A technical question about Swyer Syndrome and CAIS

[QuimReaper]

I have become interested in these syndromes as a result of their getting a lot of discussion on these boards, and although this question has nothing do with FWR, posters here seem exceptionally well-versed in DSDs, so I hope nobody minds me popping a couple of incidental questions here.

First: my understanding is that without hormone treatment, children with Swyer Syndrome never experience puberty due to lack of gonads. I'm just wondering, what actually happens in cases where Swyer Syndrome goes untreated (as must have happened historically and globally)? Or in general when someone doesn't experience puberty for some other medical reason? Do they stay in a pre-pubertal state for their whole lives, and is their life expectancy normal?

Secondly: my understanding is that people with CAIS produce testosterone, but do not at all respond to it; but that all bodies (XX or XY) produce some amount of oestrogen (I think in the pituitary gland?) and it is this that CAIS cases respond to, resulting in an apparently female appearance.

If I'm right about that, why is it that the same isn't true of Swyer Syndrome? And if I'm wrong about that, how is it that people with CAIS do experience female-typical puberty (breast growth etc., although obviously not menarche) and those with Swyer don't?

Thanks in advance to any clever MNers who can answer these!

This is really interesting about CAIS.
Is the question we should ask not so much do they have a potential advantage if competing with women based on height and lack of menstrual cycle, or do they have a potential disadvantage if competing with men based on other things, as women do?

Swyer syndrome is a DSD that only affects females.

There is a debate on whether those with CAIS should be classed as males due to their genetics or females due to their phenotype.

MarkWithac

I think it would be obvious that they have a disadvantage against men as they can not process testosterone.

What's interesting is that you would think this would also mean those with CAIS would be disadvantaged against other women, but studies suggest that isn't the case.

Are you able to explain why those affected are considered female given their XY chromosomes?

Swyer apparently considered it a male DSd.

I am perfectly happy to consider people with Swuers to be socially female, and treat them as such in all respects (not that I’d ever know). But it looks like a DSD affecting males which makes them appear fully female and prevents puberty.

Caveat for future scientific based decisions re sport.

I really can’t see a debate on the categorisation of CAIS based around phenotype. I mean that really is discussing whether someone appears feminine enough to be considered female which is against pretty much everything I believe!

Genetically, it's because they lack the SRY gene, or it's inactive for some reason.

The Y chromosome almost always has an SRY gene, and the X chromosome does not, which is why XX vs XY is a good approximation.

But it is possible for the SRY gene to be missing in an XY person (Swyer) or present in an XX person (de la Chapelle).

Swyer or course didn't know about the SRY gene or have the technology to detect it.

I've not seen any papers that would call Swyers a male DSD

Swyers syndrome occurs when the genes responsible for maleness are either missing or corrupted.

The SRY, or maleness gene, is missing from the Y chromosome, or is corrupted in some way. It is not the chromosome that determines maleness but the SRY gene which is normally located on the Y chromosome.

They could also have two altered DHH genes. Therefore the DHH protein, which is instrumental in male gonadal differentiation, is not produced. This causes a uterus and fallopian tubes to grow instead of testes.

So far, there have been several genes found that seem to affect the masculanization of humans. But there is still lots we don't know about the human genome.

I've not seen any papers that would call Swyers a male DSD

Male pseudohermaphroditism: a hitherto undescribed form
Gerald Isaac Macdonald Swyer
British medical journal 2 (4941), 709, 1955 (linked above)

He described them as male because they had XY chromosomes. Of course we now know better.

Thanks for that.

The SRY gene was first found in 1990, so any paper before then would assume Y = male. We now know better.

I would have agreed with you a couple of weeks ago before I'd done more reading, but those with CAIS honestly don't know they have XY chromosomes until they hit puberty. Their male genotype matters in a scientific context, but socially speaking you honestly wouldn't know. This I wouldn't say is "passing", it's because they have a female phenotype (although I think would fail a blood T test?).

One of the (valid) arguments we have about female sports is that a lot of the social pressures on women hinder our ability to spend the time on sports, which matters in things like darts and pool, those with CAIS will have had all the same societal disaadvantages as women too.

There's a bit more in this podcast, I think the interviewee has CAIS from memory?

I think this is why there is actually a debate; to what degree does CAIS actually give an advantage over XX women when it comes down to sport. It appears from studies PPs have provided that CAIS does give some advantage, although a PP said the study didn't check whether the people had PAIS rather than CAIS.

It was more Swuers than CAIS that I was thinking of, Witchy.

