ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Clin Endocrinol Metab. 2018;103(4):1330-1341

Glucocorticoids exert an inverted U-shaped influence on human cognition, particularly on acquiring and consolidating memory (25), whereas androgens have an overall beneficial effect on cognitive control, verbal memory, and spatial cognition in humans (26). Although previous studies in patients with CAH have consistently identified impairments in short-term and working memory performance, thought to relate to excess glucocorticoid exposure, the relationship between these cognitive abnormalities and changes in brain structure has not previously been investigated.

Here, the authors hypothesized that neural abnormalities would correlate with cognitive performance and that increased glucocorticoid exposure would be associated with poorer performance on neuropsychometric tests and reductions in neural volumes, FA, and total choline. Using multiple quantitative imaging modalities in conjunction with neuropsychological assessment enabled them to identify functionally significant biomarkers of the disease process (CAH) and treatment effects (steroid exposure) in patients with CAH. Patients had global abnormalities of cerebral white matter, with localized reductions in neural volumes in regions of the brain that have previously been documented to contain high concentrations of androgen, mineralocorticoid, and glucocorticoid receptors (25). The mesial temporal lobe was affected bilaterally, with significant reductions in white matter microstructure, right hippocampal volume, and left mesial temporal lobe choline. Interestingly, although markers of androgen exposure did not relate to the identified CNS abnormalities, exposure to higher glucocorticoid doses was associated with significantly worse cognitive performance and abnormal mesial temporal lobe total choline and white matter mean diffusivity. These findings demonstrated that CAH has a profound impact on normal brain and cognitive development, with the effects we describe most marked in the mesial temporal lobe. There is also a significant association between current glucocorticoid replacement regimens and cognitive and CNS abnormalities.

The recent development of more physiological glucocorticoid replacement regimens and other modalities that offer improved control of altered steroidogenesis in CAH may provide opportunities to use the biomarkers identified in the current study (mean diffusivity, mesial temporal lobe total choline) to assess the impact treatments on the CNS in patients with CAH. These findings are also relevant to the wider population, of whom 1% are on long-term glucocorticoid therapy (27).

25. Lupien SJ, McEwen BS. The acute effects of corticosteroids on cognition: integration of animal and human model studies. Brain Res Brain Res Rev. 1997; 24(1): 1–27.

26. Berenbaum SA, Beltz AM. Sexual differentiation of human behavior: effects of prenatal and pubertal organizational hormones. Front Neuroendocrinol. 2011; 32(2): 183–200.

27. Fardet L, Petersen I, Nazareth I. Prevalence of long-term oral glucocorticoid prescriptions in the UK over the past 20 years. Rheumatology (Oxford). 2011; 50(11): 1982–1990.