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2/04/2012
1
Prenatal testosterone and language development
Andrew Whitehouse
Overview
1. Who am I?
2. Background to the area
3. Current study
– Another terrific longitudinal study!
4. Planned work (cerebral lateralisation)
– Follow‐up study
– Autism PRISM study
5. Conclusions
My path
Speech Pathologist PhD
OxfordTelethon Institute
Me• Autism Research Team
– Research officers and assistants
– PhD Students
Background
Sex differences
• Language development
– Males < females
– First 12 months
• Frequency joint attention• Frequency joint attention
• Frequency dyadic interaction
– Rate of vocab development
– Increased risk of DLD
Whitehouse, JSLHR, 2010
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2
Sex differences
• Assuming sex differences, what may cause this?
– Socio‐developmental differences?
• Parental input?
S ifi i i fl– Sex‐specific genetic influences
• CNTNAP2 (Whitehouse et al., 2011, Genes, Brain, Behavior)
• Influence in a different way
• To a greater or lesser extent
– Another biological difference
• Hormones?
Androgens
• Androgens
– A generic term that for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors.
1. Testosterone2. Dehydroepiandrosterone (DHEAS)3. 4-androstenedione (A4)
Prenatal testosterone
• How are fetuses exposed to T?
Endogenous
Exogenous
Males have higher testosterone levels in-utero
Prenatal testosterone
1. T in blood stream2. Transceullular lipophilic pathway3. Astrocyte glial cell4. Binds with androgen receptor5. Enters nucleus, binds with DNA,
affects transcription
Testosterone
Prenatal testosterone
• Prenatal testosterone child development?
– Difficult to study in humans
• Manipulation of hormone environment unethical!
– Natural experiments
• Congenital Adrenal Hyperplasia (CAH)• Genetic deficiency in the enzyme 21‐hydroxylase
• Overproduction of adrenal androgens
• Female testosterone within or above the typical male range
Prenatal testosterone
• Congenital Adrenal Hyperplasia
– Females typically have VIQ < PIQ• Hampson et al., 1998; Kelso et al., 2000; Kelso et al., 1999; Resnicket al., 1986
rate of language difficulties– rate of language difficulties • Plante et al., 1996
• But…
– difficult to extrapolate from clinical cases to the broader population
• Two groups…
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3
Cambridge Cohort
• Cambridge Cohort
– Simon Baron‐Cohen and colleagues
– Second trimester amniotic fluid
Inverse associationBirth
Inverse association with expressive vocab
No association with verbal IQ (or PIQ)
Mixed evidence
12- 20 weeks
2 years
6-10 years
Cambridge Cohort
• Amniocentesis
– Limitations
1. Unrepresentative samples
2. Weak association with fetal circulating testosterone levelsg
Another method
• Umbilical cord blood
– Advantage
• Easily obtained at normal delivery
Another method
• Umbilical cord blood
– Limitations
• May not reflect concentrations during 1st & 2nd trimester (particularly GA weeks 8‐24).
• Perhaps advantageous?
