Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Neurodevelopmental Disorders
Published in: Journal of Neurodevelopmental Disorders 1/2015

Open Access 01-12-2015 | Research

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

Authors: Esha S. L. Jamnadass, Jeffrey A. Keelan, Lauren P. Hollier, Martha Hickey, Murray T. Maybery, Andrew J. O. Whitehouse

Published in: Journal of Neurodevelopmental Disorders | Issue 1/2015

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
Whitehouse AJ, Stanley FJ. Is autism one or multiple disorders? Med J Aust. 2013;28:302–3.CrossRef
2.
3.
Taylor LJ, Maybery MT, Whitehouse AJ. Moving beyond behaviour-only assessment: incorporating biomarkers to improve the early detection and diagnosis of autism spectrum disorders. Int J Speech-Language Pathol. 2014;16:19–22.CrossRef
4.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Washington DC: 2013.
5.
Anello A, Reichenberg A, Luo X, Schmeidler J, Hollander E, Smith CJ, et al. Brief report: parental age and the sex ratio in autism. J Autism Dev Disord. 2009;39:1487–92.PubMedCrossRefPubMedCentral
6.
7.
Manning JT, Baron Cohen S, Wheelwright S, Sanders G. The 2nd to 4th digit ratio and autism. Dev Med Child Neurol. 2001;43:160–4.PubMedCrossRef
8.
Hayward C. Gender Differences at Puberty. Cambridge University Press; 2003.
9.
Dart D. Androgens have forgotten and emerging roles outside of their reproductive functions, with implications for diseases and disorders. J Endocr Disord. 2014;1:1005.
10.
Goy RW, McEwen BS. Sexual Differentiation of the Brain. Cambridge, MA: MIT Press; 1980.
11.
Arnold AP. The organizational-activational hypothesis as the foundation for a unified theory of sexual differentiation of all mammalian tissues. Horm Behav. 2009;55:570–8.PubMedCrossRefPubMedCentral
12.
13.
14.
Kraus C, Pfannkuche K, Trillmich F, Groothuis TG. High maternal androstenedione levels during pregnancy in a small precocial mammal with female genital masculinisation. Max Planck Institute for Demographic Research Working Papers. 2008;1:2008.
15.
Hutson JM. The Hormones Regulating Sex Development. In: Disorders of Sex Development Springer. 2012. p. 23–9.CrossRef
16.
17.
Jordan-Young RM. Hormones, context, and “brain gender”: a review of evidence from congenital adrenal hyperplasia. Soc Sci Med. 2012;74:1738–44.PubMedCrossRef
18.
Knickmeyer R, Baron-Cohen S, Raggatt P, Taylor K, Hackett G. Fetal testosterone and empathy. Horm Behav. 2006;49:282–92.PubMedCrossRef
19.
Lutchmaya S, Baron-Cohen S, Raggatt P, Knickmeyer R, Manning JT. 2nd to 4th digit ratios, fetal testosterone and estradiol. Early Hum Dev. 2004;77:23–8.PubMedCrossRef
20.
Manning JT, Kilduff L, Cook C, Crewther B, Fink B. Digit ratio (2D:4D): a biomarker for prenatal sex steroids and adult sex steroids in challenge situations. Front Endocrinol. 2014;5.
21.
Voracek M, Dressler SG. Lack of correlation between digit ratio (2D:4D) and Baron-Cohen’s “reading the mind in the eyes” test, empathy, systemising, and autism-spectrum quotients in a general population sample. Personal Individ Differ. 2006;41:1481–91.CrossRef
22.
23.
Hollier LP, Keelan JA, Hickey M, Maybery MT, Whitehouse AJ. Measurement of androgen and estrogen concentrations in cord blood: accuracy, biological interpretation, and applications to understanding human behavioral development. Front Endocrinol. 2014;5:64.CrossRef
24.
Knickmeyer R, Baron-Cohen S. Fetal testosterone and sex differences. Early Hum Dev. 2006;82:755–60.CrossRef
25.
Abramovich D. Human sexual differentiation—in utero influences. BJOG. 1974;81:448–53.CrossRef
26.
