The Adrenal Gland

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The Adrenal Gland

• Adrenal Cortex
• Zona Glomerulosa-aldosterone
• Zona Fasiculata-cortisol androgens
• Zona Reticularis-androgens cortisol
• Adrenal Medulla
• Chromaffin Cells-epinephrine

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Glucocorticoids

• Cortisol
• Corticosterone
• Deoxycorticosterone
• 11-deoxycortisol
• others

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Effects of Glucocorticoids

• Carbohydrate Metabolism
• Gluconeogenesis
• Decreased Glucose Utilization
• Increased Glycogen Stores
• Protein
• Catabolic

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Effects of Glucocorticoids

• Lipid
• Decreased Lipogenesis
• Stimulated Lipolysis
• Change in distribution
• Electrolytes
• Increases Ca and Phos excretion
• Decreased Ca Absorption
• Weak mineralocorticoid action

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Effects of Glucocorticoids

• Water Homeostasis
• increased GFR
• inhibitory to ADH
• Circulation
• Permissive effect for norepinephrine
• Blood
• Increased PMNs, Platelets, RBCs
• Decreased Eosinophils and Lymphocytes

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Effects of Glucocorticoids

• Connective Tissue
• Decreased Fibroblast Proliferation
• Collagen Catabolism
• Gastrointestinal Tract
• Increased Gastrin, Gastric Acid, Pepsin
• Decreased Gastric Mucus Content Viscosity
• Decreased Gastric Mucosal Cell Proliferation

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Effects of Glucocorticoids

• Liver
• Increased Glycogen
• Increased Gluconeogenesis
• Induction of Enzymes
• Pancreas
• Anti-inflammatory
• Stabilize membrane (Cellular, Lysosomal)
• Inhibits Fibroblast Proliferation
• Inhibit WBC migration/phagocytosis

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Effects of Glucocorticoids

• Immunosuppressive
• Effect on WBCs, Macrophages
• Effect on Lymphocytes
• Appetite Stimulation
• CNS effect
• Diabetes Mellitus
• Neurologic Effects

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Therapeutic Use of Corticosteroids

• Allergic conditions
• Autoimmune disorders
• Pruritus with self-mutilation
• Destructive inflammation
• CNS trauma, shock
• Hypoglycemia, hypercalcemia
• Cancer chemotherapy

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Complications of Corticosteroid Therapy

• Iatrogenic Cushings
• Adrenocortical Suppression
• Immunosuppression
• Steroid Hepatopathy
• Wound Dehiscence
• Diabetes Mellitus
• GI Ulcers

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Complications of Corticosteroid Therapy

• Pancreatitis
• Muscle Weakness
• Osteoporosis
• Growth Retardation
• May worsen many diseases
• arthritis
• demodex
• Renal failure

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Duration Varies with Form

• Succinate - hours
• Unesterified - hours
• Acetate - days to months
• Pivalate - months

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Glucocorticoid Dosages

• Maintenance (physiological)
• Hydrocortisone 0.1-0.5 mg/lb/day
• Prednisolone 0.02-0.1 mg/lb/day
• Anti-inflammatory
• Prednisolone 0.25-0.5 mg/lb/day
• Dexamethasone 0.05 mg/lb/day

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Anti-inflammatory Therapy

• Loading dose for 5-7 days
• dogs 0.5 mg/lb/day
• cats 1-2 mg/lb/day
• Maintenance
• dogs 0.25-0.5 mg/lb q 48 hrs
• cats 1 mg/lb q 48 hrs

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Gluocorticoids in Therapy

• Immunosuppressive (dogs cats 2X)
• Prednisone 1-2 mg/lb/day
• Dexamethasone 0.1-0.2 mg/lb/day
• Shock and CNS trauma
• Prednisolone 5-25 mg/lb/day
• Dexamethasone 1-5 mg/lb/day

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Hyperadrenocorticism

• Cushings Syndrome
• Cushings Disease (PDH)
• Hyperglucocorticoidism

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Forms of Hyperadrenocorticism

