Saturday, 27 September 2008

Alleys Blind and Sighted

A common polymorphism of the SRD5A2 gene and transsexualism. Bentz EK, Schneeberger C, Hefler LA, van Trotsenburg M, Kaufmann U, Huber JC, Tempfer CB. Reprod Sci. 2007 Oct;14(7):705-9.
The relation between genetic variation of the androgen metabolism and transsexualism is unknown. In a case-control study of 100 male-to-female (MtF) transsexuals, 47 female-to-male (FtM) transsexuals, and 1670 controls, the authors assess allele and genotype frequencies of the steroid 5-alpha reductase (SRD5A2) Val89Leu polymorphism using polymerase chain reaction. Allele and genotype frequencies are not significantly different between MtF transsexuals and male controls
Allele and genotype frequencies are also not significantly different between FtM transsexuals and female controls
Of note, there is no gender-specific genotype distribution among controls. The SRD5A2 Val89Leu SNP is not associated with transsexualism, refuting SRD5A2 as a candidate gene of transsexualism.
As they say in the Classics, Bugger.

A polymorphism of the CYP17 gene related to sex steroid metabolism is associated with female-to-male but not male-to-female transsexualism
Bentz E, Hefler L, Kaufmann U, Huber J, Kolbus A, Tempfer C Fertility and Sterility , Volume 90 , Issue 1 , Pages 56 - 59
OBJECTIVE: To assess the association between transsexualism and allele and genotype frequencies of the common cytochrome P450 (CYP) 17 -34 T>C single nucleotide polymorphism (SNP). DESIGN: Case-control study. SETTING: Academic research institution. PATIENT(S): 102 male-to-female (MtF) and 49 female-to-male (FtM) transsexuals, 756 male controls, and 915 female controls.
The MtF transsexuals had an allele distribution equivalent to male controls, whereas FtM transsexuals did not follow the gender-specific allele distribution of female controls but rather had an allele distribution equivalent to MtF transsexuals and male controls. CONCLUSION(S): These data support CYP17 as a candidate gene of FtM transsexualism and indicate that loss of a female-specific CYP17 T -34C allele distribution pattern is associated with FtM transsexualism.
See also New Scientist on the subject.
While there are many women with the variant who are not transsexual and many FtM transsexuals who lack it, the finding raises the possibility that the variant makes women more likely to feel that their bodies are of the wrong sex, and that this is a result of their brains having been exposed to higher than average levels of sex hormones during development.

"It may increase the likelihood that people will become transsexual," says Tempfer. But he stresses that their cultural environment is also important.

"The present study found that a mutant gene that ultimately results in higher testosterone levels is overrepresented in female-to male transsexualism, says Mikael Landén of the Karolinska Institute in Stockholm, Sweden.

"This is in line with what we previously know about masculinisation of the brain and is therefore less likely to be a chance finding", he says. "Hence, the study is important and adds to the notion that gender identity is influenced by sex hormones early in life, and that certain gene combinations make individuals more vulnerable to aberrant effects."
That would be in accordance with the known effects of DES - and Thalidomide. For Thalidomide to cause "aberrant effects", there must be a genetic pre-disposition, which is why only 1 in 10 were affected. We know that only 1 in 5 "aberrant effects" happen after DES exposure in the first trimester, strongly suggestive of a genetic predisposition being required too.

More pieces of the puzzle. And negative results, pruning the possibility-tree, are just as valuable as the occasional "find".

In summary, the model we now have is:
  1. Hormones and/or gene sequences (not necessarily related to "sex chromosomes", but usually) cause a pre-natal pre-determined pre-disposition for later brain development.
  2. This development leads to emotional and thinking patterns that usually (not always) result in solid gender identity formation, in accordance with Diamond's Biased-Interaction model.
  3. Later still, both gross and fine structures of the brain differentiate to such an extent that they're detectable, caused by the same pre-natal factors.


Ivo Cerckel said...

For Thalidomide to cause "aberrant effects", there must be a genetic pre-disposition, which is why only 1 in 10 were affected, says you.

Interesting. I didn’t find this mentioned in
Janet McCredie (from the University of Sydney at Camperdown),
“Beyond Thalidomide – Birth Defects Explained”,
London, The Royal Society of Medicine Press, 2007.
I probably overlooked.

