Table 3.

Studies Which have Investigated Cortisol in Autism Spectrum Disorder

Cortisol in autism spectrum disorders
Authors	Sample	Study aims	Main findings
Brosnan et al. [2009]	All male and aged between 11 and 16 years and medication free	To investigate cortisol awakening response (CAR) magnitude over 2 days in 20 adolescent males with Asperger Syndrome (AS) from an institutional setting compared to 18 typically developing (TD) youth from the community.	While a significant CAR was evidenced in the TD control group (28%), this was not the case for those with AS (where CAR was only seen in 5%). In both groups, there was evidence of a normal diurnal decrease in cortisol.
Corbett et al. [2008]	Circadian rhythms of cortisol were estimated in 22 children with and 22 children without autism via analysis of salivary samples collected in the morning, afternoon, and evening over 6 separate days. The 44 subjects were predominantly male children between 6.5 years and 12 years of age (mean age 9.08 y), 22 of whom were diagnosed with autism (1 female child) according to a strict diagnosis and 22 of whom were neurotypical children (3 female children).	To replicate and extend their previous findings showing variable circadian rhythm and significant elevations in cortisol following exposure to a novel stimulus (mock magnetic resonance imaging [MRI]).	In children with ASD, a flattening of the diurnal slope over time was found in which morning cortisol levels are diminished and evening cortisol levels are elevated.
Corbett et al. [2009]	44 predominantly male children between 6‐years and 12‐years of age (mean age 9.08 years), 22 diagnosed with autism (1 female) and 22 neurotypical children (3 females).	To investigate plausible explanatory factors which may contribute to the variability in limbic hypothalamic pituitary adrenocortical (LHPA) regulation and responsivity in children with autism.	Diminishing morning cortisol was associated with sensory sensitivity and elevated evening cortisol levels were associated with poor adaptation to changes.
Corbett and Schupp [2014]	94 prepubertal male children between eight and 12 years with ASD (n = 46) and typical development (TD, n = 48)	Over three diurnal cycles, salivary samples were collected involving two morning samples: M1: Immediately upon Waking and M2: 30‐min Post Waking (M2−M1 = cortisol awakening response (CAR).	Findings revealed no significant differences, over the three days of testing, on the CAR between the groups based on magnitude, variability or the sequence. Whether the child or adult criterion was used, there were still no significant differences in the proportion of children exhibiting a CAR across the groups. So in sum, although there are differences in the regulation and responsivity of cortisol between the individuals with ASD and those without, there are no differences in the CAR between the groups.
Lydon et al. [2015]	61 children and adolescents with a diagnosis of ASD (age range from 3 to 18 years).	To investigate the relationship between a parent‐reported measure of stress, a physiological measure of stress (diurnal salivary cortisol) and a variety of topographies of challenging behavior in 61 children and adolescents with a diagnosis of ASD.	The findings indicated that there are comparable levels of stress present among children with ASD and their typically developing peers. However, for a subset of the children with ASD, stereotyped behavior may be an indicator of elevated levels of cortisol.
Tordjman et al. [2014]	55 low‐functioning children and adolescents with ASD (11.3 ± 4.1 years‐old) and 32 typically developing controls (11.7 ± 4.9 years‐old) who were age‐, sex‐, and puberty state‐matched.	To investigate cortisol levels in 55 low‐functioning children and adolescents with ASD (11.3 ± 4.1 years‐old) and 32 typically developing controls (11.7 ± 4.9 years‐old) who were age‐, sex‐, and puberty state‐matched. The Autism Diagnostic Observation Schedule (ADOS) was used to conduct behavioral assessment and salivary samples to measure levels of cortisol were collected over 24 hr.	Significantly higher levels of salivary cortisol were exhibited at all time‐points in the individuals with ASD. Compared to the typically developing control group, individuals with ASD also exhibited greater variances of salivary and urinary cortisol. A significant association was also found between salivary cortisol levels and impairments in social interaction and verbal language. Similar levels of overnight urinary cortisol excretion were found between the two groups which suggests that there are not abnormalities in the functioning of the basal HPA axis in individuals with low‐functioning ASD.
Yang et al. [2015]	ASD (n = 35), mean age 10.63 (SD = 2.64) (28 males and 7 females) and controls (n = 32), mean age 11.19 (SD = 2.61) (25 males and 7 females).	To investigate diurnal variation of cortisol (cortisol VAR), interleukin‐6 (IL‐6) and tumor necrosis factor‐alpha (TNF‐a) in order to determine whether they may be clinically useful biomarkers for ASD.	Findings revealed that, compared to the healthy controls, individuals with ASD exhibited a lower level of cortisol VAR, higher level of IL‐6 and TNF‐a. There was a significant correlation between levels of cortisol VAR, IL‐6, and TNF‐a and severity of ASD symptoms as measured using CARS. Analysis showed that cortisol VAR, IL‐6, and TNF‐a are possible biomarkers for ASD and that when cortisol VAR, IL‐6, and TNF‐a are combined, they demonstrate the highest sensitivity and specificity for ASD.
Zinke et al. [2010]	15 children with high‐functioning autism (HFA) and 25 TD children (all aged between 6 and 12 years of age). Seven of the children with HFA had comorbid conditions and six were on medication.	To investigate the CAR over two days in 15 children with high‐functioning autism (HFA) and 25 TD children	Frequency of the CAR was similar between children with ASD and those without (80 vs. 88%, respectively). No significant differences based on the adult criterion [Wust et al., 2000] were exhibited in children with ASD compared to those without a diagnosis of ASD (73 vs. 84%, respectively).

SD, standard deviation; M, mean; CAR, cortisol awakening response; AS, Asperger's syndrome; TD, typically developing; VD, vitamin D; MRI, magnetic resonance imaging; ASD, autism spectrum disorders; LHPA, limbic hypothalamic pituitary adrenocortical; Cortisol VAR, variation of cortisol; IL‐6, interleukin‐6; TNF‐a, tumor necrosis factor‐alpha; HFA, high‐functioning autism.