A technical question about Swyer Syndrome and CAIS

You're making a circular argument. You're saying a feature of the disorder is 'A' therefore an individual with 'A' isn't disordered because that's normal for someone with 'A'.

Someone with no SRY is female. The disorder is because in normal development they'd have 2 X chromosomes.

XY without an SRY is not normal development.

I’m reading Wt1 as wtf which really isn’t helping.

This has been a really interesting conversation, and I understand much better now why ‘some people’ talk about genetic sex, hormonal sex and gender expression sex (if I remember correctly).

I thought that was bollocks on the basis they meant a 50yr old chap could take oestrogen and quickly acquire all the implications and practicalities of being a woman.

I think they were using it like that, but now understand where they got the concept.

It’s really clear though, that as we already knew, DSDs have nothing whatsoever to do with trans and gender identity.
It’s only relevance to sport is the implications for competitive fairness and safety.

There no need for any of this to become public speculation and discussion of people behave appropriately.

On a simple logic level I see this, but when we’re told that female=noSRY, then I don’t.

If mere absence of a functioning SRY gene makes an individual female, then no matter what the genetic makeup the absence is correct - as the lack of SRY is not a disorder of males.

So a female can correctly be XX or XY (or a number of other things but I’m trying not to confuse myself even more! 😂) and that is correct for that female.

If XY is a correct expression of female, and XY are unlikely to have ovaries, then how can lack of ovaries in XY be considered a DSD of XY females?? That’s the default state of XY females, surely? When a DSD is a deviation from what is normally expected, I can’t see how an XY individual developing along the expected path for XY individuals is considered a deviation from the norm for XY females.

I can see it being an unexpected path for XY if XY is considered male…

I think it’s about to get even more confusing! 😆

I ended up reading all sorts of things yesterday (most of which I didn’t understand) but one article caught my eye:

Researchers identify female sex determining gene in mice

This states:
They found that one form of the WT1 protein (-KTS) was essential to gonad formation, as in its absence, neither Sertoli cells nor granulosa cells could form in both XY and XX mice.
The higher amounts of -KTS reduced the expression of Sry in XY gonads and increased genes involved in ovarian development. The production of SRY never reached the level needed to trigger testes development.
This meant that an XY mouse developed female gonads in the presence of too much -KTS, showing that the -KTS form of WT1 is an early trigger for female gonad development, regardless of XX or XY chromosomes.

So it seems as though trying to determine sex by the presence of a functioning SRY gene* isn’t enough, it has to be a dominant SRY gene. It may be that in science terms dominant is the same as functioning, but then again not.

The article describes the Wt1 gene as a gene which is an early determining factor of ovary development in mice. Females have ovaries (this seems to be the takeaway from this thread - XY females with no functioning SRY lack ovaraies and this lack is the DSD of those females - apologies if I have misunderstood), so presumably it would be incorrect to describe the differences between male and female being just a lack of the gene that determines maleness, yes?

I’m also left wondering if this -KTS/WT1 is present in XX individuals. It seems its mutated in XY individuals that possess ovaries, so is it unmutated in XX individuals with ovaries?

If, as mentioned above, it is essential to gonad formation, as in its absence, neither Sertoli cells nor granulosa cells could form does this mean that it is possible for individuals to both lack the SRY gene and Wt1 as well?

In which case, if functional SRY=male and Wt1=female, what would an individual without either be classed as?

It seems odd to consider that a female is someone lacking the male switch (SRY) if there’s evidence that there’s also a female switch. That makes female the default by the back door, and as @KeirSpoutsTwaddle said, isn’t that considered to be incorrect now?? On the other hand, if Wt1 is the ‘female switch’ then could it not equally be argued that a male is someone lacking the female switch to keep the male switch suppressed.

*From what I can work out on one of the other threads (table half way down page 2), an individual classed as female can have XY chromosomes with or without the SRY gene. The paper I found last night suggested that a mutation in another gene effectively overrides the SRY one, so producing apparently normal ovaries. I’m taking from this that the mere presence of SRY is not enough to be classed as male, so the sports testing shouldn’t rely solely on this either.

It seems unreasonable therefore to expect an XY-SRY to have ovaries.

Well yes, but that's because that's what the disorder is.

It doesn't mean they are male because you wouldn't expect to find ovaries. Any more than the trisomies aren't an extra chromosome because you'd expect an extra chromosome in someone with Downs or Edwards.

“So the sry gene (which is almost always, but not always, attached to the Y chromosome is the blueprint which drives fetal development away from default female setting.”

I thought we moved away from female as the default setting. I thought the embryo has potential for both, and develops according to the hormone mix sloshing about (technical term! 😁)

Will go back to those handy diagrams and check…

So if XY-SRY doesn't have ovaries does that mean they have testes?

Reading the IBA wording they've copped out people with DSD aren't allowed to compete on safety grounds. So maybe the IOC need to take the same view.

I came across the paper linked because I was furiously googling to see if XY individuals can have ovaries.

That was the only thing I found that seemed to indicate they can, and even that hints it’s unusual.

Why do I think it unlikely?

Well, sex is determined at conception. Usual arrangement is XX female and develops ovaries, XY male and does not.

