Adams, J. B., C. E. Holloway, F. George and D. Quig (2006). "Analyses of toxic metals and essential minerals in the hair of Arizona children with autism and associated conditions, and their mothers." Biol Trace Elem Res 110(3): 193-209.
The objective of this study was to assess the levels of 39 toxic metals and essential minerals in hair samples of children with autism spectrum disorders and their mothers compared to controls. Inductively coupled plasma-mass spectrometry was used to analyze the elemental content of the hair of children with autism spectrum disorders (n=51), a subset of their mothers (n=29), neurotypical children (n=40), and a subset of their mothers (n=25). All participants were recruited from Arizona. Iodine levels were 45% lower in the children with autism (p=0.005). Autistic children with pica had a 38% lower level of chromium (p=0.002). Autistic children with low muscle tone had very low levels of potassium (-66%, p=0.01) and high zinc (31%, p=0.01). The mothers of young children with autism had especially low levels of lithium (56% lower, p=0.005), and the young children (ages 3-6 yr) with autism also had low lithium (-30%, p=0.04). Low iodine levels are consistent with previous reports of abnormal thyroid function, which likely affected development of speech and cognitive skills. Low lithium in the mothers likely caused low levels of lithium in the young children, which could have affected their neurological and immunological development. Further investigations of iodine, lithium, and other elements are warranted.

Aneja, A. and E. Tierney (2008). "Autism: the role of cholesterol in treatment." Int Rev Psychiatry 20(2): 165-70.
Cholesterol is essential for neuroactive steroid production, growth of myelin membranes, and normal embryonic and fetal development. It also modulates the oxytocin receptor, ligand activity and G-protein coupling of the serotonin-1A receptor. A deficit of cholesterol may perturb these biological mechanisms and thereby contribute to autism spectrum disorders (ASDs), as observed in Smith-Lemli-Opitz syndrome (SLOS) and some subjects with ASDs in the Autism Genetic Resource Exchange (AGRE). A clinical diagnosis of SLOS can be confirmed by laboratory testing with an elevated plasma 7DHC level relative to the cholesterol level and is treatable by dietary cholesterol supplementation. Individuals with SLOS who have such cholesterol treatment display fewer autistic behaviours, infections, and symptoms of irritability and hyperactivity, with improvements in physical growth, sleep and social interactions. Other behaviours shown to improve with cholesterol supplementation include aggressive behaviours, self-injury, temper outbursts and trichotillomania. Cholesterol ought to be considered as a helpful treatment approach while awaiting an improved understanding of cholesterol metabolism and ASD. There is an increasing recognition that this single-gene disorder of abnormal cholesterol synthesis may be a model for understanding genetic causes of autism and the role of cholesterol in ASD.

Auyeung, B., S. Baron-Cohen, E. Ashwin, R. Knickmeyer, K. Taylor and G. Hackett (2009). "Fetal testosterone and autistic traits." Br J Psychol 100(1): 1-22.

Buitelaar, J. K., H. van Engeland, K. de Kogel, H. de Vries, J. van Hooff and J. van Ree (1992). "The adrenocorticotrophic hormone (4-9) analog ORG 2766 benefits autistic children: report on a second controlled clinical trial." J Am Acad Child Adolesc Psychiatry 31(6): 1149-56.
In a second controlled crossover trial, 20 autistic children received 40 mg/day of the neuropeptide ORG 2766, a synthetic analog of ACTH (4-9), for 8 weeks. Parents' checklist ratings (ABC) as well as clinicians' ratings (CGI) pointed to significant improvements after the course of treatment; improvements were clearest on the ABC social withdrawal subscale. The analysis of individual target symptoms and the parents' treatment preferences substantiated the beneficial effects of ORG 2766. In an ethologically analyzed playroom session, ORG 2766 treatment was associated with an improvement in the children's play behavior and a significant increase in the social interaction between child and experimenter. Gaze coordination between child and experimenter also was improved.

Buitelaar, J. K., H. van Engeland, K. H. de Kogel, H. de Vries, J. A. van Hooff and J. M. van Ree (1992). "The use of adrenocorticotrophic hormone (4-9) analog ORG 2766 in autistic children: effects on the organization of behavior." Biol Psychiatry 31(11): 1119-29.
In a double-blind placebo-controlled crossover trial, 14 autistic children were treated with the neuropeptide ORG 2766, a synthetic analog of adrenocorticotrophic hormone (ACTH) (4-9). ORG 2766 treatment (20 mg per day during 4 weeks) was associated with an increased amount and an improved quality of the social interaction of the autistic children with a familiar experimenter. These changes in interaction were clinically relevant. Following treatment with ORG 2766 gaze and smile behaviors of child and experimenter showed stronger temporal contingencies. Further, after ORG 2766, stereotypies were temporally disconnected from verbal initiatives. The data supported the notion of a stimulating effect of ORG 2766 on social interaction. The implications of these findings for the endogenous opioid theory of autism are discussed.

