HPA hormone dysregulation in pediatric disorders of learning, behavior and neurodevelopment

There is a large body of evidence that compels us not to overlook hormonal dysregulation in ADHD and other disorders of learning, behavior and brain development. A paper published not long ago in the journal European Neuropsychopharmacology addresses the broad topic of neurosteroids. The authors state in regard to the steroid hormones active in the nervous system:

"Neurosteroids play a significant role in neurodevelopment and are involved in a wide variety of psychopathological processes...there is increasing evidence for their critical role from the early stages of brain development until adolescence."

They proceed to review the involvement of neurosteroids in neurodevelopment and mental disorders in children and adolescents, noting in particular:

"Adequate physiological levels protect the developing neural system from insult and contribute to the regulation of brain organization and function. Neurosteroids may be involved in the pathophysiology and pharmacotherapy of a variety of disorders in children and adolescents, including schizophrenia, depression, eating disorders, aggressive behavior and attention deficit."

A paper published in the journal Neuropediatrics examines the association of hypothalamo-pituitary-adrenal (HPA) axis dysfunction and intelligence performance:

"The aim of the present study was to examine the effects of hypothalamo-pituitary-adrenal (HPA) axis reactivity on intelligence test performance in subjects with attention-deficit/hyperactivity disorder (ADHD). We investigated the extent to which an increase or decrease in cortisol after stress was associated with the intelligence test performance in 68 clinic-referred children with ADHD."

They administered a battery of tests for both assessment and stressor applications, plus...

"A saliva sample was collected from each subject before and after psychological testing in order to measure the level of cortisol in the saliva."

Salivary cortisol is the most reliable and necessarily non-invasive way to measure functional cortisol levels as we know here from extensive clinical experience. Their data painted a striking picture:

"Decreases in the level of cortisol after the test were correlated with poor intelligence performance and the decrease of cortisol in respect to baseline significantly affected the verbal, performance and total IQ in subjects who showed blunted responses to stress."

A fine study published recently in the Chinese Journal of Contemporary Pediatrics further investigates...

"...the function of the hypothalamus-pituitary-adrenal (HPA) axis in children with attention deficit hyperactivity disorder (ADHD)."

128 boys with ADHD at ages of 6 to 14 years were diagnosed and grouped according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV): ADHD-predominantly inattention type, ADHD-predominantly hyperactive impulsive type and ADHD-combined type. 30 healthy boys served as the control group. They tested cortisol and assessed intelligence level with Raven′s standard progressive matrices. What did the data show?

"The mean plasma cortisol level in the ADHD group was significantly lower than that in the control group. The three ADHD subgroups showed significantly decreased plasma cortisol level compared with the control group. The plasma level of cortisol was the lowest in the ADHD-HI group, followed by the ADHD-I group and the ADHD-C group."

Their conclusion should be borne in mind by both clinicians and parents:

"In the non-stress state, the HPA axis may be dysfunctional in children with ADHD, which may be attributed to the under reactivity of the HPA axis. Lower plasma cortisol...may closely be related to attention deficit, hyperactivity and impulsive behaviors."

More valuable research was published in the Yonsei Medical Journal (Korea) in which the authors state:

"Children with attention-deficit/hyperactivity disorder (ADHD) often perform poorly during cognitive tests. We sought to evaluate cortisol as potential moderator of performance in mentally challenging tasks in children with ADHD."

They measured salivary cortisol in 90 children with ADHD before and after administration of a continuous performance test (CPT). Their data adds evidence that cortisol dysregulation in association with poorer performance can be either abnormally high or low:

"Children whose cortisol level increased after testing displayed a significantly longer response time and increased response time variability scores as compared to children who did not display increase of cortisol after the CPT test."

Since activation of α1 adrenergic receptor mediates both cortisol level increase and attention impairment, they also conclude that in association with cortisol:

"The result of the current study suggests that stress-induced high norepinephrine (NE) release may accompany poorer attention performance in patients with ADHD."

The authors of a paper published in European Child & Adolescent Psychiatry offer additional evidence that children with ADHD must be evaluated as individuals for varying patterns of cortisol dysregulation:

"The aim of this study was to investigate whether a different pattern of HPA axis activity is found between the inattentive (I) and combined (C) subtypes of ADHD, in comparison with healthy control children."

They studied the effects of stress by comparing cortisol responses to a psychosocial stressor (a public speaking task). Their data revealed interesting differences:

"Children with ADHD-I showed an elevated cortisol response to the psychosocial stressor, in contrast to children with ADHD-C who showed a blunted cortisol response to the psychosocial stressor...hyperactivity symptoms were clearly related to a lower cortisol reactivity to stress. The results indicate that a low-cortisol responsivity to stress may be a neurobiological marker for children with ADHD-C, but not for those with ADHD-I."

