Elsevier

Biological Psychology

Volume 103, December 2014, Pages 48-53
Biological Psychology

Perinatal testosterone exposure and cerebral lateralisation in adult males: Evidence for the callosal hypothesis

https://doi.org/10.1016/j.biopsycho.2014.08.009Get rights and content

Highlights

  • Testosterone concentrations were measured from umbilical cord blood.

  • Language and spatial memory laterality measured in early adulthood using the functional Transcranial Doppler (fTCD).

  • Right hemisphere language lateralisation was statistically more likely for low testosterone individuals than high testosterone individuals.

  • Spatial memory laterality was not related to cord testosterone level.

  • Findings support Witelson's callosal hypothesis.

Abstract

Two competing theories address the influence of foetal testosterone on cerebral laterality: one proposing exposure to high foetal testosterone concentrations is related to atypical lateralisation (Geschwind–Galaburda hypothesis), the other that high foetal testosterone concentrations exaggerate typical lateralisation (callosal hypothesis). The current study examined the relationship between cord testosterone concentrations and cerebral laterality for language and spatial memory in adulthood. Male participants with high (>0.15 nmol) and low (<0.10 nmol) cord testosterone levels were invited to take part in the study (n = 18 in each group). Cerebral laterality was measured using functional Transcranial Doppler ultrasonography, while participants completed word generation and visual short-term memory tasks. Typical left lateralisation of language was more common in the high-testosterone group than in the low-testosterone group, χ2 = 4.50, df = 1, p = 034. Spatial memory laterality was unrelated to cord testosterone level. Our findings indicate that foetal testosterone exposure is related to language laterality in a direction that supports the callosal hypothesis.

Introduction

Two prominent theories address the influence of foetal testosterone exposure on cerebral lateralisation. Geschwind and Galaburda (1987) proposed exposure to higher levels of foetal testosterone during critical periods of prenatal neurodevelopment shifts development of structures subserving certain functions, such as language, predominantly to the right hemisphere. They further suggest that the influence of prenatal testosterone exposure on left-hemisphere growth retardation would be more apparent in men. A second theory, the callosal hypothesis put forward by Witelson and Nowakowski, 1991, Witelson, 1991, suggests that, in men, higher concentrations of foetal testosterone increases axonal pruning in the corpus callosum, which leads to a more pronounced typical lateralisation of functions.

Studies examining the two competing theories have revealed mixed findings. Accurate measurement of foetal testosterone exposure presents a methodological challenge, and studies have typically used proxy measures. A commonly used indicator of foetal testosterone exposure is the second-to-fourth digit (2D:4D) ratio, where low 2D:4D ratio is suggestive of high foetal testosterone exposure (Manning, 2002). Kallai et al. (2005) found that low 2D:4D ratio was associated with decreased right posterior hippocampus volume and larger right middle hippocampus volume in 40 healthy female adults. These findings suggest levels of prenatal testosterone are related to development of laterality in sub-cortical regions. Bourne and Gray (2009) found lower 2D:4D digit ratios were associated with stronger right hemisphere lateralisation for visuospatial attention in a sample of 77 women. Similarly, a recently conducted fMRI study found a significant negative correlation between digit ratio and extent of functional visuospatial laterality (Kalmady et al., 2013). These studies suggest that higher prenatal testosterone exposure is associated with increased right hemisphere activation for visuospatial function. However, there is some doubt as to whether 2D:4D ratio is a reliable proxy measure for prenatal testosterone exposure, since the ratio has not shown a consistent relationship to more direct measures of prenatal testosterone (Dean and Sharpe, 2013, Hickey et al., 2010, Knickmeyer et al., 2011).

