The current study was designed to explore the cortisol level in ADHD children and their correlates to severity of symptoms and associated aggressive behaviors in those children.
The data about salivary cortisol reported in the current study indicates that ADHD subjects have statistically significant lower salivary cortisol (11.826 ng/ml) level when compared to age- and sex-matched control subjects (19.619 ng/ ml with P-value 0.001). This finding is controversial in different studies and we will elaborate some examples of those studies. Our results failed to find any correlation between severity of ADHD symptoms in the children of the case group with their salivary cortisol levels.
Three distinct reasons for the low levels of cortisol in ADHD children can hypothetically be established. First, they may demonstrate a diurnal curve that is displaced, indicating that at the normal time of the morning peak, maximum levels have either been passed or not reached. There is some support from a small-scale (no.= 13) research on adults for such a theory, indicating a phase delay in people with ADHD . In our study, the low morning levels can be explained by a late morning peak.
Second, an increase in the secretion of glucocorticoids due to environmental factors for example early childhood psychosocial adversity or perinatal stress is likely to have an adverse impact on the development of brain networks in genetically susceptible children, which may explain the dysregulation of the HPA axis resulting in deficits in arousal regulation and the development of externalizing symptoms of ADHD as a result. Third, certain genetic or environmental circumstances may lead to ADHD symptoms as well as low activity of the HPA axis .
Studies with similar results included Susman et al.  who originally observed a normal diurnal pattern of cortisol in only 43% of ADHD children, indicating that in most children with ADHD the HPA axis is dysregulated. In other studies, cortisol awakening response was found to be lower in ADHD children when compared to a control group [21, 22].
A study by Isaksson and his group in 2012 found that compared to non-affected comparisons, children with ADHD had significantly lower levels of salivary cortisol. ADHD drugs and gender did not affect the cortisol levels. Cortisol levels were not affected by the co-occurring symptoms or the ADHD subtype within their study population. The symptoms of ADHD severity degree in the study group was not correlated with cortisol levels .
Isaksson and colleagues  tested salivary cortisol in 197 ADHD children and 221 controls using radioimmunoassay in a subsequent study. They found that salivary cortisol levels were considerably lower in ADHD children relative to the control group at awakening and 30 min after awakening. This may be because there is a distorted circadian rhythm associated with ADHD. A different finding to ours is that a negative correlation was documented between symptoms of ADHD and levels of cortisol at awakening and 30 min after awakening .
In accordance with our results, Hastings and colleagues  did not find any association between symptoms of ADHD and awakening levels of cortisol in their analysis of salivary cortisol in 170 ADHD children.
In addition, a recent Egyptian study comparing morning and bedtime salivary cortisol showed that the levels of cortisol in samples collected at bedtime of patients with ADHD were lower significantly compared to those of the control group with no statistically significant difference detected at the morning sample .
Hypothetically, a correlation between a HPA axis that is downregulated and ADHD fits hypotheses that consider ADHD as a consequence of under-arousal. The optimal stimulation hypothesis is one such theory, which indicates that ADHD presentations may be considered as manifestations of over activity aimed at stimulating arousal for example through taking risks, aggressive behavior, talking, attention shifting, or stimulation seeking .
Three related neuropsychological mechanisms were proposed: fight or flight, sensitivity to reward (facilitated through “behavioral activation system” the BAS), and sensitivity to punishment (facilitated through “behavioral inhibition system” the BIS). Individuals vary in accordance to this theory: some are usually inclined to seek incentives (high BAS), while others are highly motivated to resist punishing stimuli (high BIS). BIS activity triggers the termination of recurrent behavior, focuses the attention of the organism on environmental cues, and raises the physiological unspecific arousal .
It is argued that BIS functional impairment contributes to hyperactivity/impulsivity symptomatology of ADHD in addition to neurocognitive deficits in motor fluency, control of emotions and verbal and visual working memory .
Low cortisol levels in ADHD whether at baseline or in conditions of psychological stress can be due to an underactive BIS. It is proposed that impaired BIS activity is rather unique for the predominantly hyperactive/impulsive subtype or the combined subtype of ADHD . One hypothesis arising from this theory is that in these two subtypes, but not in the primarily inattentive form of ADHD, abnormalities should be observed in HPA axis activity.