Campbell, M., A. M. Small, C. S. Hollander, J. Korein, I. L. Cohen, M. Kalmijn and S. Ferris (1978). "A controlled crossover study of triiodothyronine in autistic children." J Autism Child Schizophr 8(4): 371-81.
A placebo-controlled crossover study of behavioral effects of triiodothyronine (T3) was conducted in 30 young clinically euthyroid autistic children. Multiple independent raters and multiple rating scales were used. Except for a few symptoms that were reduced on T3, the drug did not differ from placebo. Time itself accounted for most of the improvement in the whole sample. As a group, the lower IQ children responded to T3. The individual children who were responders could not be defined by any parameter.

Carter, C. S. (2007). "Sex differences in oxytocin and vasopressin: implications for autism spectrum disorders?" Behav Brain Res 176(1): 170-86.
Autism spectrum disorders (ASD) are male-biased and characterized by deficits in social behavior and social communication, excessive anxiety or hyperreactivity to stressful experiences, and a tendency toward repetitiveness. The purpose of this review is to consider evidence for a role for two sexually dimorphic neuropeptides, oxytocin (OT) and arginine vasopressin (VP), in these features of ASD. Both VP and OT play a role in normal development. VP is androgen-dependent and of particular importance to male behavior. Excess VP or disruptions in the VP system could contribute to the male vulnerability to ASD. Alternatively, protective processes mediated via OT or the OT receptor might help to explain the relatively rare occurrence of ASD in females. Disruptions in either OT or VP or their receptors could result from genetic variation or epigenetic modifications of gene expression, especially during early development. Deficits in other developmental growth factors, such as reelin, which may in turn regulate or be regulated by OT or VP, are additional candidates for a role in ASD.

Chamberlain, R. S. and B. H. Herman (1990). "A novel biochemical model linking dysfunctions in brain melatonin, proopiomelanocortin peptides, and serotonin in autism." Biol Psychiatry 28(9): 773-93.
A novel biochemical model for autism is presented, which proposes that a subgroup of autistic individuals may have a hypersecretion of pineal melatonin that produces a cascade of biochemical effects including a corresponding hyposecretion of pituitary proopiomelanocortin (POMC) peptides and a hypersecretion of hypothalamic opioid peptides and serotonin (5-HT). The model is reviewed, and supporting animal and clinical research, is summarized. The first arm of the model suggests that increases in pineal melatonin results in hypersecretion of 5-HT in hypothalamus and blood. The second arm of the model indicates that hypersecretion of melatonin also inhibits the release of hypothalamic corticotrophin-releasing hormone (CRH). Hyposecretion of CRH may result in decreased release of both pituitary B-endorphin (B-E) and adrenocorticotrophin hormone (ACTH); this, in turn, may result in decreased plasma concentrations of B-E, ACTH, and cortisol. In autism, a genetically determined hypersecretion of hypothalamic B-E may further contribute to an inhibition of pituitary B-E because of negative feedback inhibition. Therefore, autism may reflect a dysfunction in the pineal-hypothalamic-pituitary-adrenal axis which, modulates POMC and 5-HT systems of the brain. This model is consistent with numerous clinical investigations implicating hypersecretion of brain 5-HT and opioid peptides in autism. The model may have heuristic importance in guiding future research in the biochemistry of autism.
Chez, M. G., M. Aimonovitch, T. Buchanan, S. Mrazek and R. J. Tremb (2004). "Treating autistic spectrum disorders in children: utility of the cholinesterase inhibitor rivastigmine tartrate." J Child Neurol 19(3): 165-9.
Rivastigmine tartrate is a dual-action cholinesterase inhibitor shown to improve language, cognition, and global functioning in patients with Alzheimer's disease, likely via increased availability of cerebral acetylcholine. Because cholinergic receptor abnormalities can contribute to the neuropathology of autistic spectrum disorders, rivastigmine tartrate could prove to be an effective therapy for affected children. Observations of improved behavior and language output from prior open-label and double-blind treatment of autistic children with donepezil, another cholinesterase inhibitor, prompted this 12-week open-label study with rivastigmine tartrate of 32 autistic patients. Therapeutic indices were the Childhood Autistic Rating Scale, Gardner's Expressive and Receptive One-Word Picture Vocabulary tests, and the Conners' Parent Rating Scale. Testing administered at baseline, 6 weeks, and 12 weeks showed gains in both expressive speech and overall autistic behavior over baseline. These improvements were statistically significant and supported the hypothesis that treatment with cholinergic enhancing drugs in autistic spectrum disorders yields positive therapeutic effects.