Current Study
Current Study
• Aim:– To determine the association between testosterone concentrations from umbilical cord blood and early language development
Birth
T concentrations from cord blood
Language development to age 3 years
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Current Study
• Western Australian Pregnancy Cohort (Raine) Study
– 2900 pregnant women recruited between 1989 and 1991
– Randomized controlled trial of ultrasonography
• Follow‐up
– N = 2868 at birth
– Every 2 – 3 years
– Retention ~ 65%
Predictor variable
• Predictor variable
– Umbilical cord testosterone
• At birth
1989 1991 C d bl d b i d 828 bi h– 1989‐1991: Cord blood obtained at 828 births
– 2011: Analyzed for androgens
20 years
Predictor variable
• Biochemistry
– Step 1
• Measure total testosterone (LC/MS)
• SHBG (RIA)SHBG (RIA)
– Step 2
• Calculate ‘free testosterone’– Free T = Total testosterone ‐ SHBG
• Calculate BioT
– BioT = Free T + albumin‐bound testosterone
Predictor variable
40
50
60
Females
Males
0
10
20
30
40
0.08
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
0.55
0.60
0.65
0.70
0.75
0.80
0.85
0.90
1.00
1.05
1.10
1.15
1.20
1.25
1.30
1.35
1.40
1.45
1.50
1.55
1.60
1.65
1.70
2.00
3.00
4.00
Frequency
Total testosterone concentrations (nM)BioT
Predictor variable
• Biochemistry
– Step 1
• Measure total testosterone (LC/MS)
• SHBG (RIA)
– Step 2
• Calculate ‘free testosterone’– Free T = Total testosterone ‐ SHBG
• Calculate BioT
– BioT = Free T + albumin‐bound testosterone
– Quartiles: Quartile 1 (lowest) Quartile 4 (highest)
– Separately for males and females
Outcome variable
• Outcome variable
– Infant development
• Ages 1, 2 and 3 years
I f M i i Q i i– Infant Monitoring Questionnaire
• Parent‐report
• Five domains
• 12‐, 24‐, and 36‐month questionnaires
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Outcome variable
• Infant Monitoring Questionnaire
– Communication“Does your child make sentences that are three or four words long?”
– Gross MotorDoes your child run well, being able to stop himself without bumping into things or falling?
– Fine MotorDoes your child hold a pencil or crayon with his fingers and thumb the way an adult does?
– AdaptiveAfter he watches you draw a cross (+) on paper, does your child make one like yours.
– Personal/SocialWhen playing with a stuffed animal or doll, does your child pretend to feed or dress it?
Outcome variable
• Outcome variable
– Infant development
• Ages 1, 2 and 3 years
I f M i i Q i i– Infant Monitoring Questionnaire
– Parent‐report questionnaire
– 12‐, 24‐, and 36‐month questionnaires
– Clinical cutoffs for each scale at each age
• Binary variable (‘Delayed’ vs ‘Not delayed’)
Statistics
Quartile 1 (Lowest)
Quartile 2 Quartile 3 Quartile 4 (highest)
Delayed % % % %
Quartile 1 (Lowest)
Quartile 2 Quartile 3 Quartile 4 (highest)
Delayed % % % %
Statistical analyses
1. Sex differences in IMQ scores
2. Follow‐up
– BioT and IMQ scores
• Generalized Estimating Equations
– Include covariates (gestational age a birth, birthweight, socioeconomic status)
Sex differences
‘Communication’ was the only consistent sex-difference
Outcome variable
• Language delay more common in males
– What about links with BioT?
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6
Males
4
5
6
5% C
I) f
or
pairm
ent
0
1
2
3
Quartile 1 (lowest)
Quartile 2 Quartile 3 Quartile 4 (highest)
Odd
s R
atio
(95
lang
uage
Im
p
Testosterone concentrations
Males
4
5
6
5% C
I) f
or
pairm
ent
0
1
2
3
Quartile 1 (lowest)
Quartile 2 Quartile 3 Quartile 4 (highest)
Odd
s R
atio
(95
lang
uage
Im
p
Testosterone concentrations
Males
4
5
6
5% C
I) f
or
pairm
ent
0
1
2
3
Quartile 1 (lowest)
Quartile 2 Quartile 3 Quartile 4 (highest)
Odd
s R
atio
(95
lang
uage
Im
p
Testosterone concentrations
Males
4
5
6
5% C
I) f
or
pairm
ent
0
1
2
3
Quartile 1 (lowest)
Quartile 2 Quartile 3 Quartile 4 (highest)
Odd
s R
atio
(95
lang
uage
Im
p
Testosterone concentrations
Males
4
5
6
5% C
I) f
or
pairm
ent
0
1
2
3
Quartile 1 (lowest)
Quartile 2 Quartile 3 Quartile 4 (highest)
Odd
s R
atio
(95
lang
uage
Im
p
Testosterone concentrations
Females
0.8
1
1.2
1.4
% C
I) f
or
irmen
t
0
0.2
0.4
0.6
Quartile 1 (lowest)
Quartile 2 Quartile 3 Quartile 4 (highest)
Odd
s R
atio
(95
%la
ngua
ge I
mpa
i
Testosterone concentrations
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Conclusions
• Findings
– Males: testosterone from cord blood = risk for language delay
– Females: testosterone from cord blood =↓ riskFemales: testosterone from cord blood = ↓ risk for language delay
– Sex specific effects?
