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Aim: The objective of the current study was to compare the prevalence of three testosterone-related cancer diseases in the mothers of 111 individuals diagnosed as children with infantile autism (IA) with a matched comparison group of mothers of 330 children from the general population.
Method: All mothers were screened through the nationwide Danish National Hospital Register. We inquired about breast-, uterine-, and ovarian cancer diseases during an observation period of 27 years.
Results: At follow up a similar proportion of case and control mothers had a diagnosis of any cancer disease: 6.3% vs 8.5%. In addition, no single cancer disease was significantly more frequent among mothers of children with IA.
Conclusion: Our study provides no support for an (eventually androgen-mediated) increased rate of cancer in mothers of persons with IA.
INFANTILE AUTISM (IA) is a heterogeneous neurodevelopmental disorder that is characterized by deficits in socialization and communication and by the presence of repetitive and stereotyped patterns of behaviors and interests. In ICD-10,1 IA/childhood autism is classified as one of a group of related disorders collectively termed pervasive developmental disorders or autism spectrum disorders (ASD), of which it forms the main prototype.
The etiology of ASD is poorly understood. In a recent review covering 34 epidemiological surveys, 30 studies reported male : female ratios among children with ASD.2 The male : female ratio varied from 1.3 to 16.0, with a mean male : female ratio of 4:1. The constant preponderance of male individuals has yet to be explained, however understanding the basis for the male : female ratio may be an important step towards understanding the etiology of the disorder.3
In a series of papers, Baron-Cohen and colleagues have advanced a novel theory known as the extreme male brain theory of autism and the androgen theory of autism. It suggests that the behaviors seen in ASD are an exaggeration of typical sex differences and that exposure to high levels of prenatal testosterone could be involved in the sex differences in social behavior in the general population and in the male vulnerability to ASD.4 In many respects, Baron-Cohen's extreme male brain theory makes sense and has generated much new interdisciplinary research.5 Both the androgen theory and the extreme male brain theory predict that women with ASD might manifest physical masculinization, and be more vulnerable to conditions associated with elevated levels of androgens.6 In addition, there is some evidence for elevated fetal testosterone levels in parents of children with ASD: like their children, they have lower 2D : 4D (second and fourth digit) ratios (assumed to be a proxy for fetal testosterone) than expected,7 suggesting skewed hormone levels in children with ASD and their parents.
In a recent study6 The Testosterone Medical Questionnaire was completed by 54 women with ASD (50 had Asperger syndrome), 74 mothers of children with ASD, and a comparison group of 183 mothers of typically developing children to test whether women with ASD have an increased rate of testosterone-related medical conditions and behavioral traits, and to see whether mothers of children with ASD and other close relatives show similar abnormalities, as part of the broader autism phenotype. They found an increased rate of medical conditions and behavioral traits conventionally seen as associated with elevated androgen levels in women with ASD. Compared to the controls, significantly more mothers of children with ASD reported, among other diseases, a history of breast cancer and uterine cancers, and a family history of ovarian and uterine cancers. These results suggest current hormone deviances in women with ASD and their mothers and in other close relatives of individuals with ASD. In conclusion, Ingudomnukul et al.6 call upon further studies to eventually replicate these findings via clinical examination and medical records checks.
In the following we are reporting the results of a study comparing the rates of selected testosterone-related cancer diseases in the mothers of 111 individuals diagnosed as children with IA and the mothers of 330 control children from the general population, using data from the nationwide Danish National Hospital Register (DNHR) covering an observation period of 27 years.
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In a recent pioneer study, Ingudomnukul et al.6 found an increased rate of a number of medical conditions and behavioral traits conventionally seen as associated with elevated androgen levels in women with ASD. In addition, mothers of children with ASD and other close relatives had some of the same abnormalities. These findings are consistent with the androgen theory of autism, suggesting that the studied conditions and ASD share a common risk factor, presumably elevated testosterone levels. In contrast to this study we were unable to find significantly increased rates of three studied testosterone-related cancer diseases in mothers of children with IA. In addition, the proportion of case mothers diagnosed with one of the three cancer diseases (breast cancer [3.6%], uterine cancer [1.8%] and ovarian cancer [0.9%]) are all lower than in the study by Ingudomnukul et al.6
Concerning breast cancer, it has been suggested13 that a high testosterone level is protective against breast cancer before menopause (offsetting the proliferative effects of estrogen), but that post menopause testosterone may increase risk through aromatization to estrogen. If true, this would suggest that only postmenopausal cases of breast cancer would be linked to high testosterone (and thus relevant to the androgen hypothesis of ASD). Premenopausal cases might actually be less frequent in mothers of children with ASD. Our results do not support this hypothesis.
Our results are based on hospital register data, covering an entire national population, and not assessed face-to-face. It is a major advantage of the current study that bias in recalling life events was avoided as all data were collected routinely, independently of the study. Furthermore, using register data gives a complete follow up on all cases and controls without the attrition that may limit ‘personal’ follow-up studies. In the questionnaire study by Ingudomnukul et al.6 the response rate was 50.3% for ASD case mothers. The authors called attention to the possibility that individuals who were affected by the studied conditions were probably more likely to fill out the questionnaire than those who were unaffected, resulting in an overestimation of the studied diseases. A limitation of our study is that the reliability of the medical data is unknown. However, a validation study dealing with a number of diagnoses in the DHNR found validity ranging from 75% to 90%.17
In conclusion, studies of testosterone-related cancer diseases in mothers of children with ASD have so far shown inconsistent results. Additional studies with larger sample sizes of different diagnostic subgroups, comparison groups matched for age and observation period, and systematically collected data on maternal disease status will be required to determine whether there is a true association between a maternal history of testosterone-related cancer diseases and ASD in their offspring.