Railroad Construction

Fetal development is complex.  It may be easier to imagine it to be like building a railroad.  During fetal life, "train stations" are built in a hormone-free environment.  The number & location of the stations is under the control of the Gender Determining Nuclei according to either a female pattern or a male pattern.

Later in fetal life, tracks begin to be laid between the stations.  After birth, hormones stimulate a major track construction boom, especially during adolescence.    Except, a transsexual baby girl is born with a female pattern of "train stations", but is laying down a male pattern of track.  There are train stations without any track leading to them, and lines of track that don't go anywhere.

The individual can feel the increasing disorganization taking place inside her head.  At first it's just the awareness of "I'm a girl, mommy."  But as time passes,  there are areas of the brain that aren't being adequately used:  such as large bilateral female language centers that aren't getting adequate support from the testosterone that's present after birth.  The sensation leads to the first type oftranssexual distress.

After transitioning, the individual starts to have the correct hormones.  "Tracks" can finally be laid between the "stations" that have had "no service" for so long.  The individual feels a great sense of relief, but also notices the appearance of new gender-specific gifts that had been waiting dormant.  The earlier transitioning takes place -- preferably in early childhood -- the better the track layout will match the station layout.

Imagine the catastrophe caused by Puberty Denial -- the entire railroad track construction project is halted.  In later life, it may be possible to cobble together a few paths between the "train stations", but the overall system will never operate like it could've been.

The Evidence

          The evidence that transsexuality has a biologic cause is overwhelming.

          There has never been objective evidence that transsexuality might be a mental illness.

ANIMAL MODELS:  Many species have the ability to change their biological sex in order to balance the numbers -- to provide enough males & females for the species to survive.  Over the millennia, several mechanisms have evolved to make the change: some depend on ambient temperature & resultant resources, some on the individual's size & nutritional state, and others are based on age (ie, the individual's survival skills).   In most species, biologic sex isn't determined directly by chromosomes, but by environmental exposures.

And it shouldn't be a surprise that the genome has preserved remnants of these biologic processes.   The most common mechanism for gender diversity in mammals is known as Freemartin, which results from hormonal exposure.

Whenever a cow bears twins, and one of them is male while the other is female, the female calf will be born a Freemartin.  Testosterone produced by the male fetus leaks through the placenta and masculinizes the female.  The female calf is born a biologic female: he has a uterus, vagina, ovaries, etc.  But because of the fetal testosterone exposure, he has the basic personality (gender) of a steer (ie, a castrated male bovine).

          A Freemartin is a transsexual cow.  He's born with a male brain & gender but the rest of the body has female biology.   

Freemartins also occur in goats & sheep. In "higher" mammalian species, the gender (behavioral) changes are more subtle -- they have to do with mate selection, mating behavior, and dominance within the pack.

Timing is a critical aspect of causing these changes: For example, if a pregnant cow is given testosterone late in her pregnancy, a Freemartin doesn't result.   The “window of opportunity” lasts 1 - 3 weeks, early in gestation.

The exact timing of brain gender determination differs from species to species.   For example, in rats the critical time is 18-27 days post-conception.  In a Rhesus monkey it's 40-60 days post conception.

Like humans, mouse gender (behavior) depends on the status of the androgen receptor:

-- A biologically female mouse that is injected with testosterone during the "window of opportunity" will be born with a male Gender (behavior) and the Gender-Determination Nuclei in the brain will be male in appearance.

-- If a genetically engineered female mouse is used -- one without androgen receptors -- the Gender (behavior) and the Gender-Determination Nuclei remain female in spite of testosterone exposure at the appropriate time.

The actual mechanisms of differentiation -- fetal enzyme induction, etc -- have been worked out in great detail.  To find out more, read Nature's Choice by Cheryl Weill, Routledge [2009] and Cohen-Bendahan et al Prenatal Sex Hormone Effects on Child and Adult Sex-Typed Behavior: Methods & Findings, Neuroscience & Behavioral Reviews Vol 29 pp 353-384 [2005])


Intersexuality refers to a long list of naturally-occurring medical conditions that involve sexual biology.  Some conditions involve the chromosomes, some the gonads (ovaries or testicles), others involve the genitals, and so on.

It's important to note that changes in chromosomes do NOT affect the individual's Gender. Nor do changes in the gonads or genitals. These characteristics of sexual biology are NOT involved in determining Gender.

But there are a few Intersexual conditions that do affect Gender.

Androgen Insensitivity Syndrome (AIS) is the most prominent. It's the human equivalent of the mouse experiment mentioned above.   A baby with AIS develops without any androgen receptors -- even though she has XY chromosomes and testicles. Functional testosterone is produced, but there's no response because the cells lack the necessary receptors.  ALL children born with complete AIS have a FEMALE gender (personality) & gender identity.

HENCE: XY Chromosomes, testicles & testosterone don't make someone male. Nor does child-rearing, social indoctrination, harassment or psychotherapy. Being female or male depends on whether or not androgen receptors are activated between days 28 & 56 post-gestation.

