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The importance of testosterone in driving male fetal development

It’s a not widely appreciated fact that a person’s sex at birth isn’t determined directly by their genes, but is instead determined by the action (or absence of action) of androgenic hormones during a critical time period starting about 6 weeks after conception, and ending several months after birth. If, during that critical period, there are high levels of androgenic hormones (testosterone and its derivative DHT) present and able to do their job, you’ll develop as male,. Otherwise you’ll develop as female, irrespective of what your genes might say.

Although we have a sex chromosome (the Y chromosome), it only holds a few dozen functional genes, and all it actually does is instruct your undifferentiated gonads to turn into testicles. All the instructions for both male and female development are held elsewhere in your genome, and everyone has the full set of instructions for both sexes. Something has to tell your body which set of instructions to follow, and that something is testosterone. The testosterone binds to and activates androgen receptors in cells throughout that person’s body, which in turn switch on the genes that drive male development. In the absence of androgenic hormones and functional androgen receptors, a different set of instructions are followed instead, that result in female development.

In a male fetus, the primary source of androgenic hormones is the testicles. If, for whatever reason, the testicles fail to develop, androgenic hormones aren’t produced, and the result is Swyers Syndrome, a condition which produces a person who is physically female despite being genetically male. Another condition which provides even more compelling proof of how crucial androgenic hormones and androgen receptors are in determining whether you develop as male or female, is Complete Androgen Insensitivity Syndrome (or CAIS).

In CAIS, a mutation in a single gene (the one for the androgen receptor), results in a person who is to all intents and purposes a woman despite being genetically male. Although androgenic hormones (primarily testosterone and its derivative DHT) are produced in someone with CAIS just as they would be in normal male fetal development, the receptors that would detect and respond to those hormones either don’t exist or are nonfunctional, so development in that person takes place as if no androgenic hormones were present.

People with CAIS do develop internal testicles though, which (as happens in normal male development) produce a second hormone alongside testosterone, called anti-Mullerian hormone or AMH. Due to the faulty androgen receptors, the testosterone has no effect, however the receptors for AMH are fully functional in CAIS, and AMH does the same job it would do in normal male development, of suppressing the formation of female internal reproductive organs. The result later in life is a person who looks, thinks and behaves exactly like a woman, has female external genitalia (a vagina), but whose internal reproductive organs (cervix, uterus and fallopian tubes) are missing, and who has internal testicles in the place of ovaries (these people typically have normal to higher than normal male levels of testosterone too, but due to their faulty androgen receptors, it has no physical effect on them, and merely acts as a raw material from which their body makes estrogen).

Despite being genetically male and having these internal peculiarities, CAIS women look and behave no differently from ordinary women, to the point where the condition often isn’t even detected up until, as teenagers, they fail to start menstruating. Here’s a couple of youtube videos of CAIS women, and as you can see, there’s really nothing physically or in the way they behave to distinguish them from ordinary women:


CAIS is classified as a type of intersex condition, although as far as I can gather, there’s no evidence that these people undergo any male development at all, either physically or psychologically. Since the only thing that makes CAIS women different from ordinary men is that single mutation to the androgen receptor gene, this effectively proves that, in humans, male development is entirely driven through the action of androgenic hormones on androgen receptors. In CAIS, everything else apart from androgen receptors is the same, including the presence of the aromatase enzyme and the production of estrogen in the brain [This last bit is important because, in rodents, estrogen plays a significant role in masculinisation of the brain. Many researchers appear to assume that the same must apply in humans, but the fact that  CAIS women act like and identify as women proves that estrogen plays no role in human brain masculinisation.]

Swyer’s syndrome provides a second example confirming the importance of androgenic hormones in male development. In Swyer’s syndrome, the androgen receptors are fully functional, however, for whatever reason, the testicles have completely failed to develop. The result is that the hormones that would normally be produced in the testicles (testosterone and AMH) weren’t produced and so, even though that person is genetically male, development takes place as female. At the end of the pregnancy, you end up with a normal-looking baby girl who grows up to become a person who looks and behaves exactly like any normal woman would.

