Primary AI: ACTH > 11 pM • Central AI: ACTH < 2.2 pM • Must measure BEFORE exogenous glucocorticoid administration as will be suppressed almost immediately • 2 phases of steroid feedback suppression on ACTH: • Fast Phase (sec-min): membrane stabilizing effect • Delayed phase (hrs-days): mediated by glucocorticoid receptor

  19. Distinguish 1˚from Central AI Long Cortrosyn Test • Rarely needed • Done if plasma ACTH equivocal (2.2-11 pM) or result not available (i.e. not sent before the initiation of exogenous glucocorticoids) • 250 ug IV infusion over 8h x 3d • Plasma cortisols during infusion (0, 4, and 8h) • 24h UFC day prior to and on 3 days with infusion • 1˚AI: no response • Central AI: some response

  20. Anterior Pituitary Dysfn Rx • Corticosteroids • Prednisone 5 mg qhs or qam to 5/2.5 mg daily • Cortef 20 mg qhs or qam to 20/10 mg daily • Medic-alert, 2-3x dose during acute-illness • Surgery: 50mg IV preop & q8h postop • Levothyroxine • Titrate dose to mid-normal FT4 not TSH • Sex steroids • Male: testosterone 100 mg/wk IM, androgel 5g/d • Female: premenopausal OCP, postmenopausal HRT? • Growth hormone?

  21. Pituitary Apoplexy • Acute pituitary hemorrhage • Sudden severe H/A, diploplia, visual loss • Shock due to adrenal crisis • Diagnosis: pituitary MRI or CT • Rx: • urgent surgical decompression • Solucortef 50 mg IV q8h • Dopamine agonist if high PRL/known prolactinoma

  22. Normal Serum [Na] (135-145 mEq/L) Closely Guarded ADH (pM) ↓ ECFv Thirst 5 0 130 135 140 145 PNa (mEq/L)

  23. Diabetes Insipidus Polyuria: > 3 L/d +Polydipsia: > 3.5 L/d Ddx • Diabetes Mellitus • Hypercalcemia • Solute diuresis: • Volume expansion 2° saline loading • High-protein feeds (urea as osmotic agent) • Post-obstructive diuresis • Diabetes Insipidus: • Central (CDI) • Nephrogenic (NDI) • Primary (Psychogenic) Polydipsia

  24. Central (CDI) Idiopathic autoimmune Neurosurgery, head trauma Cerebral hypoperfusion Tumor Craniopharyngioma, pituitary adenoma, suprasellar meningioma, pineal gland, metastasis Infiltration Fe, Sarcoid, Histiocytosis X Nephrogenic (NDI) X-linked recessive Hypokalemia Hypercalcemia (2° to HPT in particular) Renal disease: after ATN, postobstructive uropathy, RAS, renal transplant, amyloid, Sickle cell anemia Sjogren’s Drugs: Lithium, 20% of chronic users Demeclocycline, amphotericin, colchicine Diabetes Insipidus Ddx

  25. Diabetes Insipidus • Intact thirst & access to water • Hi-normal serum sodium (142-145 mEq/L) • Polydipsia (crave cold fluids) • Polyuria, Nocturia  sleep disturbance • 1° treatment is pharmacological • Impaired thirst or access to water: • Hypernatremia • Insufficiently concentrated urine • 1° treatment is free water (enteral or IV D5W)

  26. Diabetes Insipidus • Healthy out-patients • DI with Intact thirst or access to water • Hi-normal serum sodium (142-145 mEq/L) • Polydipsia (crave cold fluids) • Polyuria, Nocturia  sleep disturbance • 1˚ Psychogenic Polydipsia • Low-normal serum sodium (135-137 mEq/L) • Anxious middle-aged women • Psychiatric illness, phenothiazine (dry mouth)

  27. 1˚ Polydipsia: “What came first?” The Polyuria or the Polydipsia? The Chicken or the Egg? (Egg)

