Hypothalamic-Pituitary-Adrenal Axis Suppression Following Topical Corticosteroid Administration

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Hypothalamic-Pituitary-Adrenal Axis Suppression
Following Topical Corticosteroid Administration

• Jean Temeck, M.D.
• Medical Officer
• Division of Pediatric Drug Development
• FDA

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Topics

• Regulation of glucocorticoid secretion
• Spectrum of hormonal effects on the HPA axis
• Spectrum of clinical manifestations of AI
• Importance of diagnosis
• Diagnostic hormonal tests
• Risk factors for HPA axis suppression

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Hypothalamus
CRH
Pituitary ACTH
Adrenal
Cortisol
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Spectrum of Effects of Exogenous Glucocorticoids
on the HPA Axis

• Effects on the HPA axis are variable as is
  individual susceptibility to suppression
• No HPA axis suppression
• HPA axis suppression secondary or central AI
• suppression of the pituitary and hypothalamic
  secretions of ACTH and CRH, respectively
• degree of suppression is variable

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Spectrum of Effects of Exogenous Glucocorticoids
on the HPA Axis

• Partial (mild) ACTH suppression
• basal ACTH cortisol levels may be normal
• pituitary response to stress is impaired, but
  adrenal response may be normal
• Complete ACTH suppression
• Adrenal gland atrophy with severe or prolonged
  ACTH suppression basal cortisol decreased
  entire HPA axis suppressed

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Clinical Spectrum

• Abnormal hormonal response clinically relevant
• May be subclinical
• Symptoms may be nonspecific and insidious
• Adrenal crisis (triggered by stress)
• fever
• severe hypotension
• shock
• coma
• death

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HPA Axis Suppression
Abnormal Hormonal Test
HPA Axis Suppression
No Symptoms
Symptoms Present
At Risk for ACUTE ADRENAL CRISIS !
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Features of Glucocorticoid-Induced Adrenal
Insufficiency

• Prevalence unknown
• lack of clinical suspicion
• absorption of topical corticosteroids may be
  unrecognized
• diagnostic hormonal testing not performed
• signs and symptoms may be subtle and non-specific
• attribution made to other causes

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Features of Glucocorticoid-Induced Adrenal
Insufficiency

• Prevalence unknown
• failure to detect if recovery of suppression is
  rapid
• failure to detect if a diagnostic test of low
  sensitivity (i.e. high false negative rate) is
  performed

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Importance of Diagnosing Adrenal Insufficiency

• Identifying patients with adrenal insufficiency,
• even if mild, is important because
• life-threatening hypotension may occur during
  periods of stress (e.g. illness, trauma, surgery)
• the condition is totally preventable if
  supplemental glucocorticoids are administered

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Diagnosis of Glucocorticoid-Induced Secondary
Adrenal Insufficiency

• Basal hormonal tests
• Dynamic testing
• tests of adrenocortical integrity (adrenal
  gland integrity only)
• tests of HPA axis integrity (hypothalamic,
  pituitary and adrenal integrity)

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Basal Hormonal Tests

• Plasma cortisol (single or multiple)
• low sensitivity, thus, often non-diagnostic
  endogenous levels variable due to pulsatile
  secretion
• 24 hour urinary free cortisol
• often non-diagnostic lack of sensitivity at low
  levels, i.e. low cortisol excretion may be normal
• errors in 24 hour urine collections

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Basal vs. Dynamic Tests

• Since basal plasma and 24h cortisol levels are
  often non-diagnostic, it is necessary to perform
  dynamic testing to diagnose adrenal
  insufficiency.
• Advantage of dynamic testing provide information
  regarding the function, reserve capacity and,
  hence, the ability of the adrenal gland or of the
  entire HPA axis to respond to stress.

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Dynamic Tests

• Dynamic tests of adrenocortical integrity
  (assesses only adrenal gland responsiveness)
• Cosyntropin (ACTH) stimulation test
• high-dose ACTH
• low-dose ACTH
• Dynamic tests of HPA axis integrity (assesses the
  responsiveness of the hypothalamus, pituitary and
  adrenal glands)
• ITT
• Corticotropin-releasing hormone test (CRH)

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Hypothalamus
CRH
Pituitary ACTH
Adrenal
Cortisol
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Diagnosis of 20 Adrenal Insufficiency

• Cosyntropin
• ?
• adrenal
• recent-onset ? mild suppression ?
• Potential false negative

• ITT or CRH
• ?
• entire HPA axis
• ?
• ?
• ITT more sensitive than cosyntropin
• CRH reports of equivalence to ITT

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High-Dose Cosyntropin Test

• Most commonly used
• Methodology
• administer supraphysiologic dose synthetic ACTH,
  IV or IM
• 125 ug if lt2 years
• 250 ug if gt2 years
• measure cortisol concentrations before and either
  30 or 60 minutes after ACTH administration
• Advantages simple, fast and inexpensive
• perform any time of day, outpatient- 30 or 60
  minutes

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High-Dose Cosyntropin Test

• Controversy regarding normal cortisol response
• criteria in cosyntropin label (30 minute test)
• basal cortisol gt5 ug/dl, increment gt 7ug/dl, peak
  gt18 ug/dl
• low basal cortisol level does not suffice to make
  the diagnosis
• since the test can be performed at any time
  during the day and only the peak plasma cortisol
  remains unchanged during the day, this single
  criterion should be used for the 30 test.
• since basal cortisol levels vary throughout the
  day and the higher the basal level, the lower the
  incremental cortisol rise, consensus regarding a
  normal response appears to be a peak cortisol
  level gt18ug/dl at 30 minutes.

