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Children with Classic Congenital Adrenal Hyperplasia Have Decreased Amygdala Volume: Potential Prenatal and Postnatal Hormonal Effects

Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development (D.P.M., J.D.F., G.P.C.); The Warren Grant Magnuson Clinical Center (D.P.M.); and Child Psychiatry Branch, National Institute of Mental Health (A.C.V., J.N.G.), National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Deborah P. Merke, M.D., National Institutes of Health, Building 10, Room 13S260, 10 Center Drive, MSC 1932, Bethesda, Maryland 20892-1932.

Children with classic congenital adrenal hyperplasia (CAH) have multiple endocrine imbalances, including prenatal glucocorticoid and adrenomedullary deficiency and androgen excess, with possible postnatal iatrogenic glucocorticoid excess, hyperandrogenism, and adrenomedullary hypofunction. Prenatal masculinization of the brain has been suggested in girls with classic CAH. Hormones of the hypothalamic-pituitary-adrenal axis and sex hormones interact with extrahypothalamic regulatory centers of the brain, including the amygdala and hippocampus. The amygdala is important in the processing of emotion and generation of fear, whereas the hippocampus plays an important role in memory. Chronic hypercortisolemia has been shown to be associated with hippocampal damage, while glucocorticoids and corticotropin-releasing factor play a major role in the regulation of amygdala function. We performed magnetic resonance imaging of the brain on 27 children with classic CAH and 47 sex- and age-matched controls. Volumes of the cerebrum, ventricles, temporal lobe, amygdala, and hippocampus were quantified. Females with CAH did not have brains with male-specific characteristics. In contrast, a significant decrease in amygdala volume was observed in both males and females with CAH (males, P = 0.01; females, P = 0.002). Iatrogenic effects on the hippocampus due to glucocorticoid therapy were not observed in children with CAH. These results suggest that prenatal glucocorticoid deficiency with resulting alterations in hypothalamic-pituitary-adrenal axis regulation, sex steroid excess, or some combination of these preferentially affect the growth and development of the amygdala, a structure with major functional implications that warrant further exploration.

D.P.M. is a commissioned officer in the USPHS.

Abbreviations: CAH, Congenital adrenal hyperplasia; CRF, corticotropin-releasing factor; HPA, hypothalamic-pituitary-adrenal; ICC, intraclass correlation coefficient; IQ, intelligence quotient; MRI, magnetic resonance imaging.

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