Our objective is to determine the role of androgens and the Y-chromosome in sexual differentiation of the brain. Women with CAIS, who only differ from typical women in that they have a Y-chromosome, and from men in that they cannot respond to…
ID
Source
Brief title
Condition
- Other condition
- Reproductive tract and breast disorders congenital
- Sexual dysfunctions, disturbances and gender identity disorders
Synonym
Health condition
Sexual differentiation of the brain
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The parameters of interest include brain morphology, the ability to detect AND,
CEOAE scores, 2D:4D ratios, brain activity in the resting state as well as in
response to AND presentation and two cognitive tasks during the fMRI
experiment, and estrogen (estradiol and ethinylestradiol), LH, FSH,
progesterone and testosterone levels on the test day.
Secondary outcome
N/A
Background summary
The sexual differentiation of the brain, to be male- or female-typical, is an
active area of research in both humans and in non-human animal models. The
precise factors that produce such sexual differentiation have yet to be fully
elucidated, but many aspects of this process have been described. The
determination of sex begins with the sex chromosomes. Females typically have
two X-chromosomes and males typically have one X- and one Y-chromosome. The
presence of the Y-chromosome begins a cascade toward the development of the
male gonads (testes), and in the absence of this chromosome, female gonads
(ovaries) develop. Sexual differentiation of the body and brain to produce a
male or female-typical phenotype is then patterned by the presence of
testosterone from testes in males, and the absence of testosterone in females.
Testosterone, acting at androgen receptors or estrogen receptors (testosterone
can be converted to estrogen by the enzyme aromatase in local tissues) produces
changes throughout the body and brain to produce a typical male, while the
absence of testosterone results in a typically female body and brain.
Recent work has shed light on previously unknown details in this process. In
particular, the contribution of the Y-chromosome, independent of its role in
directing the formation of the gonads, appears to be important in producing
sex-typical brain structure and function. The presence or absence of the
Y-chromosome, independent of testicular formation and testosterone production,
can alter sexual behavior in mice, indicating its importance in the development
of male-typical brain and behavior.
There are individuals for whom sexual development does not follow the usual
path. These individuals provide a unique opportunity to study how sex hormones
and sex chromosomes act to produce sexual differentiation of the brain. Women
with complete androgen insensitivity syndrome (CAIS) have XY chromosomes (like
males), but cannot respond to testosterone due to genetic mutations resulting
in a non-functional androgen receptor. Therefore, while they carry the
Y-chromosome, develop testes, and produce testosterone, the absence of the
androgen receptor results in a female phenotype. However, other genes on the
Y-chromosome may be producing developmental effects that are male-typical, as
in mice. CAIS women then enable us to study how the absence of the ability to
respond to androgens, and the presence of the Y-chromosome, independent of its
role in the development of the testes, produce sexual differentiation of the
brain.
Study objective
Our objective is to determine the role of androgens and the Y-chromosome in
sexual differentiation of the brain. Women with CAIS, who only differ from
typical women in that they have a Y-chromosome, and from men in that they
cannot respond to androgens, will be compared to typical males and females in
measures of brain structure and function. If androgens are necessary for the
sexual differentiation of the male-typical brain, then CAIS woman will have at
least some female-typical brain structure/function when compared to control
males. If the Y-chromosome is sufficient for the sexual differentiation of the
male-typical brain, independent of sex hormones, then CAIS women will have at
least some male-typical brain structure/function when compared to control
females.
Study design
Our subjects, CAIS women and age/education-matched heterosexual males,
heterosexual females, heterosexual transsexuals and homosexual transsexuals
(controls), will fill out questionnaires pertaining to their demographics,
health, sexuality, and gender identity. The subjects will then engage in a
number of tasks the produce sex differences in brain activity. Olfactory
performance and the ability to detect the chemosignal androstadienone (AND)
will be determined for each individual. We will record click-evoked otoacoustic
emissions (CEOAEs) at subjects ears and take a photocopy of both hands in order
to measure the length of the second and fourth digit to determine the 2D:4D
ratio. We will measure functional brain activity with functional magnetic
resonance imaging (fMRI) in response to AND, two cognitive tasks and during the
resting state, and we will also obtain structural MRI scans. We will also take
blood samples from our subjects to measure their estrogen (estradiol and
ethinylestradiol), LH, FSH, progesterone and testosterone levels on the testing
day. We will then use between- and within-group comparisons on these measures
to examine the role of sex androgens and the Y-chromosomes in the sexual
differentiation of brain structure and function.
Study burden and risks
Subjects will be asked to come to the lab once. In this session, lasting
approximately 2.5 hours, subjects will fill out our neuropsychological
questionnaires, smell different odors and be asked questions about them, have
click-evoked otoacoustic emissions recorded and digit length measured (by
photocopy), participate in fMRI scans, and provide a blood sample.
The risks associated with participation are considered negligible. Distress
due to neuropsychological testing is expected to be minimal and olfactory
chemosignal presentation is not expected to adversely affect subjects. The
fMRI scan procedure is not expected to produce any adverse effects.
.
This study can only be completed with the CAIS subject group because of their
unique sex chromosomal makeup.
Subjects will be compensated with a gift voucher worth ¤ 40,- and for their
travel expenses.
Meibergdreef 47
1105 BA Amsterdam
NL
Meibergdreef 47
1105 BA Amsterdam
NL
Listed location countries
Age
Inclusion criteria
All subjects: Right-handed, Normative olfactory performance,Written informed consent obtained;Healthy Volunteers: Heterosexual orientation, Sex-typical gender identity;Transsexual controls: Genetically male, sex-atypical gender identity;Patients: Diagnosis of complete androgen insensitivity syndrome (CAIS)
Exclusion criteria
All subjects: Smoking, Excessive drug/alcohol use, Psychiatric and Neurological illness, Significant physical illness (excluding diagnosis of CAIS), Anosmia or hyposmia, MRI contraindications ;Healthy Volunteers (20 men and 20 of 40 women): Hormone therapy or birth control pills
Design
Recruitment
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In other registers
Register | ID |
---|---|
CCMO | NL32740.029.10 |