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High-Dose Cosyntropin Test

• Disadvantage
• sensitive screening test for 10 adrenal
  insufficiency but less sensitive for diagnosing
  20 adrenal insufficiency, especially if partial
  (mild) or of recent onset. In such cases, a false
  negative test may occur. Additional testing may
  be necessary if the patient is symptomatic or
  there is a high index of suspicion of adrenal
  insufficiency.

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Low-Dose Cosyntropin Test

• Newer test
• Method not standardized regarding dose or timing
  of samples
• administer a physiologic ACTH dose intravenously
• measure cortisol before and serially post-ACTH
• Other issues
• physiologic ACTH dosing may be more sensitive
  than supraphysiologic dosing for mild or
  recent-onset secondary AI
• dose not commercially available (dilutional
  errors, variability in dose administered among
  tests, binding to plastic tubing)

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Low-Dose vs. High-Dose Test

• Low-Dose
• dose not available
• physiologic ACTH dose
• frequent, carefully timed venous sampling
• no consensus on method of performance
• no consensus regarding normal response criteria
  lower limit cortisol cut-off

• High-Dose (Standard Dose)
• dose commercially available
• supraphysiologic ACTH dose
• single cortisol level post-ACTH, no precise
  timing
• method of performance has been standardized
• peak cortisol gt18ug/dl at 30 minutes is generally
  accepted as a normal response.

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Insulin Tolerance Test (ITT)

• Hypoglycemia potent stress stimulus for ACTH
  release
• Methodology
• intravenous insulin 0.05 U/kg after an overnight
  fast
• plasma cortisol and glucose levels before and at
  30, 45, 60 and 90 minutes
• Criteria for normal response
• with serum glucose lt40 mg/dl, plasma cortisol
  should rise to gt18-20 ug/dl at 60 to 90 minutes
  post-insulin.

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Insulin Tolerance Test (ITT)

• Advantages
• direct and definitive assessment of HPA axis
• Disadvantages
• requires intensive in-patient physician
  monitoring
• risk of morbidity (seizures, neurological
  impairment) and mortality from hypoglycemia.
  Therefore, rarely, if ever, used. Safer
  alternatives are available.

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Corticotropin-Releasing Hormone (CRH) Test

• Newer test
• CRH stimulates release of ACTH and, hence,
  cortisol
• 10 (adrenal) vs. 20 (pituitary) vs. 30
  (hypothalamic)
• 10 basal ACTH is high and ? with ACTH but not
  cortisol
• 20 basal ACTH is low and does not respond to
  ACTH
• 30 basal ACTH is low and shows an exaggerated
  response to ACTH
• Methodology
• administer CRH 1 ug/kg intravenously
• measure plasma ACTH and cortisol levels
  periodically for 90 to 180 minutes post-CRH.

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Advantages of the CRH Test

• Direct and definitive assessment of HPA axis
  integrity.
• The CRH test may have equivalent diagnostic value
  to the ITT.
• Safe for outpatient use

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Disadvantages of CRH Test

• Expensive
• Requires multiple blood samples
• Errors in blood collection and storage may occur.
• Normal responses of ACTH and cortisol are
  laboratory-dependent.
• No consensus regarding criteria for a normal
  response.
• Not an FDA approved indication as a diagnostic
  for AI.
• Additional studies are needed to confirm its
  usefulness as a diagnostic test for adrenal
  insufficiency.

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Risk Factors For HPA Axis Suppression with
Topically Administered Corticosteriods

• Variable individual susceptibility and time to
  recovery.
• Risk Factors
• steroid properties
• potency
• half-life
• vehicle (e.g. cream, lotion, ointment)

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Risk Factors For HPA Axis Suppression with
Topically Administered Corticosteriods

• extent of absorption
• increased
• thin stratum corneum
• heat and moisture (enhanced by occlusion)
• abraded or inflamed skin
• dose
• concentration
• body surface area exposed
• contact time

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Risk Factors For HPA Axis Suppression with
Topically Administered Corticosteriods

• cumulative dose
• dosing interval
• duration of treatment

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Summary 1

• Topical corticosteroids are systemically
  absorbed, thereby secondary adrenal insufficiency
  may occur.
• Symptoms of AI may be subtle and non-specific.
• Diagnosis may not be suspected clinically or
  attribution is made to other causes.
• Patients with secondary AI are at risk for an
  acute adrenal crisis, regardless of the degree of
  suppression or the presence of symptoms.
• Acute adrenal crisis is preventable if
  supplemental glucocorticoids are administered
  before or early in the course of stress.

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Summary 2

• Although risk factors for HPA axis suppression
  may be present, individual susceptibility is
  variable.
• Hormonal testing is required for diagnosis.
• Basal hormonal tests are often non-diagnostic.
• Dynamic hormonal testing is generally required.
• Dynamic tests of HPA axis integrity are more
  sensitive for the diagnosis of mild or
  recent-onset secondary AI than tests which
  measure only adrenocortical reserve.

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Summary 3

• A negative high-dose cosyntropin test may warrant
  additional testing particularly if the patient is
  symptomatic or if there is a high index of
  clinical suspicion of secondary adrenal
  insufficiency.
• When HPA axis suppression is diagnosed, treatment
  should follow standard medical practice.
• Patients should be followed to document full
  recovery of the HPA axis.