Other studies have described more levels of morning cortisol in ADHD children, unlike our research , and in boys with hyperactivity/impulsivity , while other research failed to detect any variation in baseline levels of cortisol between ADHD participants and healthy controls [30,31,32].
The daily variation of the secretion of cortisol is characterized by the high waking levels, an increase further in the morning and a gradual decrease in the day till midnight . The sampling timing may, therefore, be responsible for the different results between studies. The different results could also be due to different cortisol measuring techniques, saliva collection protocols, or variation within the participants with regard to comorbid disorders. In our study, we controlled for the time of sample collection and comorbid disorders apart from disruptive behavior disorders.
In the current study, the severity of delinquent, aggressive, and externalizing behaviors of ADHD children were positively correlated with salivary cortisol levels. A recent British study reported similar findings with a positive correlation between oppositional defiant and conduct symptoms in ADHD children with their salivary cortisol levels .
One of the studies examining the relationship between ADHD, disruptive behavior disorders, and cortisol was that conducted by Kariyawasam et al. . Compared to 25 healthy controls of similar age and ethnic background, salivary cortisol was determined in thirty-two children with ADHD and comorbid oppositional defiant disorder. Salivary cortisol was lower significantly in the ADHD/oppositional defiant comorbid group compared to the control group.
If the low activity of the HPA axis and symptoms of ADHD do in fact stem from common neural deviations, low activity of the HPA axis may show this deviation at an early phase and may therefore predict the development of ADHD symptoms in the preschool years. Low activity of the HPA axis may be viewed as an earlier predictor of the progression of the disorder if this is the case . Indeed, Salis et al.  found that at age 6, a diminished diurnal salivary cortisol profile indicated a rise in externalizing symptoms till age 9.
Schloß et al. in 2018 found that at the age of 4 years low hair cortisol concentration, that is, a low HPA axis activity incorporated over a period of 3 months, anticipated increased symptoms of ADHD in the next 12 months, which was statistically significant only in the boys not in girls .
A 2018 study explored serum cortisol level in children with attention-deficit/hyperactivity disorder combined subtype and another group of children with ADHD combined subtype and comorbid conduct disorder. Among the study groups, no substantial difference in serum cortisol levels was observed. A negative correlation was also found between serum cortisol levels and oppositional defiant behavior scores .
Cortisol awakening response (CAR) is the rise in levels of cortisol of about 50% happening in some individuals 20 to 30 min following morning awakening. A study in 2009 found a blunted CAR in ADHD children with comorbid oppositional defiant disorder compared to ADHD children with comorbid conduct disorder, ADHD with no comorbidity, and healthy controls .
One study measured the diurnal pattern of cortisol in a group of thirty ADHD children, compared to a psychiatric control group consisting of twenty-one children with autism and a control group of adults. Samples of saliva were collected in the morning at 2-h periods. More samples were collected in the afternoon and evening to illustrate the diurnal pattern. The authors found that most of the children with ADHD (57%) did not exhibit a regular diurnal pattern, while diurnal rhythm abnormalities were found in only 10% of adult controls and 20% of autistic subjects .
It was found in a study of male children between 10 and 12 years of age that low levels of cortisol were associated with impulsivity and aggression after 5 years . Lopez-Duran et al.  evaluated cortisol reactivity in seventy-three 6 to 7-year-old children and found that cortisol reactivity was higher in those with forms of reactive aggression than in children with proactive aggression or those without aggression . Furthermore, another study in 2005 found that low levels of basal cortisol were correlated with callous traits in male adolescents, but this association was not valid in female adolescents. Serum concentrations of cortisol can be recognized as “emotional reactivity” biomarkers, and therefore, cortisol levels can potentially aid in predicting the type of aggression and contribute with diagnosis and treatment .
Consideration of the etiology of HPA pathology and pediatric aggression is important. Considerable research has to be done in the future to the disturbed cortisol pattern in ADHD as a biomarker to support ADHD diagnosis or to identify certain specifiers.