The perinatal androgen to estrogen ratio and autistic-like traits in the general population: a longitudinal pregnancy cohort study

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Abstract

Background

Prenatal androgen exposure has been hypothesized to be linked to autism spectrum disorder (ASD). While previous studies have found a link between testosterone levels in amniotic fluid and autistic-like traits, a similar relationship has not been found for testosterone in umbilical cord blood. However, it may be the net biological activity of multiple androgens and estrogens that influences postnatal effects of prenatal sex steroids. Accordingly, composite levels of androgens (A) and estrogens (E) were investigated, along with their ratio, in relation to autistic-like traits in young adulthood.

Methods

Sex steroid data in umbilical cord blood were available from 860 individuals at delivery. Samples were analyzed for androgens (testosterone, androstenedione, and dehydroepiandrosterone) and estrogens (estrone, estradiol, estriol, and estetrol). Levels of bioavailable testosterone, estradiol, and estrone were measured and used to calculate A and E composites and the A to E ratio. Participants were approached in early adulthood to complete the autism-spectrum quotient (AQ) as a self-report measure of autistic-like traits, with 183 males ( M = 20.10 years, SD = 0.65 years) and 189 females ( M =19.92 years, SD = 0.68 years) providing data.

Results

Males exhibited significantly higher androgen composites and A to E composite ratios than females. Males also scored significantly higher on the details/patterns subscale of the AQ. Subsequent categorical and continuous analyses, which accounted for covariates, revealed no substantial relationships between the A/E composites or the A to E ratio and the AQ total or subscale scores.

Conclusions

The current study found no link between the A/E composites or the A to E ratio in cord blood and autistic-like traits in the population as measured by the AQ. These outcomes do not exclude the possibility that these sex steroid variables may predict other neurodevelopmental traits in early development.

Electronic supplementary material

The online version of this article (doi:10.1186/s11689-015-9114-9) contains supplementary material, which is available to authorized users.

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Most cited references 64

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2nd to 4th digit ratios, fetal testosterone and estradiol.

S Lutchmaya, S. Baron-Cohen, P Raggatt … (2004)

The ratio of 2nd to 4th digit length (2D:4D) is sexually dimorphic (mean 2D:4D is lower in males than females) and is thought to be fixed early in development. 2D:4D has been reported to be related to fetal growth, hand preference, autism, Asperger's syndrome, sperm counts, family size, age at myocardial infarction in men and breast cancer in women. There is indirect evidence that 2D:4D is established in utero and is negatively related to prenatal testosterone and positively with prenatal estradiol. However, there are no studies which show direct relationships between fetal testosterone (FT), fetal estradiol (FE) and 2D:4D. To investigate the relationships between 2D:4D ratios and FT and FE from amniotic fluid. Cohort study. 33 children. Radioimmunoassays of FT and FE obtained from routine amniocentesis; 2D:4D ratios calculated from 2nd and 4th digit length of the right and left hands at age 2 years. A significant negative association between right 2D:4D ratio and FT/FE ratio, which was independent of sex. These preliminary findings lend support to an association between low 2D:4D and high levels of FT relative to FE, and high 2D:4D with low FT relative to FE.

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Reframing sexual differentiation of the brain.

Margaret McCarthy, Arthur P. Arnold (2011)

In the twentieth century, the dominant model of sexual differentiation stated that genetic sex (XX versus XY) causes differentiation of the gonads, which then secrete gonadal hormones that act directly on tissues to induce sex differences in function. This serial model of sexual differentiation was simple, unifying and seductive. Recent evidence, however, indicates that the linear model is incorrect and that sex differences arise in response to diverse sex-specific signals originating from inherent differences in the genome and involve cellular mechanisms that are specific to individual tissues or brain regions. Moreover, sex-specific effects of the environment reciprocally affect biology, sometimes profoundly, and must therefore be integrated into a realistic model of sexual differentiation. A more appropriate model is a parallel-interactive model that encompasses the roles of multiple molecular signals and pathways that differentiate males and females, including synergistic and compensatory interactions among pathways and an important role for the environment.

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The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function.

N L Chamberlain, E D Driver, R L Miesfeld (1994)

Some transcription factors contain stretches of polyglutamine encoded by repeats of the trinucleotide CAG. Expansion of the CAG repeat in the androgen receptor (AR) has been correlated with the incidence and severity of X-linked spinal and bulbar muscular atrophy (Kennedy's disease). In order to understand the relationship of this mutation to AR function, we constructed ARs that varied in the position and size of the polyglutamine tract, and assayed for the abilities of these mutant receptors to bind androgen and to activate transcription of several different AR-responsive reporter genes. Elimination of the tract in both human and rat AR resulted in elevated transcriptional activation activity, strongly suggesting that the presence of the polyglutamine tract is inhibitory to transactivation. Progressive expansion of the CAG repeat in human AR caused a linear decrease of transactivation function. Importantly, expansion of the tract did not completely eliminate AR activity. We postulate that this residual AR activity may be sufficient for development of male primary and secondary sex characteristics, but may fall below a threshold level of activity necessary for normal maintenance of motor neuron function. This functional abnormality may be representative of other genetic diseases that are associated with CAG expansion mutations in open reading frames, such as spinocerebellar ataxia type I and Huntington's disease.

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Author and article information

Contributors

Esha S. L. Jamnadass: (08) 6488 3575 , esha.jamnadass@research.uwa.edu.au

Murray T. Maybery: murray.maybery@uwa.edu.au

Andrew J. O. Whitehouse: Andrew.Whitehouse@telethonkids.org.au

Journal

Journal ID (nlm-ta): J Neurodev Disord

Journal ID (iso-abbrev): J Neurodev Disord

Title: Journal of Neurodevelopmental Disorders

Publisher: BioMed Central (London )

ISSN (Print): 1866-1947

ISSN (Electronic): 1866-1955

Publication date (Electronic): 7 June 2015

Publication date PMC-release: 7 June 2015

Publication date (Print): 2015

Volume: 7

Issue: 1

Electronic Location Identifier: 17

Affiliations

[ ]School of Psychology, University of Western Australia, 35 Stirling Hwy, Crawley, WA 6009 Australia

[ ]Telethon Kids Institute, Centre for Child Health Research, University of Western Australia, 100 Roberts Road, Subiaco, WA 6008 Australia

[ ]School of Women’s and Infant’s Health, University of Western Australia, Perth, Australia

[ ]Faculty of Health Sciences, Curtin University, Kent Street, Bentley, Western Australia 6102 Australia

[ ]Department of Obstetrics and Gynaecology, University of Melbourne and the Royal Women’s Hospital, Victoria, Australia

Article

Publisher ID: 9114

DOI: 10.1186/s11689-015-9114-9

PMC ID: 4470005

PubMed ID: 26085846

SO-VID: 2182465d-39fc-4e04-9742-3ee52064a54c

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 30 December 2014

Date accepted : 28 May 2015

Custom metadata

ScienceOpen disciplines: Neurosciences

Keywords: androgens,estrogens,autistic-like traits,sex steroids,cord blood,perinatal,autism-spectrum quotient

Data availability:

ScienceOpen disciplines: Neurosciences

Keywords: androgens, estrogens, autistic-like traits, sex steroids, cord blood, perinatal, autism-spectrum quotient

The perinatal androgen to estrogen ratio and autistic-like traits in the general population: a longitudinal pregnancy cohort study

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Abstract

Background

Methods

Results

Conclusions

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Most cited references 64

2nd to 4th digit ratios, fetal testosterone and estradiol.

Reframing sexual differentiation of the brain.

The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function.

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