Cohen, D. J., J. G. Young, T. L. Lowe and D. Harcherik (1980). "Thyroid hormone in autistic children." J Autism Dev Disord 10(4): 445-50.
Thyroid hormone plays an important role in the pre- and postnatal development and function of the central nervous system. Disturbances in thyroid hormone regulation have been hypothesized in childhood autism. We evaluated blood indices of thyroid function, including serum thyroxine, triiodothyronine, and thyroid-stimulating hormone, in a large population of autistic children. No differences were found between autistic and normal children.
Corbett, B. A., S. Mendoza, M. Abdullah, J. A. Wegelin and S. Levine (2006). "Cortisol circadian rhythms and response to stress in children with autism." Psychoneuroendocrinology 31(1): 59-68.
BACKGROUND: Autism is a severe neurodevelopmental disorder characterized by impairment in communication, social interaction, repetitive behaviors and difficulty adapting to novel experiences. The Hypothalamic-Pituitary-Adrenocortical (HPA) system responds consistently to perceived novel or unfamiliar situations and can serve as an important biomarker of the response to a variety of different stimuli. Previous research has suggested that children with autism may exhibit dysfunction of the HPA system, but it is not clear whether altered neuroendrocrine regulation or altered responsiveness underlies the differences between children with and without autism. In order to provide preliminary data concerning HPA regulation and responsiveness, we compared circadian rhythms and response to a non-social, environmental stressor in children with and without autism. METHODS: Circadian rhythms of cortisol were estimated in children with (N=12) and without (N=10) autism via analysis of salivary samples collected in the morning, afternoon and evening on 2 consecutive days. HPA responsiveness was assessed by examining the time course of changes in salivary cortisol in response to a mock MRI. RESULTS: Both groups showed expected circadian variation with higher cortisol concentration in morning than in the evening samples. The children with autism, but not typical children, showed a more variable circadian rhythm as well as statistically significant elevations in cortisol following exposure to a novel, nonsocial stimulus. CONCLUSIONS: The results suggest that children with autism process and respond idiosyncratically to novel and threatening events resulting in an exaggerated cortisol response.

Corbett, B. A., S. Mendoza, J. A. Wegelin, V. Carmean and S. Levine (2008). "Variable cortisol circadian rhythms in children with autism and anticipatory stress." J Psychiatry Neurosci 33(3): 227-34.
OBJECTIVE: Autism is characterized by impairment in communication and social interaction, by repetitive behaviours and by difficulty in adapting to novel experiences. The objective of the current investigation was to replicate and extend our previous findings showing variable circadian rhythm and significant elevations in cortisol following exposure to a novel stimulus (mock magnetic resonance imaging [MRI]). METHODS: 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. We assessed hypothalamic-pituitary-adrenal (HPA) responsiveness by examining changes in salivary cortisol in response to a mock MRI. One-half of the children were re-exposed to the MRI environment. RESULTS: Children with autism showed a decrease in cortisol in the morning over 6 days while maintaining higher evening values. Children with autism also showed more within-and between-subject variability in circadian rhythms. Although the cortisol values tended to be higher in some of the children with autism, a statistically significant elevation in cortisol in response to the initial mock MRI was not observed. Rather, both groups showed heightened cortisol at the arrival to the second visit to the imaging centre, suggesting an anticipatory response to the re-exposure to the mock MRI. CONCLUSION: Children with autism showed dysregulation of the circadian rhythm evidenced by variability between groups, between children and within individual child comparisons. Both groups demonstrated increased salivary cortisol in anticipation of re-exposure to the perceived stressor.

Corbett, B. A., C. W. Schupp, S. Levine and S. Mendoza (2009). "Comparing cortisol, stress, and sensory sensitivity in children with autism." Autism Res 2(1): 39-49.
Previously we reported that children with autism show significant variability in cortisol. The current investigation was designed to extend these findings by exploring plausible relationships between cortisol and psychological measures of stress and sensory functioning. Salivary cortisol values for diurnal rhythms and response to stress in children with and without autism were compared to parent-report measures of child stress, the Stress Survey Schedule (SSS), sensory functioning, Short Sensory Profile (SSP), and Parenting Stress Index. In autism, a negative relationship between morning cortisol and the SSS revealed that higher observed symptoms of stress were related to lower cortisol. Lower cortisol is seen in conditions of chronic stress and in social situations characterized by unstable social relationships. Sensory sensitivity painted a more complicated picture, in that some aspects of SSP were associated with higher while others were associated with lower cortisol. We propose that increased sensory sensitivity may enhance the autistic child's susceptibility to the influence of zeitgeibers reflected in variable cortisol secretion. Evening cortisol was positively associated with SSS such that the higher the level of evening cortisol, the higher the child's parent-reported daily stress, especially to changes, such as in daily routine. Regarding the response to stress, the psychological and parent variables did not differentiate the groups; rather, discrete subgroups of cortisol responders and nonresponders were revealed in both the autism and neurotypical children. The results support a complex interplay between physiological and behavioral stress and sensory sensitivity in autism and plausible developmental factors influencing stress reactivity across the groups.


