Regular articleWorking memory performance is reduced in children with congenital adrenal hyperplasia
Introduction
Classic congenital adrenal hyperplasia (CAH) is an autosomal recessive condition caused by an enzymatic deficiency. In over 90% of cases, the deficient enzyme is 21-hydroxylase, and this deficiency results in low levels of the glucocorticoid cortisol and in high levels of adrenal androgens, including testosterone, starting at about the seventh week of gestation (Merke and Bornstein, 2005, Speiser and White, 2003, White and Speiser, 2000). Androgen excess during the prenatal period causes genital ambiguity in newborn females with CAH. Management for both male and female patients includes treatment with glucocorticoids postnatally to normalize hormone concentrations (Speiser et al., 2010). Despite this treatment, postnatal glucocorticoid or androgen concentrations may be abnormal, for example, because of delayed diagnosis and treatment, or because of over- or under-treatment with glucocorticoids (Auchus and Arlt, 2013, Debono et al., 2009, Li et al., 2003, White and Speiser, 2000).
Girls and women with classic CAH have been found to show some behavioral masculinization, similar to that seen following experimental manipulations of androgens in other species (Collaer and Hines, 1995, Schwarz and McCarthy, 2008). For example, girls with CAH show increased male-typical childhood play behavior (Berenbaum and Hines, 1992, Hines, 2011, Hines et al., 2004, Pasterski et al., 2005, Pasterski et al., 2007, Pasterski et al., 2011), and women with CAH show increased interest in male-typical occupations and reduced heterosexual interests (Beltz et al., 2011, Hines, 2011, Hines et al., 2004, Meyer-Bahlburg et al., 2008, Servin et al., 2003).
The potential impact of glucocorticoid abnormality on behavior in individuals with CAH is relatively unexplored. However, glucocorticoids have been shown to have potent neurobehavioral influences, particularly in relation to learning and memory (Dominique et al., 2000, Kukolja et al., 2011, Lupien and McEwen, 1997, Lupien et al., 2002, Rimmele et al., 2013, Tollenaar et al., 2009). Research using rodents and non-human primates shows that the hippocampus, a neural region implicated in memory, is influenced by glucocorticoids during critical periods of early development (Matthews, 2001). In addition, experimentally lowering or elevating glucocorticoid levels in adult rats can cause hippocampal atrophy and memory impairments (Herbert et al., 2006, McEwen and Sapolsky, 1995).
In humans, memory deficits have been found in clinical conditions characterized by prolonged exposure to elevated glucocorticoids, such as Cushing syndrome (for a review, see Sapolsky, 2000) and in individuals receiving glucocorticoid treatment (Lupien et al., 2007, Stuart et al., 2005). In healthy adults, glucocorticoid manipulations have also been found to influence memory, particularly working memory—the short-term storage and manipulation of information (Baddeley, 1992). For example, men treated with a high dose of hydrocortisone show impaired working memory, assessed using an item-recognition working memory task (Lupien et al., 1999). Stress-induced increases in cortisol also have been associated with impaired high-load working memory performance (Oei et al., 2006).
Although glucocorticoid administration may not affect all working memory-related tasks (Vaz et al., 2011), one working memory task that has been found to be influenced in a number of studies is Digit Span, a task that requires the recall and recitation of strings of numbers both forwards and backwards. Studies of healthy young men have found impaired Digit Span performance following treatment-induced glucocorticoid elevations (Vaz et al., 2011, Wolf et al., 2001), as well as following stress-induced glucocorticoid elevations (Schoofs et al., 2009). Another study found similar impairment following stress-induced glucocorticoid elevations in both men and women who showed strong adrenergic activation following stress (Elzinga and Roelofs, 2005). Thus, research in humans, as well as in non-human animals, suggests that exposure to abnormal glucocorticoid levels, particularly glucocorticoid excess, can have a detrimental impact on working memory.
Given the evidence that glucocorticoids can influence working memory, particularly Digit Span performance, altered performance in the Digit Span test might be hypothesized in individuals with CAH. In the current study, we investigated Digit Span performance in children with CAH and in their unaffected relatives, who served as controls. We tested the hypothesis that Digit Span performance is reduced in children with CAH. Children were also given a test to assess their Vocabulary. This measure has not been related to glucocorticoid exposure, so was used as a control measure and was not anticipated to show group differences.
Section snippets
Subjects
A total of 107 children were studied, aged 7 to 11 years—57 with classical CAH (26 boys, 31 girls) and 50 unaffected siblings and cousins (20 boys, 30 girls) who served as controls. Table 1 shows the means (Ms) and standard deviations (SDs) of the ages for the four groups of children (boys and girls with CAH and control boys and girls). These children were part of a larger study designed to investigate gender-related behavior in 4–11 year old children with CAH. The Digit Span test was the only
Initial analyses
Data for age, Vocabulary and Digit Span for the full sample are shown in Table 1. Two-way (diagnosis × sex) ANOVAs on age and Vocabulary scores showed no significant main effects or interactions, indicating no significant group differences in age or Vocabulary (Table 1). Correlations of age and Vocabulary with each of the task components showed that age did not correlate significantly with DSF, r = .15, p = .120, but age did correlate significantly and positively with DSB, r = .19, p = .046, and DSC, r =
Discussion
Children with CAH, regardless of sex, showed significantly reduced performance compared to controls on DSF, DSB and DSC, with effect sizes of 0.57, 0.53 and 0.70, respectively. No group differences were seen in performance on the control measure of verbal intelligence, Vocabulary. Prior research also has found that verbal intelligence, and intelligence in general, is not altered in individuals with CAH as compared to their unaffected relatives (Berenbaum et al., 2010). Thus, our sample seems
Summary and conclusions
Our research suggests that children with CAH show reduced working memory as assessed with the Digit Span test. Future research could assess other aspects of working memory, in addition to Digit Span, as well as other cognitive abilities that relate to working memory, to assess the extent and implications of the current findings. Postnatal glucocorticoid excess appears to be the most likely explanation for the reduced working memory performance, although glucocorticoid insufficiency or the
Declaration of interest
The authors have nothing to disclose and there are no conflicts of interest.
Role of funding source
This research was supported by the United States Public Health Service, NIH HD24542 to Melissa Hines. The grant provided the funding for the research project.
Acknowledgments
We thank the families whose participation made this research possible, and the Congenital Adrenal Hyperplasia (CAH) Support Group in the UK for help with participant recruitment. Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under award number R01HD024542. The content is solely the responsibility of the authors and does not necessarily represent the official views of
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