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

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

Hypothalamus: CRH Pituitary: ACTH Adrenal: Cortisol

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

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

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

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

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

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

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

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)

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

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.

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)

Hypothalamus: CRH Pituitary: ACTH Adrenal: Cortisol

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

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

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.

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.

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)

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.

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.

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.

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.

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

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.

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)

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

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

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.

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.

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.