Croonenberghs, J., K. Spaas, A. Wauters, R. Verkerk, S. Scharpe, D. Deboutte and M. Maes (2008). "Faulty serotonin--DHEA interactions in autism: results of the 5-hydroxytryptophan challenge test." Neuro Endocrinol Lett 29(3): 385-90.
BACKGROUND: Autism is accompanied by peripheral and central disorders in the metabolism of serotonin (5-HT). The present study examines plasma dehydroepiandrosterone-sulphate (DHEA-S) and the cortisol/DHEA-S ratio following administration of L-5-hydroxytryptophan (5-HTP), the direct precursor of 5-HT, to autistic patients. METHODS: Plasma DHEA-S levels were determined both before and after administration of 5-HTP or placebo, on two consecutive days in a single blind order in 18 male autistic patients and 22 matched healthy controls. RESULTS: The 5-HTP-induced DHEA-S responses were significantly higher in autistic patients than in controls. In baseline conditions, the cortisol/DHEA-S ratio was significantly higher in autistic patients than in controls. Discussion: The results suggest that autism is accompanied by a major disequilibrium in the serotonergic system. The increased Cortisol (neurotoxic) versus DHEA-S (neuroprotective) ratio suggests that an increased neurotoxic potential occurs in autism. CONCLUSIONS: It is concluded that a disequilibrium in the peripheral and central turnover of serotonin and an increased neurotoxic capacity by glucocorticoids are important pathways in autism.

Curin, J. M., J. Terzic, Z. B. Petkovic, L. Zekan, I. M. Terzic and I. M. Susnjara (2003). "Lower cortisol and higher ACTH levels in individuals with autism." J Autism Dev Disord 33(4): 443-8.
Blood concentrations of pituitary hormones adrenocorticotropin (ACTH), prolactin, growth hormone, and adrenal hormone-cortisol were measured in 36 autistic and 27 control individuals. Individuals with autism had significantly lower serum concentrations of cortisol (p < 10(-6)), and significantly higher concentrations of ACTH (p = 0.002) than control age- and sex-matched subjects. Also, prolactin concentrations in autistic patients with epilepsy were significantly higher when compared with normal subjects. The observed hormonal changes may indicate dysfunction of the hypothalamo-pituitary-adrenal axis in individuals with autism.
de Bruin, E. I., F. Verheij, T. Wiegman and R. F. Ferdinand (2006). "Differences in finger length ratio between males with autism, pervasive developmental disorder-not otherwise specified, ADHD, and anxiety disorders." Dev Med Child Neurol 48(12): 962-5.
Children with autism have a relatively shorter index finger (2D) compared with their ring finger (4D). It is often presumed that the 2D:4D ratio is associated with fetal testosterone levels and that high fetal testosterone levels could play a role in the aetiology of autism. It is unknown whether this effect is specific to autism. In this study, 2D:4D ratios of 144 males aged 6 to 14 years (mean age 9y 1 mo [SD 1y 11 mo]) with psychiatric disorders were compared with those of 96 males aged 6 to 13 years from the general population (mean age 9y 1 mo [SD 1y 10 mo]). Psychiatric disorders were divided into autism/Asperger syndrome (n=24), pervasive developmental disorder-not otherwise specified (PDD-NOS; n=26), attention-deficit-hyperactivity disorder (ADHD)/oppositional defiant disorder (ODD; n=68), and anxiety disorders (n=26). Males with autism/Asperger syndrome (p<0.05) and ADHD/ODD (p<0.05) had significantly lower (though not significantly; p=0.52) ratios than males with an anxiety disorder, and males with autism/Asperger syndrome had lower ratios than those in the comparison group. These results indicated that higher fetal testosterone levels may play a role, not only in the origin of autism, but also in the aetiology of PDD-NOS and of ADHD/ODD. Males with anxiety disorders might have been exposed to lower prenatal testosterone levels.