In Swyer’s syndrome (unlike CAIS), there are no testicles and so the hormone AMH isn’t produced. This means the development of female internal organs isn’t suppressed, so women with Swyer’s syndrome will typically have the full set of internal female organs (apart from ovaries). Swyer’s syndrome is a lot rarer than CAIS and so I haven’t been able to find any youtube videos of people with it, but apparently the results are similar to what you get with CAIS – someone who looks and behaves exactly like a normal woman, despite being genetically male.

In summary, if a person has functional androgen receptors and androgenic hormones are present at male-typical levels during the critical period when sexually dimorphic development takes place (starting about 6 weeks after conception and ending 4-6 months after birth), you’ll end up with someone who looks male at birth and will grow up looking and behaving like a man. If the androgenic hormones are absent during that critical period (or the androgen receptors are faulty), you’ll end up with someone who has female genitals at birth, and who later in life looks and behaves like a woman. The Y chromosome doesn’t influence this process at all (apart from determining whether your undifferentiated gonads turn into ovaries or testicles), which sex you develop as is entirely determined by the action (or absence of action) of androgenic hormones during this critical period during pregnancy and immediately after birth.

In the vast majority of cases, a person will either have male-typical or female-typical levels of androgens present throughout their prenatal development, and they’ll end up fully developing as one sex. However, what happens if something goes wrong with hormone production during prenatal development?

Basically there’s two ways things could go wrong:
a). you could have below normal male but above normal female androgen levels throughout that critical period; or
b)  you could have high androgen levels for some parts of the pregnancy but low levels during other parts.

What happens under those two scenarios?

The first one is easy, it’s what you get in a conventional genetic intersex condition such as Klinefelters syndrome (XXY karyotype) or Partial Androgen Insensitivity Syndrome. You end up with a person who’s, to a greater or lesser degree, an intermediate between man and woman. Depending on the severity of the condition, the affected person may have normal male genitals and look male but with reduced masculinity, or if more severely affected they may have genitals that make it impossible to decide which sex they are at birth. Generally these people seem to end up as an intermediate between the two sexes psychologically as well (although usually people in that situation seem to end up trying to force themselves to be entirely a man or a woman, since there’s immense social pressures in our society for people to be one sex).

What happens under the second scenario though? Suppose you have normal male testosterone production during the early stages of prenatal development, but then something happens to suppress testosterone production partway through?

I couldn’t find anything in the medical or scientific literature dealing with what happens if testosterone production is interrupted partway through male development, however I did discover that a fair bit of research has been conducted on sheep in which testosterone implants were used to cause female sheep to partially develop as male. Here are 3 papers in which that experiment was carried out, describing the range of effects you typically see:

http://dev.biologists.org/content/36/1/87.long
“Effects of testosterone implants in pregnant ewes on their female offspring”, August 1976 J Embryol Exp Morphol 36, 87-99.
http://www.reproduction-online.org/content/49/2/311.long
“The sexual behaviour of prenatally androgenized ewes observed in the field”, J Reprod Fertil. 1977 Mar;49(2):311-5
http://press.endocrine.org/doi/full/10.1210/en.2002-220965
“Prenatal Programming of Reproductive Neuroendocrine Function: Fetal Androgen Exposure Produces Progressive Disruption of Reproductive Cycles in Sheep”, Endocrinology 2003 144:4, 1426-1434

Depending on the timing and duration of the exposure, you can produce female sheep with male genitals, you can cause the part of their brain that controls hormones (the hypothalamus) to behave as if it were male rather than female (resulting in impaired fertility and endocrine disorders), or you can change part or all of the courtship and mating behaviour of the animal from female to male. All these things can be changed independently of each other too, so you can produce sheep with severely masculinised genitals but normal female behaviour, or normal-looking female sheep who behave as if they are male.

