Is there a genetic cause for HBS?
by Charlotte Goiar
Copyright @ 2005-2011, Charlotte
All Rights Reserved
Scientists say they may have found genes that help explain why a tiny percentage of apparent
men see themselves as women.
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 a rare condition called HBS. Some of the people
with HBS follow through on their sense of their correct gender by receiving hormone replacement therapy (HRT) and Sex Affirmation
More broadly, the research could help clarify one of the most contentious and poorly understood questions
in biology: what creates gender identity. That is, the sense most people have that they are either a man or a woman.
The feeling is normally rather deep-seated; people do not need to examine their body to confirm it. This
sense is quite distinct from the question of which gender a person is sexually attracted to.
The question is how genes, culture, or both conspire to produce gender identity.
The researchers believe that HBS raises important questions as to what moulds gender identity in humans.
The scholars in the study included Susanne Hennigsson of Göteborg University and Mikael Landén of the Karolinska Institute
in Göteborg and Stockholm, Sweden, respectively.
They describe the research in the August issue of the scientific journal Psychoneuroendocrinology.
If their findings are correct, the risk of having HBS may depend partly on variations in the length of certain
segments of DNA where the genetic code "stutters". That is, a few "letters" of the code repeat themselves in the same order
Notably, scientists published a study in December 2004 that these repeat sequences may be the sites of some
of the most common genetic mutations, and thus may underlie some evolutionary changes in life’s history.
Evolutionary theory holds that mutations produce evolution, because the occasional mutations that are advantageous
spread through populations, changing these populations’ characteristics, and over time gradually create new species.
In the December 2004 study, researchers found that the muzzle length of dogs depends on the length of certain
In the HBS 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 HBS.
They studied several common variants affecting the length of these repeats in different people.
The researchers concluded that these variants are much more common than is HBS itself. The primary goal of
the study was not to reveal the principal cause of HBS, but rather to help explain whether the studied genes may facilitate
or prevent it.
They found one particular variant significantly associated with the frequency of HBS. The researchers saw
this variant in a gene instrumental in producing a molecule called ER-Beta. ER-Beta acts as a minuscule gateway that controls
the flow of oestrogen, a hormone, through the brain during foetal development.
Researchers think that oestrogen is responsible for developing the brain in a "masculine" manner in males
before birth. This is a paradox, as oestrogen is better known for its’ role as a female sex hormone. This is because
it influences the development of female secondary sexual characteristics at puberty.
The gene that produces the ER-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 HBS in the study, which
included 29 people with HBS (male-to-female variant) and 229 healthy males.
It is unknown exactly how this change in the ER-beta gene might contribute to HBS, the researchers said.
The gene may produce different variants of the molecular gateway, which transmit oestrogen more or less easily.
However, researchers do not know whether these cause the effect, or whether the basis is actually somewhere
Moreover, the researchers found that the two other genes that they studied also seem to influence the risk
of having HBS. However, they found that neither of these genes on its own predicted that risk. Rather, specific combinations
of all three variants seemed to be more common in cases of HBS.
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 larger in men. Researchers believe that a part of the hypothalamus, a brain region that
regulates reproductive behaviour is bigger in males.
Researchers may have found at least one brain region that is different in male heterosexuals and homosexuals,
also a part of the hypothalamus. In addition, more recently, a study found that homosexual and heterosexual men differ in
how their brain responds to a scent in male sweat.
However, scientists do not know whether homosexuality and HBS have anything in common physiologically. This
has no bearing on the fact that some people view both as aberrations. Some researchers would now say that both have a possible
genetic basis. This hypothesis lacks confirmation.
The idea that genes underlie HBS has gained support from reports on twin and non-twin siblings who both have
this condition. Also it comes 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, when "boys come to know they are boys,
and girls come to know they are girls", according to the Merck Manual of Diagnosis and Therapy, 17th Edition.
Some people behave in manners that society typically considers more appropriate for the other gender, but
this does not make them people with HBS, so long as they are comfortable with their physical gender.
Rather, people with HBS believe that they are victims of a conflict between their neurological and physical
Source: Adapted from information found in Special to World Science 11 May 2005.
A gene variant has been
identified that appears to be associated with Harry Benjamin Syndrome (HBS) – a physiological Intersexual
condition formerly know as "transssexualism".
While such genetic etiology is likely the
result of multiple genes, the researchers say the discovery suggests that Harry Benjamin Syndrome does have a genetic
The variation is in the gene for an enzyme called
cytochrome P17, which is involved in the metabolism of sex hormones. Its presence leads to higher than average tissue concentrations
of male and female sex hormones, which may in turn influence early brain development.