Auyeung B, Taylor K, Hackett G, Baron-Cohen S. Research foetal testosterone and autistic traits in 18 to 24-month-old children. Infant Behav Dev. 2010;418–424.
27.
Lutchmaya S, Baron-Cohen S. Human sex differences in social and non-social looking preferences, at 12 months of age. Infant Behav Dev. 2002;25:319–25.CrossRef
28.
Knickmeyer R, Baron Cohen S, Raggatt P, Taylor K. Foetal testosterone, social relationships, and restricted interests in children. J Child Psychol Psychiatry. 2005;46:198–210.PubMedCrossRef
29.
Chapman E, Baron-Cohen S, Auyeung B, Knickmeyer R, Taylor K, Hackett G. Fetal testosterone and empathy: evidence from the empathy quotient (EQ) and the “reading the mind in the eyes” test. Soc Neurosci. 2006;1:135–48.PubMedCrossRef
30.
Auyeung B, Baron Cohen S, Ashwin E, Knickmeyer R, Taylor K, Hackett G, et al. Fetal testosterone and autistic traits. Br J Psychol. 2009;100:1–22.PubMedCrossRef
31.
Baron-Cohen S, Auyeung B, Nørgaard-Pedersen B, Hougaard D, Abdallah M, Melgaard L. Elevated fetal steroidogenic activity in autism. Mol Psychiatry. 2014.
32.
Auyeung B, Baron-Cohen S. Fetal Testosterone in Mind: Human Sex Differences and Autism, The Primate Mind: Built to Connect with Other Minds. 2012. p. 194.
33.
Roselli CE, Estill CT, Stadelman HL, Meaker M, Stormshak F. Separate critical periods exist for testosterone-induced differentiation of the brain and genitals in sheep. Endocrinology. 2011;152:2409–15.PubMedCrossRefPubMedCentral
34.
35.
Zambrano E, Guzmán C, Rodríguez-González GL, Durand-Carbajal M, Nathanielsz PW. Fetal programming of sexual development and reproductive function. Mol Cell Endocrinol. 2014;382:538–49.PubMedCrossRef
36.
Hickey M, Hart R, Keelan JA. The relationship between umbilical cord estrogens and perinatal characteristics. Cancer Epidemiology, Biomarkers & Prevention 2014:Epub online March 17.
37.
Keelan JA, Mattes E, Tan H, Dinan A, Newnham JP, Whitehouse AJO, et al. Androgen concentrations in umbilical cord blood and their association with maternal. Fetal and Obstetric Factors. PLoS One. 2012;7, e42827.PubMedCrossRefPubMedCentral
38.
Dobbing J. The later growth of the brain and its vulnerability. Pediatrics. 1974;53:2–6.PubMed
39.
Farrant BM, Mattes E, Keelan JA, Hickey M, Whitehouse AJ. Fetal testosterone, socio emotional engagement and language development. Infant Child Dev. 2013;22:119–32.CrossRef
40.
Hollier LP, Mattes E, Maybery MT, Keelan JA, Hickey M, Whitehouse AJ. The association between perinatal testosterone concentration and early vocabulary development: a prospective cohort study. Biol Psychol. 2013;92:212–5.PubMedCrossRef
41.
Robinson M, Whitehouse AJ, Jacoby P, Mattes E, Sawyer MG, Keelan JA, et al. Umbilical cord blood testosterone and childhood internalizing and externalizing behavior: a prospective study. PLoS One. 2013;8, e59991.PubMedCrossRefPubMedCentral
42.
Jacklin CN, Wilcox KT, Maccoby EE. Neonatal sex steroid hormones and cognitive abilities at six years. Dev Psychobiol. 1988;21:567–74.PubMedCrossRef
43.
Whitehouse AJ, Mattes E, Maybery MT, Sawyer MG, Jacoby P, Keelan JA, et al. Sex specific associations between umbilical cord blood testosterone levels and language delay in early childhood. J Child Psychol Psychiatry. 2012;53:726–34.PubMedCrossRef
44.
Whitehouse AJ, Mattes E, Maybery MT, Dissanayake C, Sawyer M, Jones RM, et al. Perinatal testosterone exposure and autistic-like traits in the general population: a longitudinal pregnancy-cohort study. J Neurodev Disord. 2012;4:1–12.CrossRef
45.
Martin JT. Sexual dimorphism in immune function: the role of prenatal exposure to androgens and estrogens. Eur J Pharmacol. 2000;405:251–61.PubMedCrossRef
46.
