1. Division of Pediatric Drug Development
Hypothalamic-Pituitary-Adrenal Axis Suppression Following Topical Corticosteroid Administration
Jean Temeck, M.D.
Medical Officer
Division of Pediatric Drug Development
FDA

2. 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

3. Hypothalamus:
CRH
Pituitary: ACTH
Adrenal:
Cortisol

4. 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

5. 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

6. 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

7. Abnormal Hormonal Test
HPA Axis Suppression
Abnormal Hormonal Test
HPA Axis Suppression
No Symptoms
Symptoms Present
Stress!
Stress!
At Risk for
ACUTE ADRENAL CRISIS !

8. 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

9. 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

10. 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

11. 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)

12. 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

13. 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.

14. 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)

15. Hypothalamus:
CRH
Pituitary: ACTH
Adrenal:
Cortisol

16. 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

17. High-Dose Cosyntropin Test
Most commonly used
Methodology:
administer supraphysiologic dose synthetic ACTH, IV or IM:
125 ug if <2 years
250 ug if >2 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

18. High-Dose Cosyntropin Test
Controversy regarding normal cortisol response:
criteria in cosyntropin label (30 minute test):
basal cortisol >5 ug/dl, increment > 7ug/dl, peak >18 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 >18ug/dl at 30 minutes.

19. 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.

20. 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)

21. Low-Dose vs. High-Dose Test
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 >18ug/dl at 30 minutes is generally accepted as a normal response.

22. 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 <40 mg/dl, plasma cortisol should rise to >18-20 ug/dl at 60 to 90 minutes post-insulin.

23. 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.

24. 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.

25. 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

26. 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.

27. 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)

28. 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

29. Risk Factors For HPA Axis Suppression with Topically Administered Corticosteriods
cumulative dose:
dosing interval
duration of treatment

30. 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.

31. 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.

32. 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.