The authors of a paper published in the Journal of Attention Disorders draw our attention to the link between sensory hyperarousal and HPA axis dysregulation with their investigation of salivary cortisol levels:

"To determine if sensory overresponsivity (SOR) is a moderating condition impacting the activity of the Hypothalamic Pituitary Adrenal (HPA) Axis in children with ADHD."

Children with ADHD and known SOR were compared with those with ADHD but without SOR and normal children, all of whom participated in a Sensory Challenge Protocol. Salivary cortisol was used as a measure of HPA activity with two prechallenge and seven postchallenge samples taken. Interestingly, their data showed...

"...a borderline significant difference found between the ADHDt [without SOR] and ADHDs [with SOR] group and a significant difference between ADHDt and the typical [normal] group."

In other words, salivary cortisol measurements distinguished both ADHD groups from the normal group.Clarification of the different patterns of HPA axis dysregulation in ADHD was reported in the Journal of Abnormal Child Psychology:

"Disruptions to hypothalamic-pituitary-adrenal (HPA) axis function have been associated with varying forms of psychopathology in children. Studies suggesting children with ADHD have blunted HPA function have been complicated by the prevalence of comorbid diagnoses and heterogeneity of ADHD. The goals of this research were to assess the relations between waking and stress–response salivary cortisol levels and comorbid disruptive behavior (DBD) and anxiety (AnxD) disorders and problems in boys with ADHD, and to examine whether cortisol levels varied across ADHD subtypes."

The authors examined salivary cortisol on waking and in reaction to venipuncture (to determine stress-response levels), psychiatric symptoms and behavioral problems in 170 elementary school-age boys. The data left no doubt that there are dysfunctional subtypes of ADHD, emphasizing the importance of evaluating each child as an individual:

"Boys’ comorbid AnxD and anxiety problems were associated with greater cortisol reactivity, whereas boys’ comorbid DBD and oppositional problems predicted diminished adrenocortical activity. Reactive cortisol increases were greatest in boys with ADHD and comorbid AnxD, but without DBD...comorbid DBD predicted decreased cortisol reactivity in boys with inattentive and hyperactive subtypes of ADHD, but not in boys with combined subtype of ADHD. The results clarify previous patterns of distinct and divergent dysregulations of HPA function associated with boys’ varying kinds of psychopathology."

By the way, note that venipuncture (drawing blood) was used elicit a cortisol-modifying stress response. This is one reason why we use saliva instead of blood tests for cortisol.We can add to this a study published in the journal Child Psychiatry & Human Development that further examines HPA axis dysregulation in a specific subtype of ADHD. The authors set out...

"To investigate the hypothalamic pituitary adrenal (HPA) axis response to a stressor in adolescents with inattentive type attention-deficit hyperactivity disorder symptoms (ADHD-I)."

They too used salivary cortisol measurements as a metric in response to a social/cognitive stressor for threshold inattentive (TI), moderately inattentive (MI) and no symptom groups of healthy adolescents. A distinction was present in this study as well:

"The TI group displayed a significant decrease in cortisol post stressor whereas both the MI and comparison groups showed an increase in cortisol."

We can also appreciate a study published in the journal Psychiatry Research that looks specifically at aggressive behavior and cortisol. The authors state:

"We examined the relationship between the cortisol response to stress and aggression in patients with attention deficit hyperactivity disorder (ADHD). Based on a report stating that only some of the patients with ADHD retain their hypothalamic-pituitary-adrenal axis reactivity to stress, we separately analyzed the relationship between aggression and the cortisol response to stress in two groups according to their reactivity to stress."

Their data included psychological testing as a stress indicator with salivary cortisol measurements made before and after psychological test administration. Behavioral problems and aggression were assessed with the local (Korean) version of the Child Behavior Checklist. Their findings also showed the connection:

"The increase of the cortisol level was inversely correlated with aggression in patients who retained their reactivity to stress. The absolute value of the decrease was negatively correlated with the attention score of the CBCL for the patients who showed decreases in cortisol after stress. For the patients who showed increases in their concentration of cortisol in reaction to stress, cortisol may play a protective role against aggression."

In other words, when cortisol went down aggression went up and attention scored worse. As we can see, there is a large body of evidence showing that we must consider the possibility of hypothalamic-pituitary-adrenal dysregulation in pediatric disorders of learning and behavior. This is best assessed by the functional approach that encompasses the multiple factors such as blood sugar dysregulation, inflammation from allergy or autoimmunity, etc. that can be contributing causes to HPA axis dysfunction, along with experienced assessment of salivary cortisol levels together with associated laboratory findings.