Giarelli E, Wiggins LD, Rice CE, Levy SE, Kirby RS, Pinto-Martin J, et al. Sex differences in the evaluation and diagnosis of autism spectrum disorders among children. Disabil Health J. 2010;3:107–16.PubMedCrossRef
47.
Hönekopp J, Bartholdt L, Beier L, Liebert A. Second to fourth digit length ratio (2D:4D) and adult sex hormone levels: new data and a meta-analytic review. Psychoneuroendocrinology. 2007;32:313–21.PubMedCrossRef
48.
Hollier LP, Keelan JA, Jamnadass SL, Maybery MT, Hickey M, Whitehouse AJO. Adult Digit Ratio (2D:4D) is not Related to Umbilical Cord Androgen or Estrogen Concentrations Early Human Development. 2014.
49.
50.
Faix JD. Principles and pitfalls of free hormone measurements. Best Pract Res Clin Endocrinol Metab. 2013;27:631–45.PubMedCrossRef
51.
Newnham JP, Evans SF, Michael CA, Stanley FJ, Landau LI. Effects of frequent ultrasound during pregnancy: a randomised controlled trial. Lancet. 1993;342:887–91.PubMedCrossRef
52.
Sartorius G, Ly LP, Sikaris K, McLachlan R, Handelsman DJ. Predictive accuracy and sources of variability in calculated free testosterone estimates. Ann Clin Biochem. 2009;46:137–43.PubMedCrossRef
53.
Zlotkin S, Casselman C. Percentile estimates of reference values for total protein and albumin in sera of premature infants (less than 37 weeks of gestation). Clin Chem. 1987;33:411–3.PubMed
54.
Mazer NA. A novel spreadsheet method for calculating the free serum concentrations of testosterone, dihydrotestosterone, estradiol, estrone and cortisol: With illustrative examples from male and female populations. Steroids. 2009;74:512–9.PubMedCrossRef
55.
Baron-Cohen S, Wheelwright S, Skinner R, Martin J, Clubley E. The autism-spectrum quotient (AQ): evidence from asperger syndrome/high-functioning autism, malesand females, scientists and mathematicians. J Autism Dev Disord. 2001;31:5–17.PubMedCrossRef
56.
Austin EJ. Personality correlates of the broader autism phenotype as assessed by the autism spectrum quotient (AQ). Personal Individ Differ. 2005;38:451–60.CrossRef
57.
Hurst R, Mitchell J, Kimbrel N, Kwapil T, Nelson-Gray R. Examination of the reliability and factor structure of the autism spectrum quotient (AQ) in a non-clinical sample. Personal Individ Differ. 2007;43:1938–49.CrossRef
58.
Stewart ME, Austin EJ. The structure of the autism-spectrum quotient (AQ): evidence from a student sample in Scotland. Personal Individ Differ. 2009;47:224–8.CrossRef
59.
Russell-Smith SN, Maybery MT, Bayliss DM. Relationships between autistic-like and schizotypy traits: an analysis using the autism spectrum quotient and Oxford-Liverpool inventory of feelings and experiences. Personal Individ Differ. 2011;51:128–32.CrossRef
60.
Seron-Ferre M, Ducsay CA, Valenzuela GJ. Circadian rhythms during pregnancy. Endocr Rev. 1993;14:594–609.PubMed
61.
Hoekstra RA, Bartels M, Cath DC, Boomsma DI. Factor structure, reliability and criterion validity of the autism-spectrum quotient (AQ): a study in Dutch population and patient groups. J Autism Dev Disord. 2008;38:1555–66.PubMedCrossRefPubMedCentral
62.
63.
Quarello E, Stirnemann J, Ville Y, Guibaud L. Assessment of fetal Sylvian fissure operculization between 22 and 32 weeks: a subjective approach. Ultrasound Obstet Gynecol. 2008;32:44–9.PubMedCrossRef
64.
Knaus TA, Corey DM, Bollich AM, Lemen LC, Foundas AL. Anatomical asymmetries of anterior perisylvian speech-language regions. Cortex. 2007;43:499–510.PubMedCrossRef
65.
Binder LM, Rohling ML, Larrabee GJ. A review of mild head trauma. Part I: meta-analytic review of neuropsychological studies. J Clin Exp Neuropsychol. 1997;19:421–31.PubMedCrossRef
66.
Humphreys P, Kaufmann WE, Galaburda AM. Developmental dyslexia in women: neuropathological findings in three patients. Ann Neurol. 1990;28:727–38.PubMedCrossRef