Tonight I have learned that this isn’t quite accurate, that +SRY is male, -SRY is female. However, SRY is usually located on Y chromosome, anywhere else is not commonplace. So chance of XY-SRY having development that generates ovaries is vanishingly small as quite out of the ordinary for females. Most XY-SRY would be a condition such as Swyer’s where defined ovaries are absent.

From the paper I’m guessing that for ovaries to occur in XY-SRY there would need to be a significant mutation such as the one mentioned on the CBX2 gene.

It seems unreasonable therefore to expect an XY-SRY to have ovaries.

Have I got that wrong?

Easy! And only needs to be done once in the athletes lifetime. So cheap compared to the myriad of dope testing athletes undertake.

XY-SRY = female, expectation of ovaries

I don’t see how the last one can be true.

Why not?

I'm not a scientist but I think that article is suggesting that the CBX2 gene has effectively acted to fix what would otherwise have led to a DSD. So she has been incredibly lucky - though note this is a child and we don't know whether she will go onto be fertile, though the indication is she will be.

So genetically 'disordered' definitely with the Y instead of second X, but maybe not disorder of the DSD type.

A single x chromosome / with no sry gene makes you female. Women with Turner syndrome are undoubtedly female not male. So female is not XX it can be XO

And female bodied people can be genetically X(Y without SRy)

And male bodied people can be X(Xwith sry)

So the sry gene (which is almost always, but not always, attached to the Y chromosome is the blueprint which drives fetal development away from default female setting.

How easy is it for a lab to find the SRY gene, especially if it's in the wrong place

I'm almost starting to understand why the ioc dropped chromosome sex testing but the testosterone test just doesn't seem fair

Sorry, the more I think about this the more confusing it seems!

Starting from SRY (present is male, absent is female).
Females expected to have ovaries, males not expected to.

XY+SRY = male, no expectation of ovaries.
XX-SRY = female, expectation of ovaries
XY-SRY = female, expectation of ovaries

I don’t see how the last one can be true.

@titchy

People without an SRY are expected to develop ovaries.
You need to start from the SRY gene, not the chromosomes.

Right, ok.

So the paper below is … what?

No SRY, so ovaries expected. Ovaries are present. All good so far.
XY chromosomes are also present, which is unusual but not something to dwell on because the -SRY+ovaries is normal for females and due to lack of SRY the individual is a female.

So…no DSD then…???

Doesn’t seem quite right! 😳
Ovaries and Female Phenotype in a Girl with 46,XY Karyotype and Mutations in the CBX2 Gene

No! XX can have SRY - La chapelle syndrome.

Cheek swab to test for presence or absence of SRY.

Except people with Y chromosomes are not expected to have ovaries, so how can lack of ovaries be abnormal for a female with XY chromosomes?

No. People with an SRY gene are the ones who aren't expected to develop ovaries from gonadal tissue.

People without an SRY are expected to develop ovaries.

You need to start from the SRY gene, not the chromosomes.

So in the interest of fair sporting. Would it be fair to say initial test XX cheek swap good to play.
XY cheek swap requires further tests find out if they have ovaries or under developed testes?

Except people with Y chromosomes are not expected to have ovaries, so how can lack of ovaries be abnormal for a female with XY chromosomes?

We effectively end up with two types of female - ones for whom missing ovaries is outside the normal for their body type (XX) and ones for whom missing ovaries is the default (XY-SRY).

No. There is one type of female - people with no SRY.

As I understand all humans have tissue that should develop into either testes or ovaries, including those with DSDs including Swyers. It doesn't develop properly that's all. It's still there - it isn't missing.

Hmmmm….

Am I understanding this correctly - a human female with XY-SRY was found to have apparently normal ovaries? Apologies if I’ve misunderstood the paper.

Is this an odd presentation of Swyer’s or not? I’m guessing not because Swyer’s results in an individual with no ovaries, so this must be …. something else??

It mentions mutations of the CBX2 gene and states that this usually suppresses development of ovarian tissue in XY gonads. So presumably the mutation -although a disorder for XY individuals in general - might not be one for an XY-SRY female.

Females are expected to have ovaries, so can a mutation which allows the development of ovaries in a female (albeit one with an unexpected karyotype) really be considered a disorder??

If not, then what is the disorder part? Would that have to be the presence of a Y chromosome instead of an X?

Ovaries and Female Phenotype in a Girl with 46,XY Karyotype and Mutations in the CBX2 Gene

Do they have wider hips?
One of the things that makes men faster and stronger is the angle of the thigh bones being straight down to the knees rather than wider at the hips and angled in.

If that makes sense.

Adding:

Because if an XY individual cannot have ovaries under any circumstances, then surely an XY-SRY female cannot have a disorder whereby the ovaries are missing if their body is such that it’s make up doesn’t allow for the possibility in the first place.

This then means we have XX females who are expected to have ovaries and XY-SRY females who are never expected to have ovaries.

In which case, how can the absence of ovaries be considered the disorder in those who have never had the capacity for them?

We effectively end up with two types of female - ones for whom missing ovaries is outside the normal for their body type (XX) and ones for whom missing ovaries is the default (XY-SRY).

Is there a condition where XY could have ovaries??

Doesn't seem likely, but …?

The disorder of sexual development is the lack of ovaries and the consequent effects of that. It's female-specific because only females would be expected to have ovaries.