Growth hormone and related factors

The relationship between autism, growth hormone, and growth factors has been mentioned in the literature because of the role of neurotrophic factors, including insulinlike growth factor (IGF)-1, in brain development. IGF-1 levels in cerebrospinal fluid of children with autism were noted to be significantly lower in children with autism versus controls indicating that there might be some pathogenic role of IGF-1 in autism. IGF-1 is important in the normal development of cerebellum, and its deficiency may lead to cerebellar growth disruption. Riikonen has proposed ‘‘premature growth without guidance’’ possibly mediated by a disrupted IGF system as a possible neurobiological mechanism contributing to autism. Children with autism are known to have larger brain size and brain volume. Rates of increase in head circumference of children with ASDs were compared with brain volume on magnetic resonance imaging. It was noted that the clinical onset of autism was preceded by a rapid and excessive increase in head size at 1 to 2 months and then also at 6 to 14 months of age.

Mills and colleagues further investigated whether children with ASDs only have a larger head circumference, whether they are also taller and heavier, and whether these growth measurements are correlated with higher levels of growth factors. Children with ASDs were found to have significantly higher levels of IGF1, IGF2, insulin-like growth factor binding protein 3, and growth hormone binding protein; significantly higher weights and body mass indices; and larger head circumferences; but no significant difference in heights was found in comparison with age-matched controls. It has been suggested that accelerated head growth should be considered an early marker of ASDs. Although this demonstrated a correlation, further studies need to be undertaken to explain the role of growth factors in the etiopathogenesis of ASDs, if any.

Oxytocin

Oxytocin hormone is known to play an important role in the regulation of social recognition, affiliation, bonding, and attachment. Because one of the main deficits in ASDs is social deficit, it is not surprising that many researchers have attempted to find if there is any causative link between oxytocin and ASDs. Animal studies have shown that oxytocin and vasopressin help regulate the social behavior of prairie voles, especially the formation of partner preference. Oxytocin receptors are more directly involved in social recognition and adaptation and are found concentrated in the olfactory bulb, lateral septum, amygdala, and piriform cortex. To further elucidate the effect of oxytocin on social adaptive behavior, researchers have developed oxytocin knockout (OTKO) mice. The OTKO mice have shown failure of social adaptation on repeated exposure, which supports the hypothesis that oxytocin is responsible for integrating the social olfactory information and facilitating the consolidation of social memory in the medial amygdala.

Oxytocin has also been found to mediate feelings of trust in social interactions. This finding, in turn, promotes cooperation and interaction in social settings. Negative social emotions, such as fear and anxiety, can cause difficulties in social situations, and oxytocin is known to cause attenuation of amygdala activity, which leads to the reduction of negative feelings and anxiety associated with new or uneasy social situations, thus, promoting trustworthiness in these social situations. Oxytocin receptor gene (OXTR), located at the 3p25 region, has been researched in terms of a correlation with ASDs. A single nucleotide polymorphism of OXTR was found in children and adolescents with ASD. Aberrant methylation, genomic deletion, or epigenetic inhibition of the OXTR gene may also play an etiologic role. Peripherally circulating oxytocin may not serve as an accurate indicator of true oxytocin availability, but low levels of peripherally circulating oxytocin in children with autism were associated with poor performance on a cognitive test battery when compared with the control group. Children in the control group with a higher level of oxytocin correlated with greater social interaction and better daily living skills as compared with children with ASD. When children with autism and Asperger syndrome were given an infusion of oxytocin, their autistic behavior decreased significantly. The same group also showed that the social information retention also improved with oxytocin infusion in such individuals. There is some evidence that the systemic administration of oxytocin improves emotion recognition and repetitive behavior.

Most of the human studies, which showed a positive correlation of deficiency of oxytocin to the autistic behavior, were performed in a smaller number of subjects, and replications of results with a larger cohort are needed. Children with autism display qualitative impairment in reciprocal social interaction, inadequate understanding of social and emotional cues, along with a poor understanding and response to social signals, but whether or not deficiency in oxytocin is responsible for this presentation is still an open question.