• Bilateral Adrenocortical Hyperplasia
  (Pituitary-Dependent Hyperadrenocorticism, PDH)
  
• Adrenal Tumor (functional)
• Iatrogenic

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Pituitary Secretion of ACTH

• Pars Distalis
• ACTH secretion controlled by CRF via
  hypophyseal-pituitary portal system
  
• Pars Intermedius
• A cell pars intermedia MSH and B cell pars
  intermedia ACTH secretion controlled by
  serotonergic and dopaminergic fibers

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Bilateral Adrenocortical Hyperplasia(Pituitary
Dependent Hyperadrenocorticism)

• Functional Pituitary Tumor
• pars distalis or pars intermedia
• Boston Terriers and Boxers
• Idiopathic Adrenal Hyperplasia
• abnormalities in neuro-endocrine transmitters
• Norepinephrine, Serotonin, Dopamine
• Most common in Dachshunds and poodles
• Ectopic ACTH-Producing Tumor

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Adrenocortical Neoplasia(Adrenal Dependant
Hyperadrenocorticism)

• 10-20 of canine cases, 70 female
• Right Gland more often affected (77)
• Usually unilateral with atrophy of other
• Usually function independently of ACTH
• 60 Adenocarcinomas
• 40 Adenomas

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Iatrogenic Canine Cushings Syndrome

• Exogenous glucocorticoids causing clinical signs
  of cortisol excess
  
• There is atrophy of the adrenal zona fasiculata
• Thus have adrenal suppression despite signs of
  cortisol excess

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Clinical Signs

• Polyuria
• Polydipsia
• Polyphagia
• Pendulous Abdomen
• Muscle weakness
• Lethargy

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Dermatological Manifestations

• Alopecia
• Dermal Atrophy
• Hyperkeratosis, Comedones
• Increased bruising
• Hyperpigmentation
• Calcinosis cutis
• Poor wound healing
• Facial Dermatitis

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• Steroid Hepatopathy
• Predisposition to Infections
• Reproductive Abnormalities
• Dystrophic calcification
• Osteoporosis
• Neurological Signs d/to pit. tumor
• Panting
• Obesity
• Thromboembolism (sudden death)

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Possible Associated Syndromes

• Diabetes mellitus
• Pancreatitis
• Congestive Heart Failure
• Pulmonary Thromboembolism
• Pyelonephritis
• CNS Signs

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Differential Diagnoses

• For PU/PD
• Chronic renal disease
• Liver disease
• Diabetes mellitus
• Diabetes insipidus
• Hyperthyroidism
• Electrolyte disorders
• Primary polydipsia (psychogenic)
• Etc.

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Differential Diagnoses

• For dermatological signs
• Hypothyroidism
• Sex hormone imbalances
• Post-clipping alopecia
• Growth-hormone responsive dermatosis
• Alopecia X
• Demodecosis, dermatophytosis, etc.

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Steps in Diagnosis

• Documentation of systemic effects associated with
  high levels of glucocorticoids
  
• Confirm diagnosis of hyperglucocorticoidism
• Determine etiology of hyperglucocorticoidism

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Laboratory Evaluation

• Hemogram
• Stress Leukon
• Urinalysis
• Specific gravity
• ? Bacteriuria

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Blood Chemistry

• Glucose
• Cholesterol
• Alanine transaminase
• Alkaline Phosphatase
• BUN
• Electrolytes

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Other Tests

• Glucose Tolerance
• Blood Insulin
• Decreased total T3 T4
• Free T3 and T4 usually normal
• Endogenous TSH decreased
• Decreased serum phosphorus
• Elevated blood pressure

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Radiology

• Hepatomegaly
• Carcinomas
• Osteoporosis
• Metastatic Mineralization

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Abdominal Imaging

• Hepatomegaly
• Adrenal mass ? calcified
• Metastatic mineralization (e.g. renal)
• Ultrasonography can be very helpful in defining
  the sizes of the adrenal glands and is used to
  distinguish bilateral hyperplasia from adrenal
  tumors