If external testosterone applied partway through pregnancy can cause a female fetus to partially develop as male, then logic and commonsense says that the reverse must be true too: exposing a male fetus to testosterone-blocking drugs partway through pregnancy should produce someone who is biologically male, but has partially developed as female. Depending on the timing and duration of the exposure, you should get similar effects to those observed in the sheep experiments: genital abnormalities where the exposure takes place fairly early in the pregnancy, endocrine disorders where it occurs somewhat later, and feminized behaviour where it occurs later still.

This is where things get controversial, because although to my knowledge no experiment involving testosterone-blocking drugs has been conducted on sheep, it has (inadvertently) been conducted on human beings. Millions of them.

Since the first synthetic hormones were developed at around the time WW2 began, literally millions of nominally male people have been born who were exposed before birth to medical treatment with female hormone derivatives that have testosterone-blocking effects, in doses more than sufficient to shut down testosterone production in an adult man.  Has there been any effect on these people?

Based on what I’ve seen of the effects of the earliest of these synthetic hormones, the artificial estrogen diethylstilbestrol (or DES), the answer is yes. I’m fairly sure the effects are due to suppression of testosterone because they appear to mirror what happened in those sheep experiments, the only differences being that it’s males rather than females that are affected, and it’s people not sheep we’re talking about!

Just as with the sheep experiments, there seem to be three main groups of effects: intersex-related genital abnormalities; fertility problems and hormonal abnormalities (hypogonadism); and behavioural and psychological peculiarities that suggest female brain development has taken place. Here’s a list of the things that seem to commonly be associated with DES exposure:

Born between 1940 and 1971 (US) or 1980 (elsewhere)
Mother with a previous history of miscarriages; diabetes; other risk factors such as being in her 40s

Birth defects:
Undescended testicles
Micropenis – a fully formed but considerably shorter than normal penis
Hypospadias
Epididymal cysts of the testicles (these are apparently Mullerian remnants – fragments of female tissue that would have been absorbed in normal male development)
Vestigial female organs or organ remnants
Intersexed genitals similar to grade 3 PAIS
Other genital abnormalities (in my case a hydrocele)

Later in life:
Feminine-looking facial features, developing a body structure that’s more like the female members of your family than the male ones
Other symptoms of low testosterone such as a lack of body hair, gynecomastica and an inability to build upper body muscle
Very shy, socially passive behaviour as a teenager
Difficulty forming friendships with boys; having a special affinity with girls
Being bullied a lot; having an inability to fight back
Having no interest in sport
People tending to assume you’re gay; lots of men being attracted to you
Identifying as a woman, or part of you identifying as a woman while another part identifies as a man

To my knowledge, only one study specifically looking at the effects of DES exposure on gender identity has ever been conducted. It found that 150 out of 500 known or suspected DES sons were pre- or post-operative transsexuals, a rate hundreds of times higher than the rate for the male population as a whole:

http://www.shb-info.org/sitebuildercontent/sitebuilderfiles/desexposedhbs.pdf
“Prenatal exposure to diethylstilbestrol (DES) in males and gender-related disorders: Results from a 5-year study”

It makes me wonder how much of the transgender phenomenon of recent years is actually due to prenatal exposure to synthetic hormones.

Another recent study (produced by the organisation Hhorages France), confirms a link between prenatal exposure to synthetic hormones (DES, ethinyl estradiol or progestins) and serious psychiatric disorders, suicides, and intersex-related somatic disorders:

http://www.intechopen.com/books/state-of-the-art-of-therapeutic-endocrinology/behavioral-and-somatic-disorders-in-children-exposed-in-utero-to-synthetic-hormones-a-testimony-case#article-front

My suspicion is that the main cause of the psychological problems and suicides found in the Hhorages study was probably gender dysphoria, but that France has a culture in which gender identity issues are even more taboo than is the case in the US, hence the study authors (or perhaps even the families of those affected) have found themselves unable to talk about it.

Although DES itself is no longer used, some of the hormones in the Hhorages study are still quite widely used as treatments in cases of threatened abortion, and in pregnancies where there’s though to be a risk of premature birth.

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