Oxytocin

Oxytocin hormone is known to play an important role in the regulation of social recognition, affiliation, bonding, and attachment. Because one of the main deficits in ASDs is social deficit, it is not surprising that many researchers have attempted to find if there is any causative link between oxytocin and ASDs. Animal studies have shown that oxytocin and vasopressin help regulate the social behavior of prairie voles, especially the formation of partner preference. Oxytocin receptors are more directly involved in social recognition and adaptation and are found concentrated in the olfactory bulb, lateral septum, amygdala, and piriform cortex. To further elucidate the effect of oxytocin on social adaptive behavior, researchers have developed oxytocin knockout (OTKO) mice. The OTKO mice have shown failure of social adaptation on repeated exposure, which supports the hypothesis that oxytocin is responsible for integrating the social olfactory information and facilitating the consolidation of social memory in the medial amygdala.

Oxytocin has also been found to mediate feelings of trust in social interactions. This finding, in turn, promotes cooperation and interaction in social settings. Negative social emotions, such as fear and anxiety, can cause difficulties in social situations, and oxytocin is known to cause attenuation of amygdala activity, which leads to the reduction of negative feelings and anxiety associated with new or uneasy social situations, thus, promoting trustworthiness in these social situations. Oxytocin receptor gene (OXTR), located at the 3p25 region, has been researched in terms of a correlation with ASDs. A single nucleotide polymorphism of OXTR was found in children and adolescents with ASD. Aberrant methylation, genomic deletion, or epigenetic inhibition of the OXTR gene may also play an etiologic role. Peripherally circulating oxytocin may not serve as an accurate indicator of true oxytocin availability, but low levels of peripherally circulating oxytocin in children with autism were associated with poor performance on a cognitive test battery when compared with the control group. Children in the control group with a higher level of oxytocin correlated with greater social interaction and better daily living skills as compared with children with ASD. When children with autism and Asperger syndrome were given an infusion of oxytocin, their autistic behavior decreased significantly. The same group also showed that the social information retention also improved with oxytocin infusion in such individuals. There is some evidence that the systemic administration of oxytocin improves emotion recognition and repetitive behavior.

Most of the human studies, which showed a positive correlation of deficiency of oxytocin to the autistic behavior, were performed in a smaller number of subjects, and replications of results with a larger cohort are needed. Children with autism display qualitative impairment in reciprocal social interaction, inadequate understanding of social and emotional cues, along with a poor understanding and response to social signals, but whether or not deficiency in oxytocin is responsible for this presentation is still an open question.

Vasopressin

Arginine vasopressin (AVP), commonly known as antidiuretic hormone, has a rich receptor distribution throughout the nervous system, especially in the nasal septum, cerebral cortex, hippocampus, and hypothalamus. AVP has been implicated in various psychiatric disorders, including depression, anxiety, schizophrenia, and autism. Two main types of vasopressin receptors have been implicated in ASDs: the V1a receptors (V1a R) and V1b receptors (V1b R). The V1aR gene has been associated with autism. In animal models, V1aR and V1bR knock out (KO) mice showed impairment in social interaction when compared with normal mice; V1bR KO mice demonstrate a reduction in social motivation when challenged with olfactory discrimination tasks. The V1aR KO mice show a decrease in anxiety-related behavior and in depression. Genetic studies have shown that the AVPR1a locus acts as a mediator of social behavior, but at this time the link between genes and related behavior is not well established. Vasopressin in humans (males) is found to be associated with the generation of and reciprocation to social signals associated with courtship and aggression.

Intranasal vasopressin displayed sex-specific effects on corrugator electromyographic responses to same-sex faces after a single application in the group receiving AVP. The social communication facilitated by vasopressin was gender specific, and men and women under similar social stress used different social strategies. AVP facilitated agonistic responses in men and affiliative responses in women. Multiple studies build up increasing evidence that both oxytocin receptors and AVP receptors may have an important role in the pathophysiology of ASDs, and some degree of polymorphism in AVPR1a receptor along with other neuropeptides receptors may be responsible to expression of autism and related disorders.

