Note: This post is the continuation of a series regarding the current scientific understanding of transsexualism. It is intentionally light on scientific jargon and footnotes (though I can’t avoid them all), as it is an attempt at a narrative summary of complex underlying material. Some references are provided at the end, but none of these concepts are derived from a single source.
I left of the “Fact Not Opinions” series many months ago, so it probably makes some sense to summarize the series so far before proceeding.
The Story So Far
As the first post indicated, this series was motivated by my desire to get beyond the “X mind trapped in a Y body” analogy regarding transsexuals. After all the brain is a part of the body. If we mean “brain” when we say “mind,” then the truth we seek doesn’t lie in sharp rhetoric or forceful opinions, but rather in physical, empirical facts. Further, if these facts indicate that our bodies (especially our brains) do not match the gender we have been assigned, then our reality as transsexual beings cannot be a matter of opinion, nor can it be a matter of mental pathology. It must be a matter of fact.
The second post in the series reviewed the history of the psychiatric / psychological attempts to “cure” transsexuals by making their minds conform to their external bodies. A century of evidence strongly backs the conclusion that this approach doesn’t work. However when the alternative approach was finally attempted – using surgical reconstruction to make the bodies match the minds – it was met with success by all the relevant psychiatric measures. The psychologists still couldn’t explain why the one approach failed so conclusively, while the other approach succeeded. But evidence gradually overwhelmed disbelief, so that the “make the body match the mind” approach became the standard psychological treatment for a properly diagnosed transsexual.
The third post in the series began to explore the biological nature of gender formation. It reviewed the “nature versus nurture” controversy over the establishment of human gender identity. The two main views were represented by John Money, who believed that human babies are undifferentiated in terms of gender until many months after birth, and Milton Diamond, who believed that humans had their gender established via the Organization-Activation mechanism beginning in utero. The “John/Joan” case seemed to prove Money’s contention, while undermining any biological cause for transsexuality. However later followup studies exposed “John/Joan” as a fraud, discrediting Money’s contentions while simultaneously indicating that human gender conforms to the organization-activation theory, as Diamond predicted.
So now it’s time to get into organization-activation itself, and attempt to apply its mechanisms to understanding human sexual differentiation. But before we can do that we need to understand how organization-activation theory fits into the overall process of human sexual differentiation. And in order to do that, a primer on the topic is in order.
Beyond Chromosomes
Just about every educated person is taught that human sexual differentiation is a matter of chromosomes. If the chromosomes show an XY pattern, that indicates a male. If the chromosomes show an XX pattern that indicates a female. For the vast majority of humans this is certainly true.
But it can also be said that we know this is not true in every case. There are a number of known intersex conditions, ranging from people with rare chromosome patterns (e.g. XXY), to people born with with opposite physical anatomy than their chromosomes would indicate (i.e. XY girls, and XX boys), and this is only scratching the surface of medically known variations. In order to explain the alternative development patterns leading to these non-standard outcomes it is necessary to understand more than simply chromosome patterns. It is necessary to understand how the chromosomes themselves do the work of sexual differentiation and how, sometimes, they may not follow the expected pattern of development.
In 1947, French endocrinologist Alfred Jost demonstrated that both XX and XY mammals would develop as females if the XY mammals were castrated in utero before sexual differentiation. The implication of this work was that female represented the “default” state of sexual development in mammals. In other words, in the absence of additional factors driving a fetus to develop as a male, we get a female. But what were these additional factors driving male development? Jost’s work suggested the driving force was not chromosomes, but rather the presence of absence of the male gonad. But as all fetuses begin without sexual differentiation – including their gonads – this begged the question. How and why was the gonad differentiated in the first place, and why was there such an overwhelming correlation with the presence of a Y chromosome?
Genetic Differentiation
Studying the Y chromosome, scientists first linked the development of male testes to a single region of said chromosome (a region known as TDY, for Testes Determining Region). Subsequent research isolated testes development still further to a single gene known as SRY (for Sex-determining Region Y). Most of this was discovered by studying XX male individuals; living demonstrations of just how little Y chromosome material was needed to cause a fetus to develop as male (genetic material from a Y chromosome can pass to an X chromosome due to abnormal recombination during male meiosis). It is now believed that the SRY gene is the sole trigger which sparks an otherwise female mammal to develop as a male.
To extend the analogy of the trigger a bit further, if SRY is a “trigger,” what does it “fire?” Being a gene, SRY is essentially a blueprint for manufacturing certain proteins. So when the SRY gene is “fired,” production of SRY proteins begins. But what do these SRY proteins do?
Here we start to hit against the edge of current scientific understanding. We know that SRY proteins bind to certain genes. We don’t know exactly which genes they bind to. It is suspected that bound SRY acts as a transcription factor, causing other genes to be expressed. It is not certain which gene or genes these might be (it isn’t even known if SRY binds to one gene or multiple). In addition to causing some genes to be expressed it has also been hypothesized that SRY may cause other genes to be repressed. The exact mechanisms underlying all of this remain unknown. What is known is that both the timing and the level of SRY expression are critical. If either of these factors is off, it can lead to the development of an XY female.
In summary, the SRY gene, properly timed and expressed, will lead a mammal to develop testes. Absence or under-performance of this gene will lead a mammal to develop ovaries. The main role of both of these organs is the secretion of specific kinds of hormones.
Hormonal Differentiation
The importance of testes or ovaries in early sexual differentiation is keyed upon the hormones they secrete. Unfortunately our understanding of this at present is very one-sided.