67.
Cohen M, Campbell R, Yaghmai F. Neuropathological abnormalities in developmental dysphasia. Ann Neurol. 1989;25:567–70.PubMedCrossRef
68.
Galaburda AM, Sherman GF, Rosen GD, Aboitiz F, Geschwind N. Developmental dyslexia: four consecutive patients with cortical anomalies. Ann Neurol. 1985;18:222–33.PubMedCrossRef
69.
Plante E, Swisher L, Vance R, Rapcsak S. MRI findings in boys with specific language impairment. Brain Lang. 1991;41:52–66.PubMedCrossRef
70.
71.
Lubahn DB, Joseph DR, Sar M, Tan J-a, Higgs HN, Larson RE, et al. The human androgen receptor: complementary deoxyribonucleic acid cloning, sequence analysis and gene expression in prostate. Mol Endocrinol. 1988;2:1265–75.PubMedCrossRef
72.
Lubahn DB, Brown TR, Simental JA, Higgs HN, Migeon CJ, Wilson EM, et al. Sequence of the intron/exon junctions of the coding region of the human androgen receptor gene and identification of a point mutation in a family with complete androgen insensitivity. Proc Natl Acad Sci. 1989;86:9534–8.PubMedCrossRefPubMedCentral
73.
74.
Chamberlain NL, Driver ED, Miesfeld RL. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res. 1994;22:3181–6.PubMedCrossRefPubMedCentral
75.
Krithivas K, Yurgalevitch S, Mohr B, Wilcox C, Batter S, Brown M, et al. Evidence that the CAG repeat in the androgen receptor gene is associated with the age-related decline in serum androgen levels in men. J Endocrinol. 1999;162:137–42.PubMedCrossRef
76.
Westberg L, Baghaei F, Rosmond R, Hellstrand M, Landén M, Jansson M, et al. Polymorphisms of the androgen receptor gene and the estrogen receptor β gene are associated with androgen levels in women. J Clin Endocrinol Metab. 2001;86:2562–8.PubMed
77.
Wagner CK. The many faces of progesterone: a role in adult and developing male brain. Front Neuroendocrinol. 2006;27:340–59.PubMedCrossRef
78.
Sultan C, Balaguer P, Terouanne B, Georget V, Paris F, Jeandel C, et al. Environmental xenoestrogens, antiandrogens and disorders of male sexual differentiation. Mol Cell Endocrinol. 2001;178:99–105.PubMedCrossRef
79.
Rai D, Lewis G, Lundberg M, Araya R, Svensson A, Dalman C, et al. Parental socioeconomic status and risk of offspring autism spectrum disorders in a Swedish population-based study. J Am Acad Child Adolesc Psychiatry. 2012;51:467–76.PubMedCrossRef
Metadata
Title
The perinatal androgen to estrogen ratio and autistic-like traits in the general population: a longitudinal pregnancy cohort study
Authors
Esha S. L. Jamnadass
Jeffrey A. Keelan
Lauren P. Hollier
Martha Hickey
Murray T. Maybery
Andrew J. O. Whitehouse
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Neurodevelopmental Disorders / Issue 1/2015
Print ISSN: 1866-1947
Electronic ISSN: 1866-1955
DOI
https://doi.org/10.1186/s11689-015-9114-9

Other articles of this Issue 1/2015

Journal of Neurodevelopmental Disorders 1/2015 Go to the issue

Research

An fMRI study of facial emotion processing in children and adolescents with 22q11.2 deletion syndrome

Research

Psychiatric disorders in adolescents and young adults with Down syndrome and other intellectual disabilities

Research

Face scanning and spontaneous emotion preference in Cornelia de Lange syndrome and Rubinstein-Taybi syndrome

Research

Complete or partial reduction of the Met receptor tyrosine kinase in distinct circuits differentially impacts mouse behavior

Research

A multidisciplinary approach unravels early and persistent effects of X-ray exposure at the onset of prenatal neurogenesis

Research

Behavioral, cognitive, and adaptive development in infants with autism spectrum disorder in the first 2 years of life