Domes, G., M. Heinrichs, A. Michel, C. Berger and S. C. Herpertz (2007). "Oxytocin improves "mind-reading" in humans." Biol Psychiatry 61(6): 731-3.
BACKGROUND: The ability to "read the mind" of other individuals, that is, to infer their mental state by interpreting subtle social cues, is indispensable in human social interaction. The neuropeptide oxytocin plays a central role in social approach behavior in nonhuman mammals. METHODS: In a double-blind, placebo-controlled, within-subject design, 30 healthy male volunteers were tested for their ability to infer the affective mental state of others using the Reading the Mind in the Eyes Test (RMET) after intranasal administration of 24 IU oxytocin. RESULTS: Oxytocin improved performance on the RMET compared with placebo. This effect was pronounced for difficult compared with easy items. CONCLUSIONS: Our data suggest that oxytocin improves the ability to infer the mental state of others from social cues of the eye region. Oxytocin might play a role in the pathogenesis of autism spectrum disorder, which is characterized by severe social impairment.

Geier, M. R. and D. A. Geier (2005). "The potential importance of steroids in the treatment of autistic spectrum disorders and other disorders involving mercury toxicity." Med Hypotheses 64(5): 946-54.
Autism is a neurodevelopmental disorder that according to the Centers for Disease Control and Prevention (CDC) affects 1 in 150 children in the United States. Autism is characterized by impairments in social relatedness and communication, repetitive behaviors, abnormal movements, and sensory dysfunction. Recently emerging evidence suggests that mercury, especially from childhood vaccines, appears to be a factor in the development of the autistic disorders, and that autistic children have higher than normal body-burdens of mercury. In considering mercury toxicity, it has previously been shown that testosterone significantly potentates mercury toxicity, whereas estrogen is protective. Examination of autistic children has shown that the severity of autistic disorders correlates with the amount of testosterone present in the amniotic fluid, and an examination of a case-series of autistic children has shown that some have plasma testosterone levels that were significantly elevated in comparison neurotypical control children. A review of some of the current biomedical therapies for autistics, such as glutathione and cysteine, chelation, secretin, and growth hormone, suggests that they may in fact lower testosterone levels. We put forward the medical hypothesis that autistic disorders, in fact, represents a form of testosterone mercury toxicity, and based upon this observation, one can design novel treatments for autistics directed towards higher testosterone levels in autistic children. We suggest a series of experiments that need to be conducted in order to evaluate the exact mechanisms for mercury-testosterone toxicity, and various types of clinical manipulations that may be employed to control testosterone levels. It is hoped by devising therapies that address the steroid hormone pathways, in addition to the current treatments that successful lower heavy metal body-burdens of mercury, will work synergistically to improve clinical outcomes. In light of the fact that there are a number of other diseases that may have a chronic mercury toxicity component, such as Alzheimer's disease, heart disease, obesity, ALS, asthma, and other various forms of autoimmune disorders, it is imperative that further research should be conducted to understand mercury-testosterone toxicity.

Gillberg, I. C., C. Gillberg and S. Kopp (1992). "Hypothyroidism and autism spectrum disorders." J Child Psychol Psychiatry 33(3): 531-42.
Five children (three boys and two girls) with autism or autistic-like conditions are described. Three of them had congenital hypothyroidism and two had mothers who had probably been hypothyroid in pregnancy. It is suggested that hypothyroid hormone deficiency in early development might cause central nervous system damage such that autistic symptoms are likely to ensue. An alternative explanation might be autoimmune factors linking hypothyroidism and autism.

Grady, R. R., J. I. Kitay, J. M. Spyker and D. L. Avery (1978). "Postnatal endocrine dysfunction induced by prenatal methylmercury or cadmium exposure in mice." J Environ Pathol Toxicol 1(3): 187-97.
The subtle and delayed effects of two heavy metals, cadmium and mercury, on the pituitary-adrenal axis of mice were examined. Exeprimental animals were exposed to the toxins both in utero and neonatally via treated mothers' milk. Plasma levels of corticosterone, adrenal production of corticosterone in vitro, and the capacity of the liver to metabolize corticosterone in vitro were studied in these animals as adults. Exposure to methylmercury resulted in diminished hepatic metabolism of corticosterone in vitro due to a loss of liver mass. Adrenal function and plasma levels of corticosterone were unaffected by treatment. Cadmium-exposed animals examined at 277 days of age showed no significant differences when compared to untreated controls. However, when studied at 460-480 days of age, a sex difference in the response to cadmium exposure was noted. In males, the major effect was enhancement of hepatic reductive capacity, while in females, adrenal secretory capacity was enhanced. Possible mechanisms of action and consequences of these effects are discussed.