  28. Water Deprivation Test • Hold water intake for 2-3h prior to coming in. • Continue to hold water & Monitor: • Urine volume, UOSM q1h • Serum Na, OSM q2h • If serum OSM/sodium do not rise above normal ranges & UOSM reaches 600  1˚ Polydipsia • If serum OSM reaches 295-300 mM & UOSM doesn’t ↑ • Diabetes Insipidus established • Endogenous ADH should be maximal, check serum ADH • 2 green rubber stopper tubes, pre-chilled, on ice, need biochemist • Give DDAVP 10 ug IN • CDI: UOSM ↑ by 100-800% (complete CDI), ↑ by 15-50% (partial CDI) with absolute UOSM > 345mM • NDI: UOSM ↑ by up to < 9%, sometimes ↑ as high as 45% but absolute UOSM always < isotonic (290 mM)

  29. Diabetes Insipidus • Impaired thirst or access to water • Elevated serum sodium/OSM • UOSM < 500 mM, USG < 1.017 • If serum sodium/OSM not elevated • Not DI! • UOSM and USG are irrelevant

  30. Pituitary Surgery/Trauma • Triphasic response to surgery • Phase 1: DI • Axonal injury 2° surgery/swelling • Begins after POD #1 (pre-existing DI can occur earlier) • Lasts 1-5d • Phase 2: SIADH • Axonal necrosis of AVP secreting neurons with uncontrolled AVP release • Lasts 1-5 days • Phase 3: DI • Axonal death with cessation of AVP production • Usually permanent

  31. PNa (mEq/L) U/O (cc/h) 400 150 U/O #1 100 100 50 50 U/O #2 1 6 11 POD #

  32. PNa (mEq/L) U/O (cc/h) 400 Na #1 150 U/O #1 100 100 50 50 1 6 11 POD #

  33. PNa (mEq/L) U/O (cc/h) 400 150 Na #2 100 100 50 50 U/O #2 1 6 11 POD #

  34. #1 DI #2 Normal PNa (mEq/L) U/O (cc/h) 400 Na #1 150 Na #2 U/O #1 100 100 50 50 U/O #2 1 6 11 POD #

  35. PITUITARY SURGERY PROTOCOL Immediately Postop (in recovery room): Send serum for electrolytes, creatinine, blood sugar Send urine for USG (specific gravity) Then monitor: Accurate I&O: fluid intake & urine output hourly (q1h) with complete tally q12 hours (q12h) Serum electrolytes and USG : q12h If on steroids (decadron, solucortef, etc.) do capillary blood glucose bid If urine output > 400cc/hour: Serum OSM & urine OSM now and then q12h Serum lytes, creatinine now and then q6h USG now and then q4h Call Endocrinology Service once serum electrolytes and USG results are back for possible DDAVP and IV fluid orders Call Endocrinology Service whenever: Serum sodium > 148 Serum sodium < 130 Urine output > 400 cc/h (see above 3.)

  36. Treatment of DI • Rx Dehydration • NS initially if ECFv contraction • Then IV D5W or enteral free water to lower serum [Na] • 1-2 mEq/h if Na > 160, symptomatic (coma, SZ), acute • Otherwise 0.5-1.0 mEq/h • Insensible losses? (0.5 L/d) • Do NOT replace U/O if giving DDAVP • DDAVP (Desmopressin) • Reduces U/O and therefore simplifies fluid therapy • Long t½: duration 8-12h, up to 24h • Therefore use judiciously • DDAVP 1ug IV/SC x 1 • Only repeat if breaks-thru again (i.e. becomes hypernatremic with dilute polyuria) • Once nasal mucosa stable can switch to intranasal • Also oral form DDAVP now available DDAVP: 1ug IV/SC = 10 ug IN = 0.1 mg PO

  37. Treatment of DI • AVP, Aqueous vasopressin (Pitressin) • Only parenteral form, 5-10 U SC q2-4h • Lasts 2-6h • Can cause HTN, coronary vasospasm • Chlorpropamide(OHA which stimulates AVP secretion) • 100-500 mg po OD-bid • Only useful for partial DI, can cause hypoglycemia • HTCZ(induces volume contraction which diminishes free water excretion) • 50-100 mg OD-bid • Mainstay of Rx for chronic NDI • Amiloride(blunts Lithium uptake in distal tubules & collecting ducts) • 5-20 mg po OD-bid • Drug of choice for Lithium induced DI • Indomethacin 100-150 mg po bid-tid (PGs antagonize AVP action) • Clofibrate 500 mg po qid (augments AVP release in partial CDI) • Tegretol 200-600 mg po od (augments AVP release in partial CDI)

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