Clemens Tempfer and his colleagues at
the Medical University of Vienna in Austria discovered the variant after analysing DNA samples
from 49 men born with HBS and 102 women born with HBS, as well as 1669 non-HBS patients controls.
The finding raises the possibility that
the variant makes women more likely to feel that their bodies are of the wrong sex (HBS), and that this is a result of
their brains having been exposed to higher than average levels of sex hormones during development.
"It may increase the likelihood that people will
suffer Harry Benjamin Syndrome" says Tempfer.
"The present study found that a mutant
gene that ultimately results in higher testosterone levels is overrepresented in men born with HBS", says Mikael
Landen of the Karolinska Institute in Stockholm, Sweden.
"This is in line with what we previously know about
masculinisation of the brain and is therefore less likely to be a chance finding", he says. "Hence, the study is important
and adds to the notion that gender identity is influenced by sex hormones early in life, and that certain gene combinations
make individuals more vulnerable to Harry Benjamin Syndrome."
Source: Adapted from information found in New Scientist 29 July 2008.
In the largest ever genetic study of HBS,
Australian researchers have discovered
a DNA variation
linked to Harry Benjamin Syndrome.
The finding strengthens the view that there is a biological reason
why some people feel they are living in the wrong body, in this case men who have an strong desire to live as a woman.
Vincent Harley, of Prince Henry's Institute in Melbourne, said his team's study of 112 Australian
and American women with Harry Benjamin Syndrome found they were more likely to have a genetic variation in a gene that could
lead to a feminisation of the brain during early development.
The research confirmed that Harry Benjamin Syndrome, vulgarly know as transsexualism, was
not a lifestyle decision, as some had suggested, said another team member, Trudy Kennedy, the director of the Monash Gender
Dysphoria Clinic in Melbourne.
"People who come to our clinic describe how they knew they were different at a very early
age, just three or four years old. This is something that people are born with," Dr Kennedy said.
The findings, which are published in the journal Biological Psychiatry , were good news, said
Sally Goldner, 43, who had an inner sense she was female from a young age, despite being born with male genitalia. "Such
compelling evidence dispelling the total myth of gender identity issues being a choice is always welcome" she said.
The Australian and American team examined three sex hormone genes. They found women with
HBS tended to have a longer version of the androgen receptor gene, which could reduce testosterone action.
"It is possible that a decrease in testosterone levels in the brain during development might
result in incomplete masculinisation of the brain in women with Harry Benjamin Syndrome" Associate Professor Harley said.
But it was highly likely that other genetic factors were also involved in Harry Benjamin Syndrome,
The research was trying to solve the "fascinating" question of why people felt a particular
gender was important, but it might also lead to practical benefits in future, if genetic tests could inform decisions about
which sex children, born with ambiguous genitalia, should be raised.
Juliet Richters, an associate professor in sexual health at the University of NSW, said much
of the distress felt by women born with Harry Benjamin Syndrome was caused by cruel treatment from others.
Source: Adapted from information found in Biological Psychiatry,
27 October 2008.
Receptor Repeat Length Polymorphism
Associated with Harry Benjamin Syndrome
There is a likely genetic component to
transsexualism, and genes involved in sex steroidogenesis are good candidates. We explored the specific hypothesis that male-to-female
transsexualism is associated with gene variants responsible for undermasculinization and/or feminization. Specifically, we
assessed the role of disease-associated repeat length polymorphisms in the androgen receptor (AR), estrogen receptor
β (ERβ), and aromatase (CYP19) genes.
Subject-control analysis included 112
male-to-female transsexuals and 258 non-transsexual males. Associations and interactions were investigated between CAG repeat
length in the AR gene,
CA repeat length in the ERβ gene,
and TTTA repeat length in the CYP19 gene
and male-to-female transsexualism.
A significant association was identified
between transsexualism and the AR allele,
with transsexuals having longer AR repeat
lengths than non-transsexual male control subjects (p = .04). No associations
for transsexualism were evident in repeat lengths for CYP19 or ERβ genes. Individuals
were then classified as short or long for each gene polymorphism on the basis of control median polymorphism lengths in order
to further elucidate possible combined effects. No interaction associations between the three genes and transsexualism were
This study provides evidence that male
gender identity might be partly mediated through the androgen receptor.
a Human Molecular Genetics Laboratory, Prince Henry's Institute
of Medical Research, Melbourne, Australia
b Department of Genetics, Monash University, Melbourne, Australia
c Centre for Eye Research Australia, University of Melbourne and
Royal Victorian Eye and Ear Hospital, Melbourne, Australia
d Monash Gender Dysphoria Clinic, Moorabbin, Melbourne, Australia
e Department of Human Genetics, University of California, Los Angeles,