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Tuesday, December 16, 2014

The 4 Types of Biological Sex

 What Determines Human Sex?

Most people are taught from an early age that sex is a simple matter of either being a boy or a girl. We are taught that girls have vaginas and boys have penises. It all seems pretty straight forward. Most of the world has based our entire social structure around whether we are male or female and gender is an important role in many religions and religious practices across the world. There are even socially and legally imposed limitations or benefits based on our sex--for example: women being limited in combat roles in the military or men being ostracised for shaving their legs. Women often make less money for doing the same jobs as men—even if they are more qualified than their male counterparts.

In society sex seems pretty straight forward for most of us, and most of us feel like we have a firm grasp of what biologically makes us male or female. However, the unfortunate truth is most of us have absolutely no idea. Biologically speaking there is no distinct binary grouping of male and female—the biology is so much more complex than that. There isn’t one thing that biologically determines sex there are actually four different main categories that determine sex.  

There are 4 Types of Biological Sex (each separated into the subcategories male, female, intersex, and neuter):

  • Genital Sex (vagina, penus, intersex, neither)
  • Gonadal Sex (ovaries, testes, ovotestis, neither)
  • Genetic Sex (XX/XY, SRY+ or SRY-, SOX9/FOXL2, etc.)
  • Brain Sex (determined by brain structure, function and identity: male, female, in between, or neither)

Genital Sex is the type of sex most individuals are familiar with—well because we can see them from the outside. Genital sex is determined by the appearance—if the genitals look stereotypically male (having a penis and scrotum) then the person has a male genital sex. If a person looks stereotypically female—having the outer female anatomy: labia, clitoris, vagina etc. the person has a female genital sex.

Some individuals however are born with a genital sex between that of male and female. These individuals are intersex. Some people who are otherwise female (having ovaries, and other female anatomy) are born with penises as in various forms of clitoromeglia and hormone metabolic disorders (see http://en.wikipedia.org/wiki/Inborn_errors_of_steroid_metabolism). Some individuals who have testicles and are male in other ways have part male and part female genitalia which varies from being born with a tiny penis, being born with an enlarged clitoris and no vagina to being born with just about any combination of external male and female genitalia. In rare cases individuals are even born with a vagina and a functional penis. 5-alpha-reductase deficiency is just one of many of these type of conditions (see http://en.wikipedia.org/wiki/
5%CE%B1-Reductase_deficiency). AIS is another one of these conditions (see http://en.wikipedia.org/wiki/Androgen_insensitivity_syndrome). I have only mentioned a few, but there are hundreds of conditions that result in intersex conditions in genital sex.

Some individuals are born missing genital anatomy. Some women are born missing a vagina or a proper vaginal opening. Some genetic males are born missing their genitals and parts of their lower abdomen entirely (see http://www.newsweek.com/lab-grown-vaginas-give-
new-hope-245851 and http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1421517/). These individuals are complete or partial neuter when it comes to genital sex.
Gonadal Sex is determined by having ovaries or testicles, some mix of both, one of each or neither. ‘Common knowledge’ argues that gonadal sex and genital sex are the same, but biological reality that the lives of thousands across the world have demonstrated definitely. As discussed earlier there are hormone metabolic disorders where individuals who have ovaries are born with penises or some degree of external male anatomy. Congenital adrenal hyperplasia is one of these such cases (see http://en.wikipedia.org/wiki/Congenital_adrenal_hyperplasia_
due_to_3%CE%B2-hydroxysteroid_dehydrogenase_deficiency). In the case of CAIS (complete androgen insensitivity syndrome) individuals with testicles who are genetically male are born with complete external and sometimes partial internal female anatomy. CAIS is caused by a malformed androgen receptor gene--this makes it so their bodies can not use androgens properly (such as testosterone). These individuals almost always have female identities and a female brain sex (see http://en.wikipedia.org/wiki/Complete_
androgen_insensitivity_syndrome). Another similar condition is XY gonadal dysgenesis or Swyer Syndrome—where a genetic male fails to develop testicles and develops female external genitailia and a normal uterus and fallopian tubes, but no ovaries. Amazingly even though these individuals are genetically male (they have XY chromosomes) they can menstrate and can even get pregnant with a donor egg (see http://en.wikipedia.org/wiki/XY_gonadal_dysgenesisand http://ghr.nlm.nih.gov/condition/swyer-syndrome).