Apelin

Apelin is a recently discovered neuropeptide, essentially an endogenous ligand for the G protein-coupled receptor, which can counteract the action of arginine vasopressin. The receptors for AVP and apelin are present together in magnocellular neurons of the hypothalamus. Boso and colleagues have found significantly lower levels of apelin and high levels of AVP in patients with autism, again highlighting possible dysfunction in the AVP axis in the pathophysiology of autism.

Melatonin

The pineal gland (or pineal body) is a small endocrine gland situated in the midline close to the third ventricle. It secretes melatonin, which is responsible for the recognition of photoperiod, adjustment of circadian and seasonal rhythm, sleep induction, and facilitating the immune response. Melatonin is studied in this context because about 44% to 83% of children with ASDs display various levels of sleep disturbances. Some of the objective sleep disturbances noted in this population include longer sleep latency, more frequent awakenings, increased duration of stage 1 sleep, decreased non–rapid eye movement (REM) and slow-wave sleep (stages 3 and 4), and a lower number of rapid eye movements during REM, all of which results in an overall lower sleep efficiency. Melatonin levels are found to be lower in 65% of children with ASD, which is attributed to the deficiency of the last enzyme in the melatonin pathway known as acetylserotonin O-methyltransferase (ASMT).

Polymorphism in the ASMT gene located in the pseudoautosomal region of sex chromosomes lead to decreased transcription and, thus, a lower level of melatonin, about 50% of the concentration found in age-matched controls. A genetic predisposition was proposed because unaffected parents of children with ASDs also showed abnormal melatonin levels in blood and platelets. A study of about 400 patients with ASDs from Italy, the United Kingdom, and Finland showed several mutations in the ASMT gene. Another study has also shown duplication of the ASMT gene in ASDs, which seems to be more common than other types of mutations. This duplication may cause a defect in the expression of the ASMT proteins in children with ASDs. Another important sleep-related observation in children with ASDs is a free-running sleep-wake cycle, which responds well to the exogenous administration of melatonin; however, large, controlled studies to consolidate this finding are not available. It has been postulated that one of the initial events in the development of ASDs could be the disturbance of the sleep-wake cycle because of the deficient melatonin pathway. Melatonin is also known to impact synaptic plasticity, and its deficiency may cause a weaker neuronal network resulting in abnormal synaptogenesis.

Thyroid hormone

Fetal thyroid gland starts developing by third week, with thyroid hormone production starting by 10th week of fetal life. It is well known that adequate thyroid hormone levels are essential for the developing fetal brain and thyroid hormone deficiency during neurogenesis can adversely effect brain development. Maternal thyroxine (T4) crosses the placenta and contributes to about 20% to 44% of the total thyroid hormone pool of the fetus. Thyroid hormones play several important functions in brain development, including granule cell proliferation in the cerebellum; granule cell apoptosis; mRNAs encoding nerve growth factor and neurotrophin, which influences neuronal migration; mRNA expression and translation of reelin, which encodes a large extracellular protein; glycogenesis; effect on astrocytes, which secrete laminin, a key guidance signal for the migration of neurons, synaptogenesis, and myelination.

Rat models demonstrate that the unavailability of thyroid hormone at the time of active neurogenesis and of migrations of neurons into the cerebral cortex and hippocampus leads to irreversible damage to neurogenesis. It has been hypothesized, therefore, that disturbances in the thyroid hormone availability and metabolism during the critical periods of neural development may lead to behavioral disturbances as noted in ASDs.

Thyroid-deficient animal models have been created to elucidate the effect of thyroid hormone in newborns by adding 0.02% propylthiouracil in the drinking water of rat pups from 0 to 9 days of age. Social and behavioral changes deviant from normal neurodevelopment were observed in the exposed rat pups, including hyperactivity, decreased habituation, hypersensitivity to auditory impulses, and impairment in spatial learning. However, extensive data on the relationship of thyroid hormone and autism are not yet available.