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CT or MRI Scans

• Adrenal glands
• Hyperplasia
• Tumors
• Invasion into surrounding tissues
• Pituitary gland
• tumors

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Liver Aspirates or Biopsies

• Ultrasound-guided or laparoscope
• Steroid hepatopathy
• Centrilobular vacuolation
• Glycogen accumulation

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Exploratory

• Laproscope
• Laporatomy
• Visualize the adrenal glands
• Biopsy
• Removal a unilaterally enlarged gland

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Adrenal Function Tests

• First step is to confirm an abnormality in
  adrenal function, this confirms the diagnosis of
  hyperglucocorticoidism

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Measuring Plasma Cortisol

• EDTA
• Spin Immediately
• Freeze Plasma
• Methodology
• Fluorometric
• Competitive Protein Binding
• Radioimmunoassay
• ELISA

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Adrenal Function Tests

• Resting plasma cortisol
• ACTH Stimulation Test
• 1 unit/lb ACTH GEL IM
• Pre and 2 hour post sample
• Or 5 ug/kg synthetic ACTH IV or IM
• Pre and 1 hour post sample

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ACTH Stimulation Test Interpretation

• Normal
• pre 5-40 ng/ml or 15-110 nmol/L
• post 80-200 or 220-500 nmol/L
• PDH
• pre Normal or increased
• post 200 ng/ml or 600 nmol/L

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ACTH StimulationTests Interpretation

• ADH
• pre normal or increased
• 50 have no increase, 50 have exaggerated
  increase
  
• Iatrogenic
• pre decrease
• post has no change

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Adrenal Function Tests Interpretation

• Problems
• 10 of PDH do not have hyperplastic response and
  some tumors do

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Dexamethasone Suppression Tests

• Dexamethasone suppresses release of ACTH
  resulting in decreased cortisol secretion
  
• In PDH, low doses of DXMS do not suppress ACTH,
  high doses do
  
• Adrenal tumors function autonomously

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Low Dose Dexamethasone Suppression Test

• To differentiate a dog with normal HPA axis
  function from a dog with Cushings Syndrome
  
• 0.01 mg/kg DXMS IV
• Pre, 3 hr and 8 hr post samples for cortisol
  measurement

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Low Dose Dexamethasone Suppression Test
Interpretation

• Normal HPA axis function
• Pre 15-110 nmol/L
• 3 and 8 hour post
• PDH (bilateral adrenal hyperplasia)
• Pre often 110 nmol/L
• 3 hr post maybe 50
  of baseline ( transient ?)
  
• 8 hr post 50 of baseline

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Low Dose Dexamethasone Suppression Test
Interpretation

• Adrenal Tumors
• Pre often 110 nmol/L
• 3 and 8 hour post 50 of baseline
• Iatrogenic hyperglucocorticoidism
• This test is not indicated in diagnosis of
  iatrogenic Cushings Syndrome

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High Dose Dexamethasone Suppresssion Test

• This is done AFTER a diagnosis of
  hyperadrenocorticism has been confirmed via an
  ACTH stimulation test or a low dose dexamethasone
  suppression test
• 0.1 mg/kg dexamethasone IV
• Pre and 8 hour post samples

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High Dose Dexamethasone Suppression Test
Interpretation

• Normal test not indicated
• Iatrogenic test not indicated
• PDH (bilateral adrenal hyperplasia)
• Pre often 110 nmol/L
• Post 50 suppression (usually
• Adrenal Tumor
• Pre often 110 nmol/L
• Post does NOT suppress to

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Mega Dose Dexamethasone Suppression Test

• In past was advocated for identifying dogs with
  pituitary tumors that were relatively refractory
  to dexamethasone and only suppressed when given
  very high doses (up to 25 of dogs with tumors of
  pars intermedia)
• 1 mg/kg IV with 0 and 8 hour post
• Interpretation same as high dose DST