Some individuals are born with gonads somewhere between male or female (called ovotestes because they are a mixture of ovarian and testicular tissue) and other individuals are born with one testicle and one ovary. XX/XY tetragametic chimerism is one condition that causes cases like these (see http://en.wikipedia.org/wiki/Tetragametic_chimerism#Tetragametic_chimerism).
Other individuals of both genetic sexes are born completely missing ovaries or testicles (see http://en.wikipedia.org/wiki/Penile_agenesis_and_testicular_agenesisand http://en.wikipedia.org/wiki/Gonadal_dysgenesis).

Genetic Sex is by far the most complicated classification of sex. Those who studies biology in high school in the past 50 years probably know that having XY chromosomes means you are male and having XX chromosomes means you are female, but unfortunately it’s not that simple either. The XX or XY rule seems to work out most of the time but there are many exceptions that affect the lives of thousands across the globe. I have previously mentioned several conditions where an individual develops external genitailia and identity that does not match their genetic sex such as CAIS and Swyer Syndrome and many steroid metabolism disorders, but there are a lot of genetic issues we still haven’t considered.

I will proceed by describing several genetic factors and conditions that demonstrate that genetic sex is far more complicated than XY or XX chromosomes: 
Types of gender genetic :
  • Synthetic germ cells (made from skin cells altered into stem cells)
  • Other gender/sex related genetic markers lie outside X and Y Chromosomes

46,XX / 46,XY Tetragametic Chimerism:
Tetragametic Chimerism happens when two fertilized eggs that would normally develop into fraternal twins collide and merge growing into one body with two distinct sets of DNA. XX/XY Chimerism is when those twins would have developed as opposite sex. The result is a person who is genetically part male and part female. The individual may develop with normal male genitailia or normal female genitailia or a mix of both. The brain may develop from the male DNA or the female DNA or a mix of both—so might the rest of the organs and tissues. Here are several case studies:

XX/XY Chimera with normal male phenotype detected by two skin colors:
XX/XY Chimerism in a phenotypically normal male
Pregnancy of XX/XY Chimera with an ovotesti
xx/xy chimera born with a mix of sex organs
XX/XY chimera born as a phenotypically normal baby girl
xx/xy chimera with normal male phenotype
xx/xy fertile chimera--normal female phenotype and organs and 99% XY DNA
xx/xy found in amniotic fluid, but a normal female with XX dna is born
xx/xy normal functioning female

XX/XY, XXY/XY, XXY/XX Mosaicism:
Mosaicism is similar to Chimerism in that the individual has two cell lines (two different sets of DNA) however in Mosaicism they originated from the same fertilized egg.  The difference occurs when there is an error in DNA replication during cell division. Some of the cells develop normally but some pass along the altered genes.

Here is an interesting case study of a mosaic born from one sperm and one egg with normal XX and normal XY DNA

Klinefelter Syndrome (47 XXY, 48 XXYY, 48 XXXY, 49 XXXXY)
Klinefelters Syndrome is a condition where someone is born with a Y chromosome but more than one X chromosome. Contrary to popular belief individuals with Klinefelters can sometimes have children. Individuals with Klinefelters are usually raised as male because of their external genitailia and identities, but in rare cases they have female identities and some degree of physical feminization (see http://en.wikipedia.org/wiki/Klinefelter_syndrome)

XY SRY- females:
This is a condition where an otherwise genetic male with XY chromosomes is born with a defective Y chromosome that is missing the SRY gene sequence--this leads to the individual developing as a relatively normal, but usually sterile female. 

Here is an interesting case of an XXY SRY negative female who had children and even passed her XXY gene to her daughter:

XX SRY+ males:
This is a condition in which an otherwise genetically normal female is born with a defective X chromosome that has had the SRY gene sequence copied into it. This individual develops as a normal but sterile male.

And article comparing XX  SRY+ males with XXY males and females

FOXL2, DMRT1, WNT4, SOX9 Genes:
These genes maintain ovarian tissues and testicular tissue, meaning a defect in these genes or if they are shut off can lead to and XX individual developing testicular tissue or an XY individual developing ovarian tissue. (See:
Homozygous inactivation of Sox9 causes complete XY sex reversal in mice:

Unexplainable Genotype/Phenotype Cases:

This is a case study of a normal male (but infertile) but he is genetically female according to every known test. This and other research has demonstrated that there are genes that are important for sexual differentiation that are outside of the X and Y chromosomes.