A few published studies have utilised a more direct measure of prenatal testosterone exposure through sampling amniotic fluid during the second trimester. In two studies (Grimshaw et al., 1995, Lust et al., 2010), cerebral lateralisation of offspring was measured using a dichotic listening task, which involves simultaneous presentation of different auditory stimuli to both ears. It is argued that participants with a right ear advantage (i.e. selecting the stimulus presented to the right ear more often than the one presented to the left ear) have left hemisphere dominance for language, and vice versa for a left ear advantage (Kimura, 1961). Both studies found an association between higher levels of testosterone in amniotic fluid and increased left hemisphere dominance for language, providing support for the callosal hypothesis (Grimshaw et al., 1995, Lust et al., 2010). However, neuroimaging studies have provided contradictory evidence. In support of the Geschwind and Galaburda hypothesis, amniotic testosterone concentrations have been shown to correlate positively with increasing rightward asymmetry of the isthmus (Chura et al., 2010). Mercure et al. (2009) measured functional lateralisation for perception of words and faces using event related potentials (ERPs) in 26 typically developing school-aged boys. No relationship was observed between amniotic testosterone levels and indices of cerebral lateralisation. While sampling amniotic fluid is a more direct measure than the 2D:4D ratio of the prenatal hormone environment, a limitation of this approach is that amniocenteses are performed only in high risk pregnancies and therefore research samples are unlikely to be representative of broader populations.

Recently, a new approach to sampling foetal testosterone has emerged through measurements of umbilical cord serum, which allow for larger and more representative sampling of pregnancies. Higher concentrations of cord testosterone have been associated with reduced vocabulary in boys at 2 and 5 years of age (Farrant et al., 2013, Hollier et al., 2013), increased risk of language delay in early childhood (Whitehouse et al., 2012), and reduced spatial ability in 6 year old girls (Jacklin, Wilcox, & Maccoby, 1988). Umbilical cord blood can be easily collected from uncomplicated pregnancies following delivery, and so sex steroid concentrations reflect levels in foetal circulation at late gestation (Keelan et al., 2012). Most studies report that cord testosterone concentrations are consistently higher in males compared to females (Herruzo et al., 1993, Keelan et al., 2012, Maccoby et al., 1979, Troisi et al., 2003). The main limitation of this approach is that cord hormone concentrations may not reflect those earlier in gestation, particularly during critical periods of foetal neurodevelopment (Cohen-Bendahan, van de Beek, & Berenbaum, 2005). However, there is increasing recognition from experimental studies, that effects of prenatal hormones on the development of neural regions are not restricted to the first two trimesters, and that final trimester levels may also play a role in neurodevelopment (Roselli et al., 2011, Zambrano et al., 2014).

The current study examined the relationship between foetal testosterone and cerebral laterality in males, utilising umbilical cord blood collected at birth and a functional neuroimaging measure in early adulthood. Participants were drawn from a large population-based pregnancy-cohort study and subjects were selected based on having low- or high-concentrations of testosterone measured from cord blood. Cerebral laterality was measured using functional Transcranial Doppler (fTCD), which uses ultrasound to measure event-related changes in blood-flow velocity in the middle cerebral arteries. fTCD is based on the premise that increases in neural activity leads to greater glucose and oxygen consumption that must be replenished via enhanced blood flow to the area (Lohmann, Ringelstein, & Knecht, 2006). This method gives high correlations with existing ‘gold standard’ measures of cerebral lateralisation, such as the Wada technique (Knecht et al., 1998) and fMRI (Deppe et al., 2000).

Based on the Geschwind and Galaburda hypothesis it is predicted that high testosterone levels would be associated with less left hemisphere activation for language production and increased right hemisphere activation for visuospatial memory. Conversely, if the findings support the callosal hypothesis we would expect high testosterone levels to be associated with increased left hemisphere activation for language production and increased right hemisphere activation for visuospatial memory.