On the other hand, in severe Congenital Adrenal Hyperplasia (CAH) a biologic female (XX chromosomes, ovaries, vagina & uterus) is exposed during fetal development to testosterone produced by the Adrenal glands.  ALL of those XX-children are born with a MALE Gender; about half have a male Gender Identity.  

HENCE: XX Chromosomes & ovaries don't make someone female. Nor do social influences. Hormone exposure during fetal development affects Gender (personality & behavior), but not necessarily Gender Identity. Most of the time, Gender Identity has already been determined by the time testosterone makes an appearance in the adrenal glands.

HUMAN EXPERIMENTATION:  During the 1950-1980’s, genital surgery was sometimes done on newborn males if their genitals didn’t look quite right (so-called "ambiguous genitalia").   The testicles were removed, the genitals were altered to appear female, estrogen was given, the child was "assigned" to be a girl and the child was reared as a girl.  In ALL cases, the child grew up to have a male Gender (personality) & Gender Identity. About one-third demanded surgery & hormones to partially restore what had been taken from them.   

(Reiner et al, New England Journal of Medicine Volume 350, 333-341, 22 January 2004)

BOTTOM LINE:  Children are born with Gender (personality) and Gender Identity already established.  Social influences such as child-rearing, punishment, harassment, and psychotherapy can't change them.

          © Cassandra Branch MD

The Biologic Origin

of Transsexuality

Transsexuals get their Gender Identity the same way as everybody else:  They're born with it. 

Gender Identity is a person's innate sense of whether they are a female, a male or a blend of both.  Anatomically, it's determined by several "nuclei" located in the middle of the brain. A nucleus is a collection of neurons smaller than the head of a pin. During the past two decades, researchers have discovered that these nuclei have one shape if the brain is female, and another shape if the brain is male.

They have also discovered that transsexual females have female-appearing nuclei, even though they have testicles & a penis elsewhere. In other words, a transsexual female is born with a female brain -- which gives them a female Gender Identity. Likewise, transmen have anatomically male nuclei, in contrast to the ovaries and vagina they have elsewhere.  Transmen are born with a male brain and a male Gender Identity.

The following is an explanation of how transsexual development takes place:

The Gender-Biology Portal

Brain scans easily distinguish between men and women.

Functional Differences

It's inevitable that two brains with different structure will function differently.  A variety of tests or scans have been developed to show which parts of the brain are being used during certain tasks.  Functional MRI's (fMRI) and PET scans are used most widely.  

The pictures at left show examples of some of these tests.  In this case, the test subject is asked to take a multi-colored object and imagine what it would look like after it went through a series of rotations.  A fMRI shows which parts of the brain are used to perform the task.

Note that men (top) use different areas of the brain to do the task compared to women (2nd from the top).  A transman has a pattern of use similar to other men, while a transsexual woman uses the same parts of her brain used by other women -- and different from the parts used by men.

The obvious conclusion is that a transman has a male brain in spite of his ovaries & vagina, while a transsexual woman has a female brain in spite of her penis & testicles.

Note that a fMRI could be used to diagnose transsexuality.  Is it reasonable to believe that psychotherapy could modify which areas of the brain are in use?

See also:  Auyeung et al. Fetal Testosterone Predicts Sexually Differentiated Childhood Behavior in Girls and in Boys, Psychological Science (2009)

Gender Determination Nuclei

This is a photo of one of the gender-determining nuclei, known as the BSTc.  The nucleus is larger in a male compared to a female (top two images).

Note that the nucleus in a female transsexual (lower right) has a similar size & appearance to other women, even though the transsexual was born with testicles & a penis.

On the other hand, a gay male has brain nuclei similar to other males -- a gay male has a male Gender Identity.

A 3-Month Fetus

By now all the brain structures are present and the over-all appearance is similar to an adult brain.  The Hypothalamus and the Gender Identity Nuclei have taken their place at the center of the brain.

Fetal Development

The Gender Identity Nuclei are located in an area of the brain known as the "Hypothalamus", located in the middle of the adult brain.  The area controls emotions, basic urges, hormones and the subconscious mind.  That area of the brain begins to develop during the 4th week of fetal development, and the structure is complete by the 8th week.  After that, the hypothalamus merely enlarges & matures, while new development  takes place in other parts of the brain.  The Gender Identity Nuclei differentiate at the same time as the rest of the hypothalamus, between days 28 & 56 post-gestation.

How do we know?  It's not possible to do brain biopsies in human fetuses.  ...Even if you could, the nuclei consist of only a handful of cells at that point. However, all mammals have similar Gender Nuclei.  Most research has been done in mice:  Injection of a hormone during a specific "window of opportunity" in fetal life leads to alteration of the the mouse's gender-specific behavior during adulthood, along with characteristic changes in the structure of the nuclei.

Hormonal injections after the "window of opportunity" may result in increased aggression etc, but not to changes in gender-specific behavior or in structure of the nuclei.

​See:  Kruijver, Sex in the Brain , The Netherlands Institute for Brain Research, Amsterdam 2004

Larger Differences

Of course, formation of the Gender Differentiation Nuclei is only the beginning.  The nuclei determine the construction of communication networks and other structures throughout the brain.  Brain development continues throughout fetal life, childhood and continues until the mid-20's.  The result result is a female brain that has a very different anatomic structure compared to a male brain (or vice-versa).