Brain Sex is the most important factor in determining the biological gender of an individual. Unfortunately, brain sex is the type of sex people are usually least familiar with. Men and women not only think differently from one another the physical structure of their brains is different. The shape and function of the male and female brain develops in the womb and is influenced by the androgen (testosterone) and estrogen levels; however, it can also be influenced by genetic factors. There are many factors that can change the hormone balance in the womb and influence brain sex as a consequence.

A big difference between the male and female brain is the size and shape of the hypothalamus. The hypothalamus is the master gland that regulates hormone production in the body--including sex hormones. A female-shaped hypothalamus even sometimes attempts to regulate hormones to a female level, while a male-shaped hypothalamus attempts to regulate hormones to a male level. Studies in transsexuals and transgender individuals have shown that many of them have a hypothalamus shaped to match their gender identity--not their genital, gonadal, or genetic sex  (a transsexual is an individual with a gender identity and brain sex that does not match the other three types of sex--i.e. their body and genetics. This term should not be confused with the terms transvestite, or cross-dresser. Transsexualism is an actual inborn medical condition. Also, I should note that not all transgender individuals are transsexual. Transgender is simply a term that encompases a lot of different types of gender expression that go beyond conventional norms). These transsexual individuals often have irregular hormone levels compared to controls of their gonadal sex due to the function of the hypothalamus.

Here are a few of the many studies out there demonstrating that transsexuals have brain structures that match their identities, not their gonads:
Hormone disruptors - A hormone disruptor is a chemical that causes a change in the body’s normal hormonal balance. There are many hormone disruptors such as xenoestrogens (chemicals that act like estrogens) found in many plastics and many if not most personal care products. Pesticides, herbicides and fertilizers are hormone disruptors, along with millions of other products, food additives and medications out there. There are also many xenoandrogens (chemicals that act like testosterone). Hormone disruptors have been proven to cause intersex conditions and alteration of brainsex—they are one of the proven causes of transsexualism. DES is just one example of a medication that has been directly linked to altering the brain sex of a fetus of a pregnant mother often resulting in transsexual children (see http://en.wikipedia.org/wiki/Diethylstilbestrol).
There are also many natural factors that can disrupt the hormone balance of the womb and alter a developing fetus’ brain sex—such as stress, depression, anxiety, and trauma.

The hormone balance in the womb is not the only factor in determining brain sex. There are also genetic factors that can determine brain sex—even if the hormone balance is opposite from the resulting brain sex. XX/XY chimerism is one such case—where the child is born with a brain with XX or XY DNA and a body of the opposite genetic sex. In this case study artificial chimeras were made in quail where they grew female quail brains in male quail bodies—the resultant quail behaved more like female quail than male quail despite the fetal hormone levels. The quail showed female behavior and low male hormone levels (after maturation): http://www.pnas.org/content/100/13/7959.full



Brainsex is the only classification of biological sex that determines gender—A Proof Via Case Studies:

1. Genital Sex—Having a penis or a vagina does not determine gender:
  • Genetic males with Cloacal Exstrophy are usually assigned to female at birth because they are missing male genitalia. In this case study the gender identities of several of these individuals are studied showing that many of them identify as female and several of them as male (even though they now have female external genitailia): http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1421517/
  • The story of David Reimer is famous for disproving the idea that boys and girls simply are what we raise them to be. David was born a normal boy, but due to a circumcision accident he lost his penus. The doctor and his parents decided to have David surgically altered so he would have female genitailia. Despite David’s parents doing their best to raise him as a normal girl he grew up knowing from the start that he was a boy. (see http://en.wikipedia.org/wiki/David_Reimer).

2. Gonadal Sex—Ovaries or testicles do not determine gender:

3. Genetic Sex—Genetic makeup does not determine gender:
  • In this case study a phenotypically normal male (having full male genitalia and identifying as male) was tested to be genetically female according to all known DNA tests for genetic sex. He was sterile only because the Y chromosome is nessessary for sperm production: http://molehr.oxfordjournals.org/content/12/5/341.short

  • In this case study of an XX/XY tetragametic chimera she was completely phenotypically female (see looked completely female) and had only female reproductive organs and 99% XY DNA (i.e. she was 99% genetically male). She idetifies as female and was also able to bear children: http://humrep.oxfordjournals.org/content/16/1/56.short

4. Brain Sex—Brain Sex determines gender:
    In all of these case studies the only constant that determines an individual’s gender is what the individual identifies as. An individual’s gender identity is therefore determined by the sex of the brain (i.e. the brain structure).

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