Gender identity, sex hormones & the developing brain

The sexual differentiation of the human brain with regard to sexual orientation
and gender identity, i.e. the feeling of being a man or a woman, proceeds under
the influence of sex hormones during embryonic development. Since the sexual
differentiation of the genitals takes place earlier in development than the
sexual differentiation of the brain, these two processes may occur
independently. It is thus possible that hormone levels are somehow disrupted at
the time of brain sexual differentiation which may explain the phenomenon of
Gender Identity Disorder (GID), which is characterized by a conviction of
having been born in the body of the opposite sex. GID often shows up before
puberty. At present, these young GID patients are treated with a GnRH
(Gonadotropin-Releasing Hormone) agonist to suppress puberty until they are
allowed to start with cross sex-hormone treatment. However, it is unknown
whether pubertal hormones influence gender identity. In other words, is gender
identity already established during prenatal development or does it need to be
consolidated by sex hormones during puberty?
GID often shows up before puberty and is then called *early onset* GID. When
the gender dysphoric feelings start after puberty, this diagnosis subtype is
called *late onset* GID. Comparison of the two subtypes of GID may provide
information regarding a differential neurobiological aetiology of GID.

To compare sex differences in brain functioning using functional magnetic
resonance imaging (fMRI) in healthy pre-pubertal boys and girls with a group of
children diagnosed with GID. Subjects will have a second fMRI scan, as soon as
they enter puberty. In a second experiment, a group of adolescent GID patients
will be scanned twice, once before and once during their cross-sex hormone
treatment. Sex differences in brain functioning will be compared to a healthy
age-matched control group. We will use hypothalamic responses to pheromones as
one task since sex differences have been reported in these responses in adults.
By means of a neuropsychological test session and a measure of otoacoustic
emissions, gender differences will be assessed on a behavioural as well as
physiological level.
The prenatal androgen exposure of a group of adult natal males with GID will be
estimated retrospectively by means of measuring OAEs and the second to fourth
digit ratio (2D:4D).

The present study is an observational, longitudinal study, having a
within-subjects (repeated measures) 2x2x2 factorial design, with three
independent variables: time (1st measurement, 2nd measurement), sex (male,
female), and diagnosis of GID (yes, no). Two age groups, peripubertal children
and adolescents, will be seen twice during their development.
Two groups of natal men diagnosed with GID, one group with the *early onset*
and one with the *late onset* subtype will be compared.

Participants are asked to come to the lab two times, for respectively 1,5 hours
(screening session) and 3 hours (actual testing session, fMRI experiment). For
the screening, subjects are asked to bring early morning saliva and urine
samples; they will be seen for a physical examination by a paediatrician, and
will receive an olfactory function test.
During the test session subjects undergo a neuropsychological assessment, a
measure of click-evoked otoacoustic emissions, and an fMRI session. The risks,
associated with participation, can be considered negligible and the burden can
be considered minimal. The current study can be regarded as group-related.
Because the aim of the study is to investigate the effects of pubertal hormone
changes on gender identity and brain function, the participation of
pre-pubertal children is required.
Adult participants will be asked for a 15 min test session for the assessment
of CEOAEs and 2D:4D measurement. The risks, associated with participation, can
be considered negligible and the burden can be considered minimal.