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Problems with Dexamethasone Suppression Tests

• Rate of metabolism of dexamethasone varies
  between dogs and affects test results
  
• Up to 25 of dogs with tumors of pars intermedia
  do not suppress
  
• Dogs with adrenal tumors may have fluctuations in
  baseline cortisols that mimic suppression

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Combination testing

• Some endocrinologists have recommended
  combinations of an ACTH stimulation test and a
  high dose dexamethasone suppression however these
  often have confusing results and are not
  recommended

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Urine Cortisol Creatinine RatioJAVMA
200163-1641

• Normal mean 5.7
• 40 PDH dogs mean 337.6
• 23 other dogs with PU/PD mean 42.6
• Sensitive as screening test
• Not specific
• individual dogs overlapped in PDH and PU/PD gps)

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Endogenous ACTH

• Elevated in PDH
• Suppressed with adrenal tumors and dogs with
  iatrogenic hyperglucocorticoidism
  
• ACTH is secreted episodically so wide normal
  range and overlaps are seen
  
• ACTH is not stable and requires special sample
  handling

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Examples of Test Results
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Treatment

• General supportive care for any secondary
  infections or diseases such as hypertension and
  diabetes mellitus
  
• Specific treatment of Cushings Syndrome depends
  upon identification of the underlying cause (PDH,
  adrenal tumor or iatrogenic)

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Treatment Pituitary Dependent Hyperadrenocorticis
m

• Hypophysectomy
• requires surgical expertise or many
  complications
  
• Require glucocorticoids, thyroxine, ? ADH
• Bilateral Adrenalectomy
• Surgical complications may occur
• Paracostal approach preferred
• Require mineralcorticoids ? glucocorticoids

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Lysodren (o,pDDD)

• Most common treatment of PDH
• Concentrated in adrenal cortex
• Selective necrosis of zona fasiculata and zona
  reticularis
  
• If overdose can also destroy the zona glomerulosa

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Lysodren Induction

• Accurate Weight
• Baseline 24 hours water consumption
• Baseline eosinophil and lymphocyte number, Bun,
  electrolytes

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Lysodren Induction

• Give 25 mg/kg BID until
• Appetite decreases
• Decrease water consumption (
• Eosinophils 300/?l or Lymphs 1000 /?l
• 7-10 days (range 4-30)
• Minimal Response on ACTH Challenge
• Adverse signs
• Lysodren maintenance
• 25 mg/kg twice weekly
• (Sunday PM, Thursday AM)

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Monitoring o,pDDD Therapy

• Clinical observations
• appetite, drinking, general attitude
• laboratory
• CBC, BUN, electrolytes, UA with culture
• q 1-3 months
• ACTH stimulation
• q month until stable
• q 3-6 months for life

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Ideal ACTH Stimulation Results for Dogs on
o,pDDD Therapy

• Low normal resting cortisol
• Minimal response to ACTH
• post

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Lysodren Maintenance

• Usually 25 mg/kg twice weekly
• Adjust based on ACTH response
• Often require increases in Lysodren dose during
  the first year of treatment (have progressive
  increases in ACTH)
  
• Recheck ACTH response at end of a new induction
  or one month after dosage change

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Example Cases

• Dog with PDH has been on Lysodren 25 mg/kg twice
  weekly
  
• ACTH response test pre 220, post 660
• Would recommend repeating Lysodren induction,
  e.g. 25 mg/kg BID for 5 days then recheck ACTH
  response test
  
• At recheck pre 80, post 60
• Resume 25 mg/kg twice weekly

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Example Case

• Dog has been on Lysodren maintenance 25 mg/kg
  twice weekly
  
• ACTH response test pre 150, post 210
• Recommend increasing maintenance dose and recheck
  ACTH response in one month
  
• 37.5 mg/kg twice weekly (or 25 mg/kg three days
  per week)

