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Causes of central adrenal insufficiency in children

Causes of central adrenal insufficiency in children
Condition Comments
Transient central adrenal insufficiency (due to pituitary or hypothalamic suppression)*
Cessation of chronic high-dose glucocorticoid therapy Most common cause of central adrenal insufficiency. These drugs reversibly suppress the hypothalamic-pituitary-adrenal axis.
After cure of Cushing syndrome
  • Resection of an adrenal cortisol-secreting tumor
  • Resection of an ACTH-secreting tumor
 Elevated concentrations of cortisol suppress hypothalamic production of CRH, which, in turn, inhibits ACTH production from corticotroph cells.
Medications
  • Megestrol acetate (Megace) therapy
 A high-dose progestin with glucocorticoid activity[1]. Adrenal insufficiency may occur during therapy or upon withdrawal.
  • Chronic opioid use
 Related to cumulative opioid dose[2].
  • Mifepristone
 Anti-progestational agent and glucocorticoid receptor antagonist.
  • Antipsychotics (eg, chlorpromazine); antidepressants (imipramine)
 Inhibit glucocorticoid-induced gene transcription.
  • Etomidate
 Possible central effect[3].
  • Immune checkpoint inhibitors (CTLA4 blockade)
 Hypophysitis; hypopituitarism[4].
Anorexia nervosa Adrenal insufficiency is rare, although some hypothalamic dysfunction is common.
Critical illness-related corticosteroid insufficiency (CIRCI) CIRCI has characteristics of central adrenal insufficiency, with complex dysregulation of the HPA axis[5]. CIRCI also involves primary adrenal dysfunction and tissue corticosteroid resistance.
Permanent central adrenal insufficiency (due to pituitary and/or hypothalamic dysfunction)
Congenital
Brain malformationsΔ
  • Optic nerve hypoplasia/septo-optic dysplasia (eg, HESX1, other mutations)
  • Other brain malformations, especially with midline and/or craniofacial defects
 Optic nerve hypoplasia is associated with a variety of CNS and endocrine abnormalities, some with syndromic features.
Syndromes with hypothalamic dysfunction
  • Prader-Willi syndrome
  • ROHHAD syndrome
  
Genetic causes of pituitary hormone deficiencies Variable phenotypes, with single or multiple pituitary hormone deficiencies including ACTH deficiency, with variable order of onset and variable severity[6,7].
Acquired
Brain lesion or injuryΔ
  • Brain tumor
  • Brain hemorrhage
  • Brain trauma or surgery
  • Cranial irradiation
 Multiple pituitary hormones may be affected (GH, LH, FSH, TSH, ACTH, and/or ADH). The most common deficits are GH, LH, and FSH, causing growth abnormalities and delayed puberty, respectively. However, these disorders also may be rarely associated with precocious puberty, the mechanism of which is unknown.
Infiltrative diseasesΔ
  • Iron overload (hemochromatosis, thalassemia)
  • Sarcoidosis
  • Langerhans cell histiocytosis

ACTH: adrenocorticotropic hormone; CRH: corticotropin-releasing hormone; CIRCI: critical illness-related corticosteroid insufficiency; HPA: hypothalamic-pituitary-adrenal; CNS: central nervous system; ROHHAD: rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation; CPHD: combined pituitary hormone deficiency; GH: growth hormone; LH: luteinizing hormone; FSH: follicle-stimulating hormone; TSH: thyroid-stimulating hormone; ADH: antidiuretic hormone (vasopressin).

* These disorders cause temporary isolated ACTH deficiency due to suppression of hypothalamic CRH secretion.

¶ Refer to UpToDate content on causes of secondary and tertiary adrenal insufficiency in adults.

Δ These brain disorders may cause adrenal insufficiency by interfering with pituitary ACTH secretion (secondary adrenal insufficiency) or with hypothalamic CRH secretion (tertiary adrenal insufficiency).
References:
  1. Li T, Cunningham JL, Gilliam WP, et al. Prevalence of Opioid-Induced Adrenal Insufficiency in Patients Taking Chronic Opioids. J Clin Endocrinol Metab 2020; 105:e3766.
  2. Mann M, Koller E, Murgo A, et al. Glucocorticoidlike activity of megestrol. A summary of Food and Drug Administration experience and a review of the literature. Arch Intern Med 1997; 157:1651.
  3. Molenaar N, Bijkerk RM, Beishuizen A, et al. Steroidogenesis in the adrenal dysfunction of critical illness: impact of etomidate. Crit Care 2012; 16:R121.
  4. Wright JJ, Powers AC, Johnson DB. Endocrine toxicities of immune checkpoint inhibitors. Nat Rev Endocrinol 2021; 17:389.
  5. Annane D, Pastores SM, Arlt W, et al. Critical illness-related corticosteroid insufficiency (CIRCI): a narrative review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM). Intensive Care Med 2017; 43:1781.
  6. Patti G, Guzzeti C, Di Iorgi N, et al. Central adrenal insufficiency in children and adolescents. Best Pract Res Clin Endocrinol Metab 2018; 32:425.
  7. Bosch I Ara L, Katugampola H, Dattani MT. Congenital Hypopituitarism During the Neonatal Period: Epidemiology, Pathogenesis, Therapeutic Options, and Outcome. Front Pediatr 2020; 8:600962.
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