I am not a scientist. I am just a thalidomide monster.
Aberrant means deviating from the norm, says Random House Webster’s.

Is it also genetic disposition which determines how far one deviates from the norm?
I read that one tablet of thalidomide suffices to cause the damage.
Does this mean that the extent of the damage,
the extent to which the infant (’s limbs) will deviate from the norm,
is not determined by the number of tablets taken?
Can even many tablets (in the sensitive period) lead to “small” damage?

I am “only” missing the right forearm.
Could that have happened even if my mother was fed many tablets (in the sensitive period)?

Anonymous said...;_ylt=ApfTFnOuN.slGKJvZYeOG1nsy6IX;_ylv=3?qid=20080926214829AAA9lEf

Please try Yahoo! Answers.

Zoe Brain said...

Hi Ivo! Good to have you here.

You'd know better than I, but I think only having one effective arm is worse than being called a "thalidomide monster" or exhibiting an "aberrant effect".

But the latter two must get your goat sometimes. When my GP called me a "freak" it was in the context of us joking together about how utterly anomalous my blood tests were. Plus the natural MtoF transition, of course.

I'll go back and trace my dead-tree sources. This was an outgrowth of research triggered by Huang and MacBride's "controversial" (to say the least) paper in 1998. See British Medical Journal Jan 1998.

The observation was made that parents thought to be thalidomide-affected were more likely to have children with the same symptoms than others. This could be explained by the worrying - and disproven thank goodness - hypothesis that Thalidomide was a mutagen, not a teratogen - that it affected the genotype, not just the phenotype, the genes not just the bodily expression of those genes.

It could also be explained by mis-diagnosis of thalidomide affectation, that the drug had nothing to do with it. This was thought to be the answer in the late 90's

As I understand it - and I'll need to check - the truth was more complicated. Thalidomide caused an increase in problems in those with increased numbers of the sequence GGGCGG in their genes. This leads to both an increased susceptibility to Thalidomide damage, and also an increase in "natural" problems. There was selection in the sample, those *not* affected by Thalidomide administration had fewer GGGCGG sequences than those that were.

I remember the "only 1 in 10 were affected" figure, but don't have the supporting data to hand. It sounds plausible though, tens of millions were born at the time, and hundreds of thousands affected. Certainly more mothers were given Thalidomide than gave birth to Thalidomide-affected children. I think an assay of the sales figures led to the conclusion.

Thalidomide is now being used as an anti-cancer drug, and that also brought up the issue of why certain patients responded well, others less so with increased toxicity.

But again, I'll have to chase up the references.

Thanks for being here. My own metabolic weirdness looks like it's genetic, not environmental. My mother took neither DES nor Thalidomide.

Zoe Brain said...

Anonymous - answered.

Zoe Brain said...

Ivo - forgot to mention - I don't gave any data on dose/response rates for Thalidomide. That you only had minor (relatively.....) damage suggests your chance of having children with problems will be indistinguishable from those of the general population. Maybe even less.

Ivo Cerckel said...

Hi Zoe,

Thank You for welcoming me.

I have two children, born 2001 and 2005. None of them is affected.

Thalidomide is now being used as an anti-cancer drug?
Yes, I have some opinion about that.

Thalidomide - Dishonest Drug
April 6th, 2008 by Ivo Cerckel

Let me add:
Human nature is so constituted that some individuals who have inside knowledge about the effects of thalidomide will ‘always’ deliberately and unnoticeably cause the serious harm thalidomide can ‘so easily’ cause.
They do that precisely because the damage is so serious to the mother and to the child
and because they can do that so easily and without being noticed.
It may be that ‘in clinical trials’, thalidomide is shown to be effective against many things.
But ‘in real life’, it is given to unsuspecting girls.
Or will a utilitarian argue that this should be weighed against the lives which can be saved through thalidomide?
Perhaps, the utilitarian should be reminded of the surprising ignorance among younger doctors about its dangers, especially in countries where it was never an issue.
Utilitarianism is the ‘ethical’ doctrine that the moral worth of an action is solely determined by its contribution to

Now, let me read your original post. (I concentrated on thalidomide ...)

