Pituitary Insufficency

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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, V 1 , V 2 , 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, V 1 , V 2 (LR 6 SO 4 ) 3 V 1 V 2
  • 4.  
  • 5.  
  • 6.  
  • 7. H-P-A Axis
  • 8. Cushing’s Disease Ectopic ACTH High ACTH Cushing’s
  • 9. 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%)
  • 10. 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 2 nd 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%
  • 11. 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 ACTH Independent CT abdo Adrenal Surgery ACTH dependent 1 st 8mg O/N DST or HDDST 2 nd CRH Test if above test negative CRH Test Pituitary MRI Pituitary Surgery IPSS
    • Ectopic ACTH
    • CT thorax, abdo
    • Thyroid U/S
    • Octreotide Scan
    Continue search for ectopic source Remove ectopic source < 1.1pM >2.2pM 1.1-2.2pM No Stim Positive Stim Conclusive (>0.8-1.0cm) Inconclusive >2 basal >3 CRH <1.5 basal <2 CRH Conclusive No CRH stim No DXM suppression Stim by CRH or DXM suppresses
  • 12. 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)
  • 13.  
  • 14. 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
  • 15.  
  • 16. 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
  • 17. 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
  • 18.  
  • 19. 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
  • 20. 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]
  • 21. 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)
  • 22. 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
  • 23. 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
  • 24. 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
  • 25. 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
  • 26. 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?
  • 27. 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
  • 28.  
  • 29. P Na (mEq/L) 130 135 140 145 0 5 ADH (pM) Thirst ↓ ECFv Normal Serum [Na] (135-145 mEq/L) Closely Guarded
  • 30. Diabetes Insipidus
            • 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
    Polyuria: > 3 L/d + Polydipsia: > 3.5 L/d
  • 31. Diabetes Insipidus Ddx
    • 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
  • 32. 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)
  • 33. 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)
  • 34. 1 ˚ Polydipsia: “What came first?” The Chicken or the Egg? (Egg) The Polyuria or the Polydipsia?
  • 35. Water Deprivation Test
    • Hold water intake for 2-3h prior to coming in.
    • Continue to hold water & Monitor:
        • Urine volume, U OSM 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 & U OSM 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: U OSM ↑ by 100-800% (complete CDI), ↑ by 15-50% (partial CDI) with absolute U OSM > 345mM
          • NDI: U OSM ↑ by up to < 9%, sometimes ↑ as high as 45% but absolute U OSM always < isotonic (290 mM)
  • 36. Diabetes Insipidus
    • Impaired thirst or access to water
        • Elevated serum sodium/OSM
        • U OSM < 500 mM, U SG < 1.017
    • If serum sodium/OSM not elevated
        • Not DI!
        • U OSM and U SG are irrelevant
  • 37. 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
  • 38. 1 6 11 POD # 50 100 150 P Na (mEq/L) 50 100 400 U/O (cc/h) U/O #1 U/O #2
  • 39. 1 6 11 POD # 50 100 150 P Na (mEq/L) 50 100 400 U/O (cc/h) Na #1 U/O #1
  • 40. 1 6 11 POD # 50 100 150 P Na (mEq/L) 50 100 400 U/O (cc/h) Na #2 U/O #2
  • 41. 1 6 11 POD # 50 100 150 P Na (mEq/L) 50 100 400 U/O (cc/h) Na #1 Na #2 U/O #1 U/O #2 #1 DI #2 Normal
  • 42. PITUITARY SURGERY PROTOCOL
    • Immediately Postop (in recovery room) :
      • Send serum for electrolytes, creatinine, blood sugar
      • Send urine for U SG (specific gravity)
    • Then monitor :
      • Accurate I&O: fluid intake & urine output hourly (q1h) with complete tally q12 hours (q12h)
      • Serum electrolytes and U SG : 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
      • U SG now and then q4h
      • Call Endocrinology Service once serum electrolytes and U SG 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.)
  • 43. 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
  • 44. 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)