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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 4 1760-1765
Copyright © 2003 by The Endocrine Society

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

Deborah P. Merke, Jeremy D. Fields, Margaret F. Keil, A. Catherine Vaituzis, George P. Chrousos and Jay N. Giedd

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.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
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.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CHILDREN WITH CLASSIC congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency are exposed prenatally to low cortisol and high androgens, whereas postnatally they may be exposed to excess exogenous glucocorticoids, a frequent complication of therapy (1, 2). In addition to impaired adrenocortical function, classic CAH is characterized by compromised adrenomedullary function (3). The effects of these multiple hormonal imbalances on the brain are unknown. However, prenatal masculinization of the brain has been suggested in girls with classic CAH based on psychological and behavioral testing (4).

The effect of glucocorticoid deficiency on the developing fetal brain is unknown, but elevation of corticotropin-releasing factor (CRF) is expected due to lack of normal feedback inhibition. The amygdala is important in the processing of emotion and the generation of fear (5), and glucocorticoids and CRH stimulate the amygdala (6, 7, 8). Androgens are also known to influence amygdala size and function (9, 10). The hippocampus plays an important role in memory and in the tonic inhibitory control of the hypothalamic-pituitary-adrenal (HPA) axis, whereas chronic hypercortisolemia has been shown to be associated with hippocampal damage in animals (11) and atrophy in adult patients with Cushing’s syndrome (12, 13).

We performed magnetic resonance imaging (MRI) of the brain on 27 children with classic CAH and 47 sex- and age-matched healthy subjects, and examined areas of the brain known to be affected by hormones of the HPA axis and androgens. The volumes of the cerebrum, ventricles, temporal lobe, hippocampus, and amygdala were quantified.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Twenty-seven children with classic CAH (11 females, aged 4–11 yr; 16 males, aged 6–16 yr) were studied. None of the patients with CAH was treated in utero with dexamethasone. Eighteen of the children with CAH were classified as salt-losers. The average age of onset of glucocorticoid therapy was 13 ± 13 d for the salt-losers (range, birth to 7 wk), and 3.2 ± 1.9 yr for the nonsalt-losers (range, birth to 5 yr). MRI of the brain of 47 healthy age- and sex-matched control subjects (13 females, aged 4–12 yr; 34 males, aged 5–17 yr) were obtained from an ongoing study of normal brain development (14) using subjects recruited from the community.

All subjects underwent physical and neurological examinations. Control subjects with physical, neurological, and personal or familial psychological abnormalities (one first degree relative or >20% of second degree relatives with psychiatric diagnosis) were excluded. Tanner staging of patients with CAH was determined by breast development (females) or testicular size (males) and by a self-administered questionnaire in control subjects (15).

The study was approved by the institutional review boards at the National Institute of Mental Health and the National Institute of Child Health and Human Development. Each parent gave written informed consent, and children over the age of 7 yr gave their assent.

Intelligence quotient (IQ) testing

Psychological evaluation included the 12 handedness items from the Physical and Neurological Examination for Subtle Signs inventory. The Wechsler Intelligence Scale for Children was administered to subjects under 16 yr of age. The Wechsler Adult Intelligence Scale was used to evaluate subjects 16 yr of age or older. Full scale IQ scores were prorated based on the Vocabulary and Block Design subtests of the Wechsler Intelligence Scales.

MRI

All subjects were scanned on the same GE 1.5 Tesla Signa scanner (General Electric Medical Systems, Milwaukee, WI). Axial slices, 1.5-mm thick, and coronal slices of 2 mm were used. Head positioning was standardized by assuring that the left lateral inferior orbital ridge and the meatus of each ear were coplanar within the axial plane and that the subject’s nose was placed in the 12 o’clock position.

All persons involved in the process of obtaining brain measurements were blinded to all subject characteristics, including age, sex, and diagnosis. The volumes of the cerebrum, ventricles, temporal lobe, hippocampus, and amygdala were quantified using techniques previously validated (14). Total cerebral volume was quantified using a semiautomated program that combines tissue classification based upon MRI voxel signal intensity with a probabilistic atlas to provide a priori knowledge of brain anatomy. Each axial slice of the brain was then edited by experienced raters to remove artifacts. Intraclass correlations for the volumes of the edited brains were 0.99 for interrater reliability.

Lateral ventricular volumes were measured in the coronal plane using an operator-supervised thresholding technique that segmented cerobrospinal fluid from brain tissue. This analysis was carried out using an image analysis program, NIH Image 1.61 (16). Interrater reliability was 0.97.

Measurements of the temporal lobe, amygdala, and hippocampus were made by manually tracing in the coronal plane by a single experienced operator (J.D.F.) who was blind to any subject characteristics (Fig. 1Go). Because even at a histological level, precise delineation of the amygdala/ hippocampal boundary can be difficult, the slice containing the most anterior portions of the mamillary bodies was used to define the most anterior portion of the hippocampus (inclusive) (17, 18). Reliabilities for the quantification of each of the structures were established by having 2 raters (A.C.V. and J.D.F.) initially measure 10 subjects twice to determine interrater intraclass correlation coefficients (ICCs). After completion of image analysis for the study, ten previously measured subjects were remeasured to account for possible drifts in rater assessment and establish intrarater ICCs. Interrater ICCs were 0.96 for the temporal lobe, 0.84 for the amygdala, and 0.87 for the hippocampus, and intrarater ICCs were 0.99 for the temporal lobe, 0.86 for the amygdala, and 0.80 for the hippocampus.



