Corticotropin-Releasing Hormone Testing in Assessment of Hypothalamic-Pituitary-Adrenal Axis Function in Infants with Congenital Central Hypothyroidism
The ACTH deficiency in neonates with multiple pituitary hormone deficiencies (MPHDs) results in sustained hypoglycemia and neuroglycopenia and is a major cause of morbidity and mortality. Under basal conditions, clinical signs of hypothalamus-pituitary-adrenocortex (HPA) axis dysfunction are usually absent and the HPA axis is probably the most difficult to assess in the neonate. For the assessment of HPA axis function in the neonate the corticotropin-releasing hormone (CRH) test (in which both the ACTH secretion by the pituitary gland and the subsequent cortisol secretion by the adrenal cortex can be evaluated) was considered as the most relevant choice. The overall aim of the study by van Tijn and colleagues was to develop a diagnostic workup for fast and reliable assessment of HPA axis function in neonates with congenital hypothyroidism of central origin (CH-C), detected by neonatal screening.
This was a Dutch nationwide prospective study (enrollment 1994–1996). Patients were included if neonatal CH screening results were indicative of CH-C and HPA axis function could be tested within 6 months of birth. Nine male and 3 female infants with CH-C and 4 infants with false-positive screening results or transient hypothyroidism were included in the study.
The assessment of HPA axis function was based on CRH and ACTH tests, multiple random plasma cortisol samples taken in the 24-hour period between thyrotropin-releasing hormone (TRH) and CRH tests, determination of cortisol excretion in 24-hour urine samples collected during this same interval, and long-term follow-up. For each patient the results of all endocrine examinations, including the other hypothalamic-pituitary axes, in combination with the results of cerebral MRI, added up to profiles on which overall diagnoses of HPA function were based. Diagnoses were reevaluated after 5 and 10 year follow-up (false positives, 3 to 5 year follow-up).
Of the 12 CH-C patients included in the overall analysis, 3 showed diminished peak responses to CRH of both ACTH and cortisol (subjects 1–3). In addition, their highest measured random plasma cortisol concentrations and 24-hour urine cortisol excretions were below the predefined cutoffs. Another 4 infants (subjects 4–6 and 12) showed adequate ACTH peak response, but diminished cortisol peak response. This discordant response was considered abnormal. All 4 subjects with false-positive screening results included in the overall analysis were diagnosed as having sufficient HPA axis.
The CRH test proved to be a fast and reliable tool in the assessment of HPA axis dysfunction in asymptomatic neonates at risk for serious morbidity and mortality when congenital hypothyroidism had been detected. The discordant response type with normal ACTH, but low cortisol response, which has not been described before, may be an early phase of HPA axis dysfunction. A prolonged follow-up until the age of 10 years in some patients confirmed the neonatal diagnosis and the choice of early hydrocortisone replacement therapy.
van Tijn DA, de Vijlder JJ, Vulsma T. Role of corticotropin-releasing hormone testing in assessment of hypothalamic-pituitary-adrenal axis function in infants with congenital central hypothyroidism. J Clin Endocrinol Metab. 2008;93:3794-3803.
The cortisol peak response to CRH is the most valuable marker of HPA axis function. Ten years of follow-up have shown that it has the highest predictive value of all criteria evaluated in this study. In neonates with hypoglycemia and/or persistent jaundice, HPA deficiency can be suspected. However in the most cases there is no clinical indicator to avoid the high risk of death in early MPH deficiency. With the background provided by neonatal screening for hypothyroidism as suggested by the Dutch set-up1 the CRH test appears to be the most valuable tool for early diagnosis of HPA axis dysfunction and for hydrocortisone treatment. As already known, hypothalamic-pituitary MRI would show in a large proportion of these cases; the most significant developmental abnormalities would be an ectopic posterior pituitary.
Raphaël Rappaport, MD
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