The present study found higher level of cortisol excretion in autistic children (LFA and MFA) than in the control group. Children with typical development showed a significantly lower cortisol excretion at noon time than LFA group.
The HPA axis, like most biological systems, is highly regulated and dependent on the ability of the system to maintain, respond to, and reset itself for homeostasis. Dysregulation of the HPA axis may manifest as disruptions in circadian rhythms, which in turn are represented by the pulsatile release of cortisol (24
). A study in children with autism showed alterations in the normal circadian patterns of cortisol (25
). The value of urinary free cortisol in assessing of adrenocortical function was first pointed out by Cope (26
), who found that it detected increased adrenocortical function. Other studies also confirmed that an increase in the plasma concentration of free cortisol was accompanied by a linear increase in cortisol excretion in the urine (28
). Urinary free cortisol in 24-hour samples has been widely used to assess basal cortisol secretion and has the theoretical advantage of being unaffected by possible cortisol circadian rhythm differences.
Normal physiological rhythms are responsible for all behavioral variables, including sleep organization and propensity, subjective alertness, and cognitive performance, which are disturbed in autistic children. There is increasing evidence to support the role of the sleep-wake cycle and the endogenous circadian system in the pathogenesis of major psychiatric disorders (29
), and disturbed nocturnal sleep is a common observation among autistic children.
Our study also found a positive correlation between the elevated level of cortisol and the severity of autism. Cortisol secretion has earlier been shown to also markedly increase in response to stress, and autism has often been characterized as a disorder accompanied by increased arousal, stress, and sensory sensitivity (30
). It was also shown that more severe autism led to more abnormal diurnal rhythm (33
), which is in accordance with the present study.
Studies on major neurotransmitter systems (serotonin, catecholamine) strongly suggest that a major role in autism could be played by neurochemical factors (34
). In the present study, urinary vanilyl mandelic acid, a marker of catecholamine metabolic status, was significantly higher in autistic children than in control group, which may be related to frequent stressful situations to which autistic children are subjected. The increased response to stressors could be due to worse handling of stress, over-elicitation of the physiological response, or dysfunctional stress response systems (35
In this study, 5-hydroxyindoleacetic acid, a major metabolite of serotonin was significantly higher in LFA and MFA group and not significantly in HFA group than in the control group. Individuals with autism have been reported to have significantly higher serotonin (5-hydroxytryptamine) levels in whole blood and platelets (36
). Though a higher level of serotonin has been reported in the blood of autistic children (37
), the present study found significantly lower excretion level of 5-hydroxyindoleacetic acid in LFA and MFA group than in control group, which may be due to altered activity of monoamine oxidase, the enzyme responsible for oxidative deamination of serotonin to form the corresponding aldehyde, which is further oxidized to 5- hydroxyindoleacetic acid.
In the recent years, there has been a spate of research into the role of serotonin in neuropsychiatric conditions in childhood. Interestingly, Cohen et al (38
) have reported lower concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid in the cerebrospinal fluid in autistic than in non-autistic psychotic children. The interpretation of this finding is far from clear, however, neither group differed significantly from controls, whose concentration was between the autistic and psychotic group. Boullin et al (39
) reported increased serotonin efflux as a finding specific to autism, but this was not confirmed by Yuwiler et al (40
). Hence, the serotonin findings may well be important, but their meaning remains obscure. So far, attempts to relate serotonin concentration to clinical differences in autistic groups or groups with mental retardation have been rather disappointing (41
Along with metabolic and rhythmic disturbances, there is emerging evidence of the contributing role of abnormal fatty acid metabolism in the pathology of autism (42
). The present study showed a higher level of excretion of prostaglandin E2
in autistic children than in control group. There is evidence for increased prostaglandin metabolism in individuals with autism spectrum disorders (43
). Eicosanoids, particularly prostaglandin D2
are known to have sedative properties and to be involved in the control of the sleep-wake cycle (44
), which was disturbed in autistic children in the present study.
There are reports (42
) suggesting that fatty acid homeostasis may be altered in autism as a result of insufficient dietary supplementation, genetic defects, functional alteration of enzymes involved in their metabolism, or various environmental agents such as infections, inflammation, and drugs. Eicosanoids, derived from highly unsaturated fatty acids released from cell membranes by phospholipases and produced by cyclooxygenases, are required for normal functioning of synaptic junctions (45
). Thus, any abnormality in phospholipase activity could result in alteration in neuronal structure and functions. Docosa-hexenoic acid and other free fatty acids can modulate abnormal electrical discharges from neurons (46
) and a deficit of these fatty acids could increase susceptibility to epileptic seizures, which occurs in many patients with ASDs. In addition, the involvement of prostaglandin E2
signaling in early developmental process, including formation of dendritic spines and neuronal plasticity, is also emerging (47
A major limitation of our study is that we did not determine the blood and saliva levels of corticosteroids, free cortisol, vanilyl mandelic acid, 5- hydroxyindole acetic acid, and prostaglandin E2, which still remains to be done, preferably in a study involving a greater number of children. Abnormal physiological rhythm found in autistic children should also be further investigated.
This study found that abnormal function of the HPA axis, evidenced by abnormal pattern of cortisol excretion in autistic children, could be strongly correlated with the severity of the disorder. Further studies on the factors responsible for abnormal circadian rhythm are needed, be it a gene, environmental stimuli, or an enzyme defect.