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Example case

• Dog has been on maintenance Lysodren 25 mg/kg
  twice weekly
  
• ACTH response test pre 20, post 35
• Recommend stopping Lysodren for one month and
  rechecking, if cortisol levels have increased
  would then restart Lysodren at a lower dose (e.g.
  25 mg/kg once weekly)

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Client Education re Lysodren

• Lysodren is a very potent medication related to
  DTT
  
• Lysodren is very effective for the treatment of
  Cushings Diseases but its use MUST be carefully
  monitored
  
• Veterinarian should be called anytime the dog has
  a decrease in appetite or seems listless or has
  any other symptoms of illness
  
• Prednisolone is an antidote, owner should give
  0.5 mg/kg if the dog shows listlessness or any
  symptoms of illness or if known stress will be
  occurring (grooming, travel, boarding, etc.)

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Concurrent Cushings and Diabetes Mellitus

• Roughly regulate with insulin
• Induction dose 25 mg/kg o,pDDD per day
• Prednisolone 0.1 mg/kg given daily during
  induction and for 3-5 days after cessation of
  daily Lysodren
  
• Maintenance 25 mg/kg o,pDDD twice weekly
• Expect dramatic decrease in insulin required

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Alternate Medical Therapies

• Cyproheptadine (blocks serotonin)
• 0.05 mg/kg QID
• side effects hyperphagia, weight gain, vomiting,
  diarrhea
  
• Bromocriptine (dopamine agonist)
• 0.05-0.1 mg/kg/day bid
• Side effects anorexia, vomiting, behavioral
  changes, depression

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Alternate Medical Therapies

• Aminoglutethimide-blocks steroid synthesis
  however only works short X
  
• Metyrapone-blocks steroid synthesis
• 25 mg bid
• Trilostane-blocks steroid synthesis
• Early trials using 20-120 mg/dog look promising
• Mifepristone (RU486)-inhibits cortisol binding to
  receptors
  
• High levels of cortisol will override its
  effectiveness

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Ketoconazole

• Inhibits 11-hydroxylase and 14-demethylation
  enzymes in steroid synthesis
  
• May block steroid receptors
• Starting dose 10 mg/kg BID
• recheck ACTH stimulation in 10 days
• if cortisol 100 nmol/L increase to 15mg/kg BID

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Ketoconazole Side Effects

• Anorexia
• discontinue for 24 hours
• Vomiting
• Hepatotoxicity
• monitor chemistry panels
• Lightening of the haircoat

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Ketoconazole

• Advantages
• no danger of destroying the adrenal glands
• Also treats any secondary Malassezia infections
• Rapid decreases in serum cortisol
• Disadvantages
• Expensive
• Must be given BID
• Can cause anorexia, GI upsets, hepatic damage

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L-Deprenyl (Anipryl)

• Irreversible inhibitor of monoamine oxidase type
  B (increases CNS dopamine)
  
• Is most effective in cases with tumors of pars
  intermedia (approx 30 of canine pituitary
  tumors)
  
• Proposed to down regulate ACTH production

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L-Deprenyl

• Is FDA approved for the treatment of canine PDH
• Evidence of effectiveness was based on owners
  observations that treated dogs had more energy
  (perhaps due to the drugs amphetamine activity)
  
• No effect on serum cortisol level, liver enzymes,
  etc.

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L-Deprenyl

• Does not require monitoring of ACTH response
  (does not decrease)
  
• Side effects include vomiting, diarrhea,
  restlessness, lethargy, salivation, anorexia,
  deafness, pruritus, licking, shivering,
  trembling, shaking, drug interactions with other
  MOA inhibitors
• ?????consider in very early cases, otherwise do
  not recommend this drug as does not prevent
  progression of disease in most dogs

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Radiation Therapy for PDH

• Cobalt therapy
• reduces size of pituitary tumors
• may ameliorate neurologic signs
• Seldom decreases ACTH secretion
• No effect on adrenocortical hyperplasia