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  		Figure 1. Boundaries for measurements of the amygdala and hippocampus.

 
Statistical analysis

Data were analyzed separately for males and females. Comparisons between the two groups were performed using the two-sample two-sided t test or Fisher’s exact test. The relationship between amygdala volume and age between and within the two groups was investigated by analysis of covariance and linear regression analysis. Values are expressed as the mean ± SD unless otherwise specified.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Clinical and psychological findings

There were no significant differences between children with classic CAH and the healthy control group with respect to age, height, weight, pubertal stage, percent right-handedness, and IQ (Table 1Go). Both children with CAH and the control children had above average prorated Wechsler Full Scale IQs (Table 1Go).


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  		Table 1. Characteristics of 27 children with classic CAH and 47 sex- and age-matched controls

 
At the time of evaluation, bone age was advanced by 2 yr or more in nine patients with CAH (eight boys and one girl), reflecting significant past exposure to excess sex steroids. Eighteen patients had a bone age within 2 SD units from their chronological age, and no patient had a significantly delayed bone age. The average hydrocortisone dose was 14.6 ± 6.4 mg/m2·d.

MRI findings

Total cerebral volumes and temporal lobe volumes were comparable between children with CAH and control subjects (Table 2Go). However, there was a trend toward decreased cerebral volumes in girls with CAH (P = 0.07). There were no differences in ventricular volumes between CAH patients and controls.


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  		Table 2. Cerebral volumes in children with CAH and sex- and age-matched controls by gender (mean ± SEM)

 
A decrease in total amygdala volume was observed for both boys (P = 0.01) and girls (P = 0.002) with CAH compared with age- and sex-matched controls (Table 2Go). This difference remained significant when adjusted for total brain volume (P = 0.03) and was present across all ages (Fig. 2Go). A decrease in amygdala volume was observed bilaterally in girls with CAH compared with controls, but the significant decrease in amygdala volume was significant on the left only for boys. Overall, the left mean amygdala volume of boys and girls with CAH was approximately 20% smaller than the left mean amygdala volume of age- and sex-matched control subjects (Table 2Go).



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  		Figure 2. Left and right amygdala volumes for children with CAH ({square}) and age-matched controls ({blacksquare}) in relation to age and gender. Linear regression curves are displayed for children with CAH (dashed lines) and age-matched controls (solid lines). A maturational increase in the volume of the amygdala was observed in boys (A and C).

 
A maturational increase in the volume of the amygdala was observed in boys only and was most significant in the normal controls (Fig. 2Go). This progressive increase in the volume of the amygdala was observed bilaterally in male controls (left, P = 0.009; right, P < 0.001), but only in the right amygdala of boys with CAH (P = 0.025), and was absent in females. All observed differences in amygdala volume between patients with CAH and control subjects remained significant after adjusting for the effect of age.

In contrast to the amygdala, no absolute difference in total, left, or right hippocampal volume was observed in either boys or girls with CAH compared with control subjects (P > 0.4). Overall, hippocampal volume was very similar (difference within 5%) in children with CAH and controls. Given our sample size and the variability of our hippocampal measurements, our power to detect a 10% difference in hippocampal size between our control and CAH groups was 81% for boys and 64% for girls. Moreover, there was no significant trend in hippocampal volume with age in controls or patients with CAH.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We found that children with classic 21-hydroxylase deficiency have smaller amygdala volumes compared with age- and sex-matched healthy children, and this difference was independent of gender. In this population of children with adrenal insufficiency, obvious iatrogenic effects on the brain due to glucocorticoid therapy were not observed.

In our study the children with classic CAH had above-average intelligence. This most likely was the result of a sampling bias and reflects the population seen at our institution. Most importantly, this above-average intelligence was also observed in our healthy controls. Cognition has been studied in patients with CAH with inconclusive findings (4). Patients with CAH have been reported to have higher than average intelligence (19), although similar to that of their unaffected siblings (20), whereas lower than average intelligence has also been reported in CAH (21, 22).

The majority of psychological and behavioral studies of patients with CAH have focused on possible androgen effects on the brain. Compared with their unaffected sisters, girls with CAH have more male-typical childhood play (23, 24, 25), are more likely to report the use of physical aggression (26), score lower on measures related to empathy (27), and have better spatial abilities (28, 29). These findings have been suggested to be due to excess androgen effects on the developing brain. The children in our study were not evaluated for male-typical behavior.