For example, a female has large language centers in the Temporal Lobes on both sides of the brain.  The connections between the centers are also large and well developed (the Corpus Callosum).  A male brain has one primary language center on only one side.  The Corpus Callosum is smaller.  ...And so on.

Much of this development occurs without the intervention of sex hormones (estrogen & testosterone).  Every fetus, female or male, has a brain specifically designed to resist sex hormones.  After all, a male fetus has to form a male brain in spite of being bathed in the mother's estrogen.  There are many lines of defense against maternal hormones, but the ultimate block is known as the "blood-brain barrier" which is impervious to sex hormones.  After birth, most of these defenses are gone, making the brain more responsive to the hormones that are in the blood.


 -- Brain differentiation to female or male occurs before the formation of gonads, without the influence of estrogen or testosterone.  The Y-Chromosome does NOT play a role.

-- Gonadal differentiation to female or male occurs after brain differentiation is complete.  It requires expression of the Y-Chromosome and leads to sex hormone production. 

Brain and gonadal differentiation are separate and independent processes that occur at different times during fetal development.  A transsexual is someone with a brain that followed one path and gonads that followed another path. 

The Androgen Receptor

This is an artist's rendition of the Androgen Receptor sitting on the a cell (the red ball).

The cell has various receptors on its surface, the black spots.  The Androgen Receptor is the yellow "splat" near the top.

Notice that the Androgen Receptor has a pocket in the middle, shaped so that a testosterone molecule fits perfectly (the chain of black hexagons) -- thereby activating the cell.

Except there's another small "keyhole" at the bottom of the pocket (not shown).  By fitting various "keys" into the "keyhole", it's possible to change the pocket enough that molecules other than testosterone will activate the cell.

The "keys" are known as cytokines, molecules much smaller than hormones.

Genital Development

By 8-weeks, the Gender Identity Nuclei are set; the individual's Gender Identity has been irrevocably established.  Now it's time to form the gonads.  At first, the primitive gonadal germ cells could go either way -- female or male.   The SRY complex on the Y-Chromosome activates and tells the germ cells to become male.  ...Of course, if there's no Y-Chromosome, the germ cells develop along the female path.

Soon after differentiation, the gonads begin secreting hormones:  male gonads (testicles) produce testosterone, while female gonads (ovaries) produce estrogen.  Testosterone in turn triggers genital growth in the male pattern (penis & scrotum), while a lack of testosterone leads to female genitals (clitoris, labia & vagina).

BY THE WAY:  Relative finger length is also different for females compared to males.  ...And it correlates with BRAIN Gender, not gonadal Sex.  Why?  Because the fingers form at the same time as the brain, not the gonads.

An 8-Week Fetus

The fetal appearance is on the left. the appearance of the brain & spinal cord is shown right.

At this point, the hypothalamic area of the brain is complete; the "gray matter" (cerebrum) is beginning to form (the round bulge at the end of the diagram right).

By now one can see legs, arms and even fingers.  In the lower abdomen, the gonads are beginning to differentiate (ovary or testicle); but there are no genitals.

A 4-Week Fetus

The hypothalamic area of the brain is the first organ to form in the body.

Note that at this point, only buds are present for the arms & legs.  The gonads & genitals haven't begun to form.

The Androgen Receptor

Gonadal differentiation occurs due to activation of the Y-Chromosome.  Brain differentiation occurs as the result of activation of the Androgen Receptors of the Gender Identity Nuclei in the Hypothalamus of the brain.  The brain doesn't care whether there's a Y-Chromosome or not.

Every cell in the body is covered with receptors -- specially tailored slots waiting from messages from "headquarters", the brain.   When a messenger molecule arrives, it looks for its receptor.  If the receptor is present, the messenger fits into the slot like a key and activates the cell.  If the receptor isn't present, then the messenger keeps looking -- the cell isn't activated.  

Androgen Receptors respond to testosterone molecules.  Usually.  ...Except we've seen that testosterone isn't present between days 28 through 56 of fetal development.  To meet the need, the Androgen Receptor has a small switch that modifies the slot so a different key -- messenger molecule -- can fit into the slot and activate the cell.

​Brain differentiation during fetal development results from non-testosterone activation of the Androgen Receptor.  Which messenger molecule does the job depends on the circumstances, and is determined by the setting of the switch.  

For example, high levels of maternal stress modify the Androgen Receptor so that it can be activated by Cortisol, a stress hormone.  If an entire community is under stress, there will be a shift in newborn personalities toward the male side (Cortisol activation of the Androgen Receptor).  The community will have more people with a warrior mentality.  ...And yes, many of those warriors will be transmen.

Another example involved the use of Diethyl Stilbesterol (DES), a synthetic hormone commonly given during the 1950's & 1960's to prevent miscarriages.  It turned out that the hormone filled the Androgen Receptor slot without activating it.  When the usual male-activation hormones arrived, the slots were already filled.  The cell didn't get activated, so it remained female.  The result:  large numbers of transsexual female children were born (female brain, but with a penis.) 

The New Gender Paradigm