But equally, if CAIS is a male dsd because genetically male despite phenotypically female…
Why isn’t Swyers, as it’s the missing male gene that’s the problem?

Unless we’re describing women as men who are missing a gene?

Neither Swyers nor CAIS are female because they look female. Surely?

Im not saying we shouldn’t treat them as female, just that it’s a male DSD not a female one.

I know I’m lacking the knowledge for it.

And appreciate the explanations!

Because those with Swyer's don't have the gene/s that determine the male sex.

Those with CAIS do have the gene/s that determine maleness, but their inability to process testosterone produces a female phenotype.

Surely the disorder is the missing gene? If they were female they weren’t going to have the missing gene in the first place?
So it isn’t missing?

Ergo, the disorder produces a female.

Do you have the genes that determine you are male?

Yes = Male
No = Female

It doesn't matter if they are found in the 'wrong' place. What matters is you having them (and them working).

So would the fairest thing for people with these XY dsd to compete with women but have to lower their testosterone? I feel that if you've been brought up as a woman and have female appearing genitalia then who is anyone to tell you you're a man? I feel really sorry for the athletes involved in this but understand the fairness aspect.

I would be interested to know whether people with CAIS are over represented in elite sports before forming an opinion

It would be pointless for those with CAIS to reduce testosterone. It doesn't matter how much they have, their body doesn't recognise it.

Those with Swyers will be on hormone therapy and would most likely be tested to make sure they aren't 'doping'. It would be unlikely for those with Swyers to become elite athletes.

Semenya, who has 46XY-5ARD, was given two choices either compete in the male category or lower testosterone. Semenya chose to lower testosterone, but their performance struggled. Those with this condition may be wrongly noted at female at birth, but their sex would become apparent at puberty.

Personally, I think anyone that has gone through male puberty should play in the male category. No one should be lowering their hormone levels to fit into categories.

https://www.gloshospitals.nhs.uk/our-services/services-we-offer/pathology/tests-and-investigations/testosterone/

@woofyoof @Maaate & anyone else

i don’t think it’s as simple to ratio 1:1 T levels between men & women and say the jump between the top end for women & bottom range for men is only 6. I don’t think it would be a linear scale.

Look at the range difference between men & women. Huge.

"For instance, the frequency of complete androgen insensitivity syndrome (CAIS) among athletes is 1:421 whereas the incidence among the general population is 1:20,000."

This is the claim that is banded about. It comes from this study.
www.nature.com/articles/nrendo.2011.213

The issue is that this result has never been replicated or substantiated.

The athletes didn't have genetic testing to separate those with PAIS to those with CAIS.

This is from Carole Hooven, whose PhD covered sex differences and testosterone. Twix link for those with access.
x.com/SwipeWright/status/1602493614302568448?t=GtPL_CXxMPPLmiTdTBrVvg&s=19

Please clear this up:

• Embryo with XY chromosomes develops normally then the individual has the SRY gene on the Y chromosome. Baby is MALE.

• Embryo with XY chromosomes develops abnormally and has 5-ARD. Baby is MALE.

• Embryo with XY chromosomes develops abnormally and has an extra X chromosome (XXY). Baby is MALE.

• Embryo with XY chromosomes develops abnormally and the individual is missing the SRY gene on the Y chromosome. Baby is FEMALE.

Why is Swyer’s considered a DSD of females? If the embryo did not have an abnormality then the individual would be a normal XY male. All the other XY DSDs give males with varying states of feminisation.

I understand that the SRY gene determines the sex - but as the SRY gene is normally found on the Y chromosome and is absent in Swyer’s, why is this NOT a male with a missing SRY, why is it considered a female with a missing X chromosome and instead a misplaced Y chromosome?

Surely the disorder is the missing SRY? Missing, that is from the male, not something that is ever missing from the female?

Or is it a disorder of females who gain a Y that just so happens to be missing the SRY gene?? And if they ‘gained’ a Y that happened to have the SRY, they’d just be an ordinary, run-of-the-mill male??

😫

Exactly!

To be male you have to have the genes that determine maleness.

A male can't be missing the SRY (or other sex determining) genes because the SRY (...) gene is what determines a person to be male.

I think your opinion stems from the belief that Y=males, but we now know that is not the case. SRY (...) = male.

Adding:

If Swyer’s is a DSD of females, who somehow swap an X chromosome for a Y chromosome that’s missing the SRY gene, then doesn’t that mean that XY males are females who swap an X chromosome for a Y chromosome that happens to be complete with the SRY gene??

😫

Colour me confused!