Structural differences between the brains of men and women (10, 30) have been interpreted as evidence that behavioral differences between these groups are probably due to hormonal differences in early development of the brain. The amygdala is one area of the brain that has sexual dimorphism; it is larger in adult men than women (10). Little is known regarding the sexual dimorphism of the human brain anatomy during childhood, a time of emerging sex differences in behavior and the sexually specific hormonal changes of puberty. However, a maturational increase in the volume of the amygdala has been observed in healthy boys, but not girls (31), suggesting an androgen effect on the brain. Moreover, animal studies have shown androgen effects on the amygdala (32, 33), including identifying the amygdala as a critical region for the actions of androgens in influencing masculinized social behavior (34). Androgen manipulation has also been shown to alter the size of the amygdala in rats, which is typically larger in males than in females (35). In our study we observed a maturational increase in the volume of the amygdala in boys only. This trend was most significant in the control group and corresponded to their pubertal development. This pubertal increase in the size of the amygdala was less significant in the boys with CAH, possibly due to previous prepubertal adrenal androgen exposure or other unknown factors. CAH girls’ brains did not have male-specific characteristics, but, rather, both boys and girls with CAH had a smaller amygdala volume compared with their healthy counterparts. This contrasts with the expected increase in amygdala size due to excess androgen exposure.

White matter abnormalities on MRI images have been previously reported in children with CAH (36, 37), possibly due to glucocorticoid therapy. Children with CAH often require supraphysiological doses of glucocorticoid to adequately suppress adrenal androgen production (1, 2). Prolonged exposure to glucocorticoids has been shown to have adverse effects on the hippocampus (12). The hippocampal formation plays an important role in learning and memory, is involved in the fine-tuning of the HPA axis by participating in glucocorticoid negative feedback, and contains the highest concentration of corticosteroid-binding sites in the entire brain (38). Animal studies (11) and human studies of adult patients with chronic hypercortisolemia (12) have shown that prolonged exposure to glucocorticoid excess results in hippocampal atrophy and memory dysfunction. Hippocampal atrophy has also been described in neuropsychiatric diseases associated with hypersecretion of glucocorticoids, such as severe depression (39, 40, 41). Our children with CAH had hippocampal volumes very similar to the controls.

CAH is a genetic disease where there is a block in cortisol production. Therefore, affected fetuses are glucocorticoid deficient, and an overall elevation of CRF is expected due to the lack of feedback inhibition. Similarly, hyperactivity of the hypothalamic-pituitary corticotroph axis has been suggested in the 21-hydroxylase-deficient mouse (42). On the other hand, CRF generated in the central nucleus of the amygdala is glucocorticoid inducible, revealing a positive feedback effect of the HPA axis on the amygdala (43). CRF and CRF-binding sites in the brain and pituitary appear prenatally and are present in the human fetus at 12–13 wk gestation (44), whereas ACTH can be detected as early as 7 wk (45). At 26 wk gestation, the concentration of ACTH in the fetus corresponds to levels seen in full-term newborn infants, reflecting early maturity of the HPA axis (46).

CRF is the prime regulator of the endocrine stress response, and CRF hypersecretion has been associated with several neuropsychiatric diseases, such as depression (47, 48, 49), anxiety (50), and anorexia nervosa (51, 52). Exposure to early adverse events, such as child abuse or child neglect, has been shown to result in hypersecretion of CRF and persistent alterations in the HPA axis (53, 54, 55). The increased vulnerability to stress-related psychiatric disorders observed in people exposed to early life stresses may be mediated by alterations in CRF secretion and persistent sensitization of the HPA axis (56). The effect of CRF hypersecretion due to a genetic condition, such as CAH, rather than an environmental cause, such as abuse, is unknown.

The amygdala plays a central role in processing emotion (5), and CRF mRNA has been found in the amygdala (57). Changes in amygdala function have been implicated in the pathophysiology of adult anxiety and depressive disorders (48, 58, 59). Amygdala function has also been shown to be affected in both anxiety and depression during childhood and adolescence (60). Selective disease of the amygdala can yield deficits in the ability to judge and to correctly link emotion to thought (61), whereas the level of impairment of emotional memory in patients with Alzheimer’s is related to the intensity of amygdala damage (62). The left amygdala has also been implicated as having a more dominant role than the right amygdala (61, 63). The smaller amygdala volumes we observed in patients with CAH were most significant on the left. The functional implications of these findings are unknown.

Our findings suggest that prenatal glucocorticoid deficiency, excess adrenal sex steroids, or both affect the growth and development of the amygdala. The exact hormone responsible for the observation of a smaller than expected amygdala size in both boys and girls with classic CAH is unknown, but may include excess androgens, estrogens, or progestins; endogenous deficiency or exogenous excess of glucocorticoids; or some combination of these. Further psychological and functional studies in patients with endocrine disorders are needed to elucidate the effect of prenatal and postnatal hormone exposure on the brain and to evaluate the clinical implications of differences in the amygdala structure of patients with CAH.


   Acknowledgments
 
We thank the patients and their families for participation in this study, Ms. Donna Peterson for assistance with data management, Ms. Erin Rawson for help with manuscript preparation, and Dr. Robert Wesley for assistance with statistical analysis.


   Footnotes
 
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.

Received November 6, 2002.

Accepted January 15, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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