Feeling “trapped” in the wrong sex: a genetic condition?
May 11, 2005
Special to World Science
Scientists say they may have found genes that help
explain why a tiny percentage of men see themselves as women, cruelly trapped in
the wrong body.
The researchers say the
findings are very preliminary and should be “interpreted with the utmost
caution,” due to the small sample size used in their study.
Nonetheless, they say, the
results might shed some light on the rare condition, transsexualism. It is
estimated to afflict about one in 30,000 men, some of whom follow through on
their sense of their correct gender by getting sex-change operations.
More broadly, the research could help clarify one of the most contentious and
poorly understood questions in biology: what creates “gender identity”—the
sense most people have that they are either a man or a woman. The feeling is
normally rather deep-seated; people don’t need to repeatedly examine their
body shapes to confirm it. The feeling is also considered distinct from the
issue of whom a person is sexually attracted to.
The question is how genes, culture or both conspire to produce gender identity.
Transsexualism “raises important questions as to how the gender identity is
moulded in humans,” wrote the researchers, who included Susanne Hennigsson of
Göteborg University and Mikael Landén of the the Karolinska Institute in Göteborg
and Stockholm, Sweden, respectively. They described the research in the August
issue of the scientific journal Psychoneuroendocrinology.
If their findings are correct, the risk of becoming a transsexual may depend
partly on variations in the length of certain segments of DNA where the genetic
code “stutters,” that is, where a few letters of the code repeat themselves
in the same order many times over.
Notably, scientists found in a study published last December that these repeat
sequences may be the sites of some of the most most common genetic mutations,
and thus may underlie some of the fastest evolutionary changes in life’s
history. Evolutionary theory holds that mutations are responsible for evolution,
because the occasional mutations that are advantageous spread through
populations, change their characteristics, and over time gradually create new
In that study of last year, researchers found that the muzzle length of dogs
depends on the length of certain repeat sequences.
In the transsexualism study, the researchers examined a repeat sequence in each
of three genes known to affect the sexual development of the brain, in hopes
that one or more of these might shed light on transsexualism. They studied
several common variants affecting the length of these repeats in different
These variants “are all much more common than is transsexualism” itself,
they wrote. “Hence, the goal of this study was not to reveal the primary cause
of transsexualism,” but rather to help explain “whether the studied genes
may facilitate or prevent” it.
One particular variant seemed significantly associated with the risk of
transsexualism, they found. This variant was in a gene responsible for producing
a molecule called ER-Beta. This molecule acts as a minuscule gateway that
controls the flow of estrogen, a hormone, through the brain during fetal
Estrogen is thought to be responsible for wiring the brain in a “masculine”
way in healthy males before birth—although, paradoxically, the substance is
better known as a female sex hormone. This is because after birth, it influences
the development of female sexual characteristics.
The gene that produces the Estrogen Receptor-beta receptor contains a section
called a CA repeat sequence, so called because C and A are names for two
“letters” of the genetic code which, here, are repeated many times in a row.
The researchers found that longer CA repeats were associated with a greater risk
of transsexualism in the their study, which included 29 male-to-female
transsexuals (men who wish they were women) and 229 healthy males.
It is unknown exactly how this change in the Estrogen Receptor-beta gene might
contribute to transsexualism, the researchers said. The gene may produce
different variants of the molecular gateway, which transmit estrogen more or
less easily; but it’s unknown whether one of these might be the reason for the
effect, or whether the reason is something else.
Moreover, the researchers found that the two other genes that they studied might
also influence the risk of becoming a transsexual. But neither of these genes on
its own predicted that risk, they found. Rather, specific combinations of all
three gene variants seemed to be more common among transsexuals.
The other two genes studied were genes encoding the production of molecules
called aromatase and androgen receptor. These genes, too, are believed to help
determine how “masculine” the brain becomes.
More masculine, in this context, means that certain brain structures are
relatively smaller or larger in males than in females, possibly reflecting the
relative importance of those brain structures in each sex.
Researchers have found that parts of the frontal cortex, the seat of many
reasoning functions, and the limbic cortex, involved in emotions, are bigger
compared to other brain areas in women than in men. Parts of the parietal
cortex, which contributes to spatial perception, and the amygdala, which
responds to emotionally arousing information, are bigger in men. A part of the
hypothalamus, a brain region that regulates reproductive behavior, is also
believed to be bigger in males.
At least one brain region has also been found to be different in male
heterosexuals and homosexuals, also a part of the hypothalamus. And more
recently, gay and straight men have been found to differ in how their brain
responds to a scent in male sweat.
But scientists don’t know whether homosexuality and transsexualism have
anything in common biologically, beyond the fact that some people view them both
as aberrations—and that now, both are being found to have a possible genetic
The idea that genes underlie transsexualism, at least among men who want to be
women, has gained support from reports on twin and non-twin siblings who both
have “this very rare condition, and from reports on families with more than
one member” having it, Henningsson and colleagues wrote.
“Gender identity” is typically established by 18 to 24 months of age,
according to the Merck Manual of Diagnosis and Therapy, 17th edition. By this
time, “boys come to know they are boys, and girls come to know they are
Some people act in ways typically considered more appropriate for the other sex,
but this doesn’t make them transsexuals, as long as they’re comfortable with
their physical gender. Rather, transsexuals “believe that they are victims of
a biologic accident,” the manual says, “and that they are cruelly imprisoned
within a body incompatible with their gender identity.”