overview - mcri.edu.au

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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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


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 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


• 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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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)


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)


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)


Odd

s R

atio

(95

lang

uage

Im

p


Males

4

5

6

5% C

I) f

or

pairm

ent

0

1

2

3

Quartile 1 (lowest)


Odd

s R

atio

(95

lang

uage

Im

p


Males

4

5

6

5% C

I) f

or

pairm

ent

0

1

2

3

Quartile 1 (lowest)


Odd

s R

atio

(95

lang

uage

Im

p


Males

4

5

6

5% C

I) f

or

pairm

ent

0

1

2

3

Quartile 1 (lowest)


Odd

s R

atio

(95

lang

uage

Im

p


Females

0.8

1

1.2

1.4

% C

I) f

or

irmen

t

0

0.2

0.4

0.6

Quartile 1 (lowest)


Odd

s R

atio

(95

%la

ngua

ge I

mpa

i


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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


• 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


• 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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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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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: [email protected]

Website: http://autism.childhealthresearch.org.au

pT language delay

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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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