Studies of non-human mammals show that androgens, particularly testosterone (T), during early development play a major role in sexual differentiation of the brain, with long-term consequences for behavior. Research on clinical populations suggests that prenatal T exposure has similar effects in humans, increasing male-typical behavior and reducing female-typical behavior. Almost nothing is known, however, about the impact of early T exposure on the structure of the human brain. In addition, the brain mechanisms underlying T-related behavioral changes are unknown. This project will study brain structure and behavior in individuals with one of two disorders of sex development (DSD, also called intersex conditions) that are characterized by androgen abnormality beginning prenatally: 1. Congenital adrenal hyperplasia (CAH), which causes overproduction of adrenal androgens; and 2. Complete androgen insensitivity syndrome (CAIS), which involves an inability to respond to androgens, and so an effective lack of androgen exposure. CAH affects both males and females, and 35 men and 35 women with CAH will be compared to 35 male and 35 female controls. Individuals with CAIS are XY females, and 35 females with CAIS will be compared to 35 male and 35 female controls. State-of- the-art imaging technology will be used to map brain structure. Also, aspects of behavior, known to show substantial sex differences, and for which there is evidence of a relationship to prenatal T exposure, will be assessed. Specifically, these are mental rotation ability, targeting ability, and propensities to physical aggression (where men score higher than women), and verbal fluency, fine motor ability and empathy (where women score higher than men). The information obtained will provide convergent evidence regarding the influence of T on human brain and behavior. Convergent evidence is important because ethical considerations preclude experimental manipulations of T during early human development. Instead, naturally occurring conditions that involve T excess or deficiency will be studied. Each condition involves consequences in addition to T abnormality. Therefore, confidence that testosterone caused any brain or behavior differences is strengthened when data from both conditions suggest this conclusion. For instance, prior research indicates that, with respect to physical aggression, men score higher than women, and females with CAH score higher than other females. If XY females with CAIS resemble women rather than men in regard to physical aggression, confidence that T is the responsible agent will be increased. The information obtained will enhance understanding of the neural mechanisms involved in sexual differentiation of human brain and behavior, and so will be relevant to the many psychological disorders that differ by sex. It will also be relevant to clinical management of individuals who have experienced T abnormality before birth, for any of several reasons, including genetic disorders, such as CAH or CAIS, or other disorders of sex development, maternal treatment with hormones during pregnancy, or contact with environmental endocrine disruptors.

Public Health Relevance

There are large sex discrepancies in many neurological and behavioral disorders, including, e.g., autistic spectrum conditions, depression, conduct disorder, Parkinson's disease, and Alzheimer's disease. The proposed work will expand understanding of the effects of testosterone on the developing brain and behavior and so should ultimately contribute to more effective prevention or treatment of these sex-linked disorders. Also, the research will involve individuals with one of two intersex disorders (also known as disorders of sex development), congenital adrenal hyperplasia, and complete androgen insensitivity syndrome, and so should inform their treatment, including the continuing debate regarding sex assignment and clinical management in these and other intersex conditions, as well as prove relevant to offspring of pregnancies where androgenic or anti-androgenic hormones have been prescribed for medical reasons, or of pregnancies involving exposure to environmental agents influencing androgen concentrations or activity.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD081720-01A1
Application #
8963733
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Freund, Lisa S
Project Start
2015-08-14
Project End
2020-05-31
Budget Start
2015-08-14
Budget End
2016-05-31
Support Year
1
Fiscal Year
2015
Total Cost
$332,114
Indirect Cost
$14,501
Name
University of Cambridge
Department
Type
DUNS #
226552610
City
Cambridge
State
Country
United Kingdom
Zip Code
CB2 1-TN
Kurth, Florian; Jancke, Lutz; Luders, Eileen (2017) Sexual dimorphism of Broca's region: More gray matter in female brains in Brodmann areas 44 and 45. J Neurosci Res 95:626-632
Luders, Eileen; Kurth, Florian; Pigdon, Lauren et al. (2017) Atypical Callosal Morphology in Children with Speech Sound Disorder. Neuroscience 367:211-218