Early research into sexual differentiation was based in the belief that the development of a male required biological processes triggered by hormones, while the development of a female merely required the absence of these hormones and processes. It is now known that this assumption was false. Both paths of development require distinct and equally complex biological processes triggered by the presence and/or absence of hormones. However there remain strong indications that one of the key roles of male hormones during fetal development is to counter certain “default” female development pathways. Nonetheless, our knowledge of hormones in male development is greater than the female equivalent at the present.
Hormones are often called the body’s “chemical messengers.” They work by penetrating target cells and binding to specific receptors. Once a hormone finds its proper receptor it causes certain genes to be expressed, which in turn cause certain proteins to be created, which in turn trigger still further development. If a hormone cannot bind to its target receptor, it can have no effect. (So far we have followed a well researched path involving the development of hormone secreting glands. Keep in mind that the far less understood processes underlying the development of cellular hormone receptors are equally important to sexual differentiation.)
In mammalian sexual differentiation hormones first play an active role in the development of distinct sets of anatomical structures.
Anatomical Differentiation
A clear example of male hormones inhibiting an otherwise female direction of development involves MIS, the müllerian inhibiting substance (sometimes called AMH, or anti-müllerian hormone). Regardless of eventual sex, all mammals possess the building blocks for two sets of internal reproductive structures known as the Müllerian and Wolffian ducts. The Müllerian duct is capable of developing into female internal structures (fallopian tubes, uterus, cervix, etc.). The Wolffian duct is capable of developing into male internal structures (epididymis, vas deferens, seminal vesicle, etc.). Once the male testes develop they begin to secrete the MIS hormone, which has the dual purpose of developing the cells which produce testosterone and causing the Müllerian duct to degenerate. In the absence of this hormone, the Wolffian duct will degenerate and the Müllerian duct will develop. This is one of many examples illustrating that ultimately it is the presence or absence of hormones driving the sexual differentiation of a bi-potential anatomy.
The continuing development of the male testes leads to the development of two additional key hormones, testosterone and dihydrotestosterone, or DHT. Testosterone triggers Wolffian duct development , and serves as a building block for the creation of DHT. DHT is responsible for the development of male internal and external anatomical structures. Further, DHT is known to have a role in organizing (per organization-activation theory) sexual differentiation in the brain (more about that in a moment).
External genitalia are determined by the effect of DHT around the 9th week of fetal development. At this time the external genitalia consist of a bi-potential genital ridge rich in DHT receptors. In the presence of sufficient quantities of DHT, the genital ridge will develop into a scrotum and penis. In the absence of DHT (or if this is lacking in sufficient quantity), the genital ridge will develop into a labia and clitoris.
All the physiological sexual differentiation examined to this point is capable of speaking to the vast majority of currently known intersex conditions. But it still cannot explain transsexualism. In order to do this we need to take one further step.
Organization-Activation
We are now at the point of mammalian sexual differentiation where organization-activation theory comes into play. A quick definition:
The organization-activation theory posits that the nervous system of a developing fetus responds to prenatal androgens so that, at a postnatal time, it will determine how sexual behavior is manifest.
from the Abstract: Clinical implications of the organizational and activational effects of hormones. Diamond M., Horm Behav. 2009 May;55(5):621-32.
Lest this simple definition is unclear, I’d like to restate it. Diamond is suggesting that sexual differentiation in the brains of mammals – including humans – is accounted for by prenatal male hormones, exactly the same way they account for the development of earlier anatomical structures. This prenatal brain differentiation accounts for later differentiation in behavior between males and females.
This notion, if true, is directly applicable to exploring a biological basis for transsexualism. We have already established that if an XY individual lacks sufficient male hormones, that individual will develop the anatomy of a female. Conversely, if an XX individual begins producing sufficient male hormones, that individual will develop the anatomy of a male. Interruptions or variations in expected hormones cause interruptions of variations in expected sexual differentiation – causing total sexual reversal in extreme cases. Organization-activation suggests that this very same principle is at work in the sexual differentiation of an area of mammalian biology (i.e. the brain) linked to identity and behavior.
Or, in Diamond’s own words:
I believe that transsexuals are intersexed in their brains as others are or might be more obviously so in their gonads, genitals, hormonal character, receptor, enzymatic or chromosomal constitution. And it is this brain intersexuality that biases the person to assert his or her gender identity.
If Diamond is correct it should be possible to find sexually differentiated structures within the brain within which transsexuals match their stated gender identity while at odds with their chromosomes or external anatomy. But that’s getting ahead of ourselves. We’ll save that for another post.
In Summary
For those who stuck with the post this far, let’s sum up. Here is what we know about the process of sexual differentiation in mammals (including humans):
- Chromosomes carry sexually differentiating genes (chromosomal differentiation).
- These genes, once expressed, (genetic differentiation) …
- … cause the development of hormone secreting organs . These distinct sets of hormones (hormonal differentiation)…
- … result first in the development of sexually differentiating anatomical structures (anatomical differentiation)…
- and later the same hormones play a role in sexual differentiation of the brain (organization-activation).
Further Reading:
Sex Determination and Gonadal Development in Mammals
Beginner’s guide to genetics: Sex and genetics
Chromosomal Sex Determination in Mammals
PowerPoint Slideshow: “DISORDERED OR JUST DIFFERENT? MYTH, SCIENCE AND SEXUALITY.”
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