• Circulatory system
• Central Nervous System as well?
Planned studiesHappening right nowHappening right now
Mechanisms
• How does prenatal T influence language?
– Cerebral lateralization
al
Left
Whitehouse & Bishop, Neuropsychologia, 2009
Vis
uosp
atia
Language
Right
Right Left
Cerebral lateralisation
• LI as a failure to develop lateralisation?
• Long history (1920s)
– Mixed evidence
– For: • Structural: Cohen et al., 1989; Jernigan et al., 1991; Plante et al., 1991; Gauger et al., 1997; Herbert et al., 2003; Jäncke et al., 2007)
• Functional: Tzourio et al., 1994; Chiron et al., 1999; Bernal and Altman, 2003; Lou et al., 1984, 1990; Ors et al., 2005).
– Against: • Shafer et al., 2000; Trauner et al., 2000; Preis et al., 1998
Samuel Orton
Cerebral lateralisation
• Oxford study
– Adults with:• SLI
• ASD
t Hem
isph
ere
• SLI history
• Typical
– fTCD• Word generation
Left
Rig
ht H
emis
pher
e
Whitehouse & Bishop, Brain, 2009
Cerebral lateralisation
• Prenatal testosterone cerebral lateralization
– Long history (1980s)
– Geschwind and Galaburda
Evidence– Evidence
• Congenital Adrenal Hyperplasia
– Handedness, dichotic listening
• Mixed at best
– Fell out of favour
– Let’s try again with modern methods
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8
Planned Studies
1. Raine study follow‐up
– 50 low BioT and 50 high BioT (for each sex)
– fTCD
• Word generation (left hemisphere)• Word generation (left hemisphere)
Left Right
Sex differences?
Planned studies
2. Prenatal investigation of autism
“I knew from the very first time I held him in my arms that there was something different about him.”
Genetic evidence
Postnatal evidence
DoHAD
Prenatal
Planned studies
• But ASD is diagnosis in postnatal life…
– How do we study the prenatal period?
1%
18.7%
ASD ‘Low’ risk
‘High’ risk
Ris
k o
f AS
D
Planned studies
Planned studies
• PRISM
– Pregnant women with an existing child with ASD
Birth
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Planned studies
2. PRISM
– Pregnant women with an existing child with ASD
Follow development of child
Birth
Planned studies
N = 100 N = 100
Case families
Control families
Conclusions
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10
Key messages
• Summary:1. Prenatal period is an important epoch
• Testosterone (Whitehouse et al., in press, JCPP)
• Vitamin D (Whitehouse et al., 2012, Pediatrics)
2. Biology is also important…
Implications
• Once we identify mechanisms, we can:
1. Promote the healthiest prenatal environment possible
2. Furthermore, we could: • Identify subgroups of LI
• Increase monitoring of ‘at risk’ children.
• Development of more targeted interventions
Next steps
• Further examine: Prenatal testosterone
exposure
– Human replication
– Animal models
– Randomised controlled trials
Language development
Cerebral lateralisaion
Acknowledgements
Psychologists
Cheryl Dissanayake (La Trobe)
Lauren Hollier (UWA)
Murray Maybery (UWA)
Obstetricians
Pharmacologist
Jeff Keelan (UWA)
Paediatrician
Eugene Mattes (UWA)
Michael Sawyer (Adelaide)Obstetricians
Tony Murphy (UWA)
John Newnham (UWA)
Craig Pennell (UWA)
Michael Sawyer (Adelaide)
Gynaecologist
Martha Hickey (Melbourne)
Thank you
Email: awhitehouse@ichr.uwa.edu.au
Website: http://autism.childhealthresearch.org.au
pT language delay
2/04/2012
11
Predictor variable
T
T
TT
Free TBound T
TT
T
T
Brain tissue
T
T
SHBG
T
T
SHBG
T
T
SHBG
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