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Surgery for Adrenal Tumors

• Adrenalectomy is treatment of choice
• 50 of tumors malignant and locally aggressive
• do CT scan or MRI to assess
• intra- and post-operative glucocorticoids
  short-term minerolocorticoids as contralateral
  gland atrophic

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Lysodren for Adrenal Tumor

• Chemoablate the tumor
• 25 mg/kg BID for 14-30 days or until develop
  complete adrenal insufficiency
  
• Start Florinef at 0.1 mg/10kg SID to BID on day 7
  of treatment
  
• may need to also supplement with pred

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Ketoconazole for Adrenal Tumor

• Blocks synthesis of cortisol
• 10-15 mg/kg BID for life
• No effect on the tumor,
• ameliorates clinical signs

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Iatrogenic Cushings Disease

• Any or all of clinical and laboratory changes may
  be present
  
• Effects depend on type, dose, frequency and
  duration of therapy
  
• Diagnosis via ACTH challenge
• Crisis Treatment (following abrupt withdrawal)
• IV fluids
• Glucocorticoids

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Iatrogenic Cushings Disease

• Maintenance during weaning off steroids
• Physiological replacement doses
• hydrocortisone 0.5-1 mg/kg/day
• prednisone 0.1-0.25 mg/kg e.o.d.
• Use ACTH Challenge to assess recovery
• Give 10X maintenance before stress

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Iatrogenic Cushings Disease

• Prevention
• Use corticosteroids sparingly
• Use short acting forms
• Reserve long acting forms or DEPO for problems
  that require only 1 or 2 doses

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Feline Hyperadrenocorticism
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Clinical Features

• Females predisposed (91)
• Middle-aged to older
• Truncal alopecia
• Hyperpigmentation
• Think skin
• Muscle wasting
• pendulous abdomen

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Clinical Features

• Weight loss
• Polyphagia
• Diarrhea
• Infections
• Hepatomegaly
• PU/PD (late onset)
• Diabetes mellitus

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Laboratory Finding

• Hyperglycemia
• Hypercholesterolemia
• Glucosuria
• Lymphopenia
• Eosinopenia
• Mature leukocytosis
• Increased SAP

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Pituitary-Adrenal

• Function Tests

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Low Dose Dexamethasone Suppression Test

• Normal cats will suppress cortisol levels by 50
  following 0.01 mg/kg DXMS IV
  
• Many cats with non-adrenal illnesses DO NOT
  suppress cortisol levels by 50 following 0.01
  mg/kg DXMS
  
• Rules out normal cats, may not distinguish
  between adrenal disease and other systemic
  diseases causing PU/PD/PP, thin skin, etc.

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High Dose Dexamethasone Suppression Test

• 0.1-1.0 mg/kg IV
• This is used as a SCREENING test for
  hyperadrenocorticism in cats
  
• Sample at 0 and 8 hours
• Normal cats and cats with non-adrenal illnesses
  will have cortisol

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Endogenous ACTH Response Test

• Normal range 20-100 pg/ml
• May be helpful in distinguishing between PDH and
  adrenal tumors in cats
  
• Adrenal tumors have low levels
• PDH is associated with high levels
• Overlaps do occur

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Abdominal Ultrasonography

• Best method of differentiating PDH and adrenal
  tumors in cats

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Therapy

• o,pDDD not effective in decreasing cortisol
  concentrations in cats
  
• Ketoconazole not effective in decreasing
  cortisol concentrations in cats
  
• Metyrapone not effective in cats
• Cobalt Radiation may abalate pituitary tumor
  without any effect on cortisol levels

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Therapy

• Adrenalectomy
• Unilateral if adrenal tumor
• Bilateral for PDH
• Pre and post-surgery give glucocorticoids and
  Florinef esp. if bilateral surgery to be done,
  maintain on fluids, continue treatment of
  diabetes (noting that insulin requirement likely
  to drop)

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Prognosis

• Guarded in cats due to high incidence of
  complications relating to the Cushings disease
  or to inability to manage post-operative
  hypoadrenocorticism