1. Table 1. Serial low dose ACTH stimulation test results
Repeating ACTH stimulation test is necessary to diagnose ACTH deficiency in neonatal hypopituitarism with initial false negative result
Loyal K. Coshway, MD, Justin A. Indyk, MD, PhD, and Sasigarn A. Bowden, MD. Pediatric Endocrinology, Nationwide Children's Hospital, Columbus, Ohio, United States
Discussion
Background
Case 2
Term female infant evaluated at age 10 days for hypoglycemia.
Pituitary testing showed:
Normal peak cortisol on a low dose ACTH stimulation test
Abnormal thyroid function testing at age 16 days with low free T4 0.7 ng/dL ( ) and normal TSH 2.43 µIU/mL (0.9-10).
Abnormal growth hormone level of 2.8 ng/mL at the time of hypoglycemia.
Brain MRI revealed pituitary hypoplasia and ectopic posterior pituitary bright spot in the floor of 3rd ventricle (Figure 2a & 2b).
Both levothyroxine and growth hormone replacement were started.
Repeat cortisol level (8am) drawn at age 21 days was 1.1 µg/dL. Repeat ACTH stimulation test performed at age 22 days showed low baseline and peak cortisol. The patient was then started on hydrocortisone
In these 2 cases, robust cortisol response on initial ACTH stimulation test obtained on 9-10 days of life provided a falsely reassuring assessment of the hypothalamic-pituitary-adrenal axis.
Repeat testing showed inadequate response, necessitating adrenal replacement therapy.
Initial false-negative adrenal function test
Important to repeat ACTH stimulation testing in infants with congenital hypopituitarism for timely diagnosis of ACTH deficiency.
Adrenal reserve provided by upregulation of fetal steroidogenic enzymes by placental CRH and pro-opiomelanocortin is a possible mechanism for a high cortisol response on initial testing.
CRH directly induces transcription of fetal adrenal steroidogenic enzymes and cortisol production.
ACTH levels decline in late pregnancy although fetal steroidogenesis and adrenal growth increases, indicating the effect of CRH.
Majority of fetal CRH is derived from the placenta-- normal fetal adrenal maturation may occur even in infants with pituitary dysfunction.
We hypothesize that withdrawal of placental hormonal stimulation leads to adrenal atrophy and eventual failure of the low dose ACTH stimulation test in the neonatal period.
Low dose adrenocorticotropic hormone (ACTH) stimulation test has been the test of choice to evaluate adrenocortical function in neonates with suspected ACTH deficiency.
Limited data about its sensitivity in this age group.
Neonates are a unique population due to transitioning from the placental hormonal milieu to sole dependency on endogenous hormonal production after delivery
Placenta produces corticotropin releasing hormone (CRH) and pro-opiomelanocortin.
Methods
Case reports
ACTH low-dose stimulation test was done by giving 1 mcg of cosyntropin with baseline cortisol and post-cosyntropin cortisol levels .
Normal ACTH stimulation test was defined as stimulated cortisol value ≥ 18 μg/dL .
Table 1. Serial low dose ACTH stimulation test results
Patient 1
Patient 2
Age at first ACTH stimulation test
9 days
10 days
Baseline cortisol (μg/dL)
2.8
10.9
Stimulated Cortisol #1 (μg/dL)
36.2
26.9
Stimulated Cortisol #2 (μg/dL)
27.1
29.6
ACTH level (normal, 6-48 pg/mL) NA 11
Age at second ACTH stimulation test
2 months
3 weeks
<1
2.5
8.7
8.3
Stimulated Cortisol #3 (μg/dL)
5.9 26
Results
Case 1
Term female infant evaluated at age 9 days for hypernatremia
Diagnosed with diabetes insipidus and septo-optic dysplasia.
Pituitary testing showed
Normal peak cortisol on a low dose ACTH stimulation test
Normal thyroid function with free T4 1.1 ng/dL ( ) and TSH 2.52 µIU/mL (1-12)
Re-admitted at age 2 months for jaundice and hypoglycemia.
Repeat ACTH stimulation test showed low baseline cortisol and low peak cortisol with borderline low free T4 of 0.7 ng/dL (normal ) and normal TSH 3.4 µIU/mL (0.8-8). Growth hormone level of 5.8 ng/mL at the time of hypoglycemia was concerning for deficiency.
She was then started on hydrocortisone, levothyroxine, and growth hormone replacement.
Brain MRI showed absent pituitary bright spot (Figure 1).
References
Chakravorty A, Mesiano S, Jaffe R Corticotropin-Releasing Hormone Stimulates P450 17α-Hydroxylase/12,20-Lyase in Human Fetal Adrenal Cells via Protein Kinase C. JCEM. 84:
Mastorakos G and Ilias I Maternal and Fetal Hypothalamic-Pituitary-Adrenal Axes During Pregnancy and Postpartum. Ann NY Acad Sci. 997:
O’Grady M, Hensey C, Fallon M, Hoey H, Murphy N, Costigan C, Cody D Lack of Sensitivity of the 1-μg Low-Dose ACTH stimulation test in a paediatric population with suboptimal cortisol responses to insulin-induced hypoglycaemia. Clin Endocrinol (Oxf). 78:
Sirianni R, Rehman K, Carr B, Parker R, Rainey W Corticotropin-Releasing Hormone Directly Stimulates Cortisol and the Cortisol Biosynthetic Pathway in Human Fetal Adrenal Cells. JCEM. 90:
Smith R, Mesiano S, Chan EC, Brown S, Jaffe R Corticotropin-Releasing Hormone Directly and Preferentially Stimulates Dehydroepiandrosterone Sulfate Secretion by Human Fetal Adrenal Cortical Cells. JCEM. .83:
Thaler L, Blevins L The Low Dose (1-μg) Adrenocorticotropin Stimulation Test in the Evaluation of Patients with Suspected Central Adrenal Insufficiency. JCEM 83:
Figure 1. Brain MRI of Case 1 showed absent pituitary bright spot and large choroid plexus cyst
Figure 2a & 2b. Brain MRI of Case 2 showed pituitary hypoplasia and ectopic posterior pituitary bright spot in the floor of 3rd ventricle