Why is autism more common in males?

Simon Baron-Cohen

Autism Research Centre

Cambridge University

Cambridge-DenmarkCollaborators

Michael V Lombardo, Bonnie Auyeung,

Bhismadev Chakrabarti, Liliana Ruta,

Bent Nørgaard-Pedersen, David Hougaard, Morsi Abdallah,

Lars Melgard, Arieh Cohen

Other Collaborators

• Psychology and Brain Scanning

Sally Wheelwright, Johnny Lawson, Nigel Goldenfeld, Jen Richler, Jen Connellan, Anna Bakti, Carrie Allison, Ed Bullmore, Howard Ring, Xavier Chitnis, Chris Ashwin, Lindsay Chura, Meng-Chuan Lai, John Suckling

• Hormones and Genetics

Gerald Hackett, Kevin Taylor, Rebecca Knickmeyer, Emma Ashwin, Svetlana Lutchmaya, Melissa Hines, Lindsey Kent, Frank Dudbridge, Erin Ingudomnukul

Why the male bias?

•Classic autism: 4:1 •Asperger Syndrome: 9:1

•Social•Clinical factors•Genetics•Hormones (sex steroids/androgens)•An extreme of certain male-typical traits?

Brain Volume

Lenroot & Guidd, Neuroimage, 2007,

Alonso-Nancalareset et al, 2008, PNAS

Knickmeyer et al 2008 J Neurosci

Lenroot & Guidd, Neuroimage 2007Gilmore et al (2007) J. Neuroscience.

Grey Matter

White Matter

Gray Matter VolumeLenroot & Guidd, Neuroimage 2007

Frontal Lobe

Temporal Lobe

males > femalesAmygdala

Good et al. (2001) Neuroimage

females > malesPlanum Temporale(Heschl’s Gyrus)/Wernicke’s)

Hines (2003)

Child’s play

Pierce et al (2010)

Alexander and Hines 2002

Monkey play

Physics, computer science, engineering, mathematics

Primary school, counseling

Occupations

Reilly 2012, Plos-One

EmpathyIdentify another person’s thoughts and feelings

respond with an appropriate emotion

Systemizing

Analysing or building a system

sarcastic stern

suspicious dispirited

FemalesFemales MalesMales ASAS

22.122.1 19.5 19.5 16.616.6

(2.0)(2.0) (2.6)(2.6) (2.9)(2.9)JCPP1997

Females > Males > Autism

Left Inferior Frontal Gyrus

fdfd

Females > Males > Autism(EQ)

• People often tell me I went too far in driving my point home in a discussion

• I often find it difficult to judge if something is rude or polite

ASAS 20.420.4 (11.6)(11.6)

MalesMales 41.841.8 (11.2)(11.2)

FemalesFemales 47.247.2 (10.2)(10.2)

JADD 2004

Females > Males > Autism

Corpus Planum Callosum Temporale

Systemising Quotient

Autism > Males > Females

ASAS 35.935.9 (15.2)(15.2)

MalesMales 30.3 30.3 (11.7)(11.7)

FemalesFemales 24.124.1 (9.5)(9.5)

ASAS ControlsControls

16.316.3 10.310.3

(3.1)(3.1) (2.8)(2.8)

Autism > Males > Females

FemalesFemales MalesMales ASAS

66.766.7 46.246.2 32.232.2

(36.7)(36.7) (20.5)(20.5)(27.0)(27.0)

JCN, 1997

Autism > Males > Females

Females > Males > Autism

Posterior Parietal Cortex

BC et al, 2001

ASAS 35.835.8 6.56.5MalesMales 17.817.8 6.86.8FemalesFemales15.415.4 5.75.7

Autism > Males > Females

AQ

Autism > Males > Females

AmygdalaSchumann et al 2010 J Neurosci

DiffDiff MenMen WomenWomen ASAS

E > SE > S 1717 4444 11

S > ES > E 5454 1717 2727

S >> ES >> E 66 00 6565

Int. J. Clin Neuropsych (2006)

% %

Pierce et al 2010Arch Gen Psychiatry

Fetal sex steroids (androgens)

• fetal testosterone (FT)

• males produce double

• organizational effects

Cambridge Amniocentesis Study• 12-19 weeks in pregnancy (n = 619)

• 12, 24, 48, 96 months follow-up

Feeling sorry

interested

bored

joking

Em

path

y

Fetal Testosterone

Systemizing

Euro J Endocrin 2006

Attention todetail

Auyeung et al, 2012

JADD, 2001; Auyeung et al, 2009

Autistic traits

My child prefers to do things with others rather than on his/her own.

My child prefers to do things the same way over and over again.

Corpus callosum(Chura et al 2009)

Planum TemporaleLombardo et al 2012

Autism and AS (n=70)

Historic Birth Cohort Denmark (n>100,000)

Singletons born 1993-99 (n=19,677)

Controls (n=219)

progesterone

17α-hydroxy cortisol

progesterone

androstenedione

testosterone The Δ4-sex steroid pathwayCYP17-mediated (Chakrabarti et al 2009)

Cambridge-Denmark Study: ASC (n = 59) Controls (n = 219)

HSD17B4

HSD17B2*

CYP11B1*

ESR1

ESR2

HSD11B1

LHCGR

CYP17A1

CYP19A1

SCP2

EQ /AQAS case-control

10 sex steroid genes

(* = EQ only)Chakrabarti et al, 2009 Autism Research

Hormonal factors• Puberty (Tordjeman et al, 1997; Ingudomnukul et al, 2007)

• Polycystic Ovary Syndrome (PCOS)(Ingudomnukul et al, 2007; Kao et al, 2010)

• 2D:4D ratio(Manning et al 2001; Swettenham et al, 2006; Noipayak, 2009)

• Salivary testosterone (Schmidtova et al, 2010)

• Serum androstenedione(Ruta et al 2011)

Conclusions / Future directions

• Fetal androgens/sex steroids play a role in sexual dimorphism in brain development and behaviour, especially autistic traits

• Fetal sex steroids interact with genetic factors and postnatal experience

• The Cambridge-Denmark study is the strong test of the fetal androgen theory of autism

www.autismresearchcentre.com

Thanks to

The Nancy Lurie Marks FoundationMedical Research Council UK

Wellcome Trust UKTarget Autism Genome

NIHR CLAHRC

The steroidogenic pathway