Section snippets

Participants

Volunteers from the Western Australian Pregnancy Cohort (Raine) Study participated in the current study. Between May 1989 and November 1991, 2900 pregnant women were recruited from King Edward Memorial Hospital or nearby private practices. Eight-hundred and fifty-nine children (430 male; 429 female) had umbilical cord serum collected at birth. Right-handed male participants were selectively recruited to take part in the study based on the cord testosterone concentrations. In order to create

Results

Table 1 presents data on the chronological age, BioT concentrations and psychometric scores of participants in the two groups. Independent samples t-tests showed no significant differences between the two groups for chronological age, WASI PIQ or TROG scores. As expected based on group selection criteria, there was a statistically significant difference in BioT concentrations (Cohen's d = 3.21) (Table 2, Table 3).

Analysis then turned to the data obtained through fTCD. There were no significant

Discussion

We found that a significantly higher proportion of participants with low umbilical testosterone levels exhibited atypical lateralisation for language than those with high umbilical testosterone. This finding is in line with the callosal hypothesis, which proposes that higher levels of foetal testosterone increase axonal pruning in the corpus callosum, resulting in more pronounced typical lateralisation (Witelson, 1991). The current finding is consistent with results reported by both Lust et al.

Acknowledgements

The authors would like to acknowledge the National Health and Medical Research Council (NHMRC) and the Telethon Kids Institute for their long term contribution to funding the Raine study over the last 20 years. The androgen analysis was funded by Australian Rotary Health. Core Management of the Raine study has been funded by the University of Western Australia (UWA), Curtin University, the UWA Faculty of Medicine, Dentistry and Health Sciences, the Raine Medical Research Foundation, Telethon

References (50)

  • M. Hickey et al.

    Maternal and umbilical cord androgen concentrations do not predict digit ratio (2D:4D) in girls: A prospective cohort study

    Psychoneuroendocrinology

    (2010)
  • L.P. Hollier et al.

    The association between perinatal testosterone concentration and early vocabulary development: A prospective cohort study

    Biological Psychology

    (2013)
  • J. Kallai et al.

    MRI-assessed volume of left and right hippocampi in females correlates with the relative length of the second and fourth fingers (the 2D:4D ratio)

    Psychiatry Research: Neuroimaging

    (2005)
  • R.C. Knickmeyer et al.

    2D:4D ratios in the first 2 years of life: Stability and relation to testosterone exposure and sensitivity

    Hormones and Behavior

    (2011)
  • J.M. Lust et al.

    Sex specific effect of prenatal testosterone on language lateralization in children

    Neuropsychologia

    (2010)
  • G.A. Mathews et al.

    Androgenic influences on neural asymmetry: Handedness and language lateralization in individuals with congenital adrenal hyperplasia

    Psychoneuroendocrinology

    (2004)
  • E. Mercure et al.

    IQ, fetal testosterone and individual variability in children's functional lateralization

    Neuropsychologia

    (2009)
  • D.P. Merke et al.

    Congenital adrenal hyperplasia

    Lancet

    (2005)
  • S.C. Mueller et al.

    Early androgen exposure modulates spatial cognition in congenital adrenal hyperplasia (CAH)

    Psychoneuroendocrinology

    (2008)
  • L.R. Stroud et al.

    Long-term stability of maternal prenatal steroid hormones from the national collaborative perinatal project: Still valid after all these years

    Psychoneuroendocrinology

    (2007)
  • A.J.O. Whitehouse et al.

    Hemispheric division of function is the result of independent probabilistic biases

    Neuropsychologia

    (2009)
  • S.F. Witelson

    Neural sexual mosaicism: Sexual differentiation of the human temporo-parietal region for functional asymmetry

    Psychoneuroendocrinology

    (1991)
  • S.F. Witelson et al.

    Left out axoms make men right: A hypothesis for the origin of handedness and functional asymmetry

    Neuropsychologia

    (1991)
  • E. Zambrano et al.

    Fetal programming of sexual development and reproductive function

    Molecular and Cellular Endocrinology

    (2014)
  • N.A. Badcock et al.

    Using functional transcranial doppler ultrasonography to assess language lateralisation: Influence of task and difficulty level

    Laterality: Asymmetries of Body, Brain and Cognition

    (2012)
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