Ivo Cerckel said...

Maybe, I’m autist …

The Early Origins of Autism

by Patricia M. Rodier

Continuation: page 2 of 5

In their 1994 study Miller and Stromland added another environmental contributor to autism: thalidomide exposure in utero. All their subjects -- Swedish adults born in the late 1950s and early 1960s exhibited some of the malformations for which thalidomide is infamous: stunted arms and legs, misshapen or missing ears and thumbs, and neurological dysfunctions of the eye and facial muscles. Because scientists know which organs of the embryo are developing at each stage of pregnancy, they can pinpoint the exact days when a malformation can be induced: the thumb is affected as early as day 22 after conception, the ears from days 20 to 33, and the arms and legs from days 25 to 35. What made the new study so exciting for me was Miller and StrOmland's discovery that most of the thalidomide victims with autism had anomalies in the external part of their ears but no malformations of the arms or legs. This pattern indicated that the subjects had been injured very early in gestation -- 20 to 24 days after conception -- before many women even know they are pregnant.

Zoe Brain said...

In treatment of possibly fertile females, Thalidomide is *always* administered with a contraceptive.

It's saved the lives of many people with biliary tract problems. The properties that made it such an awful nightmare, a disaster, for a growing foetus are the same properties that can save lives.

The question is, have we learned the lessons so it doesn't happen again? The DES cover-up suggests we haven't. Though that was a smaller disaster, it continued to be administered for 30 years.

It's impossible to test drugs completely for safety - the number of possible drug and symptom combinations greatly exceeds the number of people who have ever lived. But cutting corners in a reasonable safety program is inexcusable.

I'm glad your children are doing well. My son is 7, and he's the centre of my existence.

He's also mildly Intersexed.

Autumn Sandeen said...

My apologies for not commenting on your blog in awhile, Zoe. :( I guess I just get pretty busy sometimes.

But with that said, this piece is one of the reasons I like reading your blog -- this is another pretty interesting study with pretty interesting possible ramifications. That you keep up on these kind of studies, and that you are very good at "translating" these kinds of studies into language us non-scientists can understand -- well, again, that's one of the reasons I keep coming back to this blog.

Plus, that you're up on planetary astronomy is pretty kewl too. :)

Ivo Cerckel said...


I suppose many people also tried to bring you back to so-called normalcy/normality.

What about cutting their fingers in order to make thalidomide monsters more conforming to the norm?

Thalidomide had been tested
September 28th, 2008 by Ivo Cerckel
From The Sunday Times
September 28, 2008
Thalidomide: Survival instinct
Some were abandoned by parents too traumatised to cope, or sent to special boarding schools. They were issued with painful, ill-fitting false limbs to make them look more “normal”, and well-meaning surgeons removed fingers and toes for cosmetic reasons, removing what little dexterity they had.

Zoe Brain said...

Ivo, they're still doing it. Or something similar.

Please read Square Peg, Round Hole.

I hadn't realised that Thalidomide victims were treated the same way, but it makes sense.

We have to change things. Thanks for bringing this to my attention, the problem is even bigger than I thought. And Enough is Enough.

Anonymous said...

I'm curious, what do you think of old Dr. (not!) Sam Vaknin?

Zoe Brain said...

I think that as a neuro-anatomist, he's a good macro-economist.

Rather full of himself though. Like me, I guess.

My blog is a blog, and my opinions my own. I have no formal qualifications in the area worth mentioning - maybe a few more than Dr V, but none of any substance.

What I do do though is not just make flat, opinionated statements. I give references to the primary sources, and explain my reasoning. Still, the article you linked to is a FAQ, necessarily condensed. Much of it contains some truth, but is quite misleading.

People sometimes seek sex reassignment because of advantages and opportunities which, they believe, are enjoyed by the other sex.
Such people are not transsexual, and cannot be diagnosed as such. The diagnostic criteria specifically excludes them.

See GID Diagnostic Features :
This cross-gender identification must not merely be a desire for any perceived cultural advantages of being the other sex.

If you search on "Blanchard" on my blog, you'll see my opinions of his neo-Freudian views.

Ivo Cerckel said...


Sorry, I had read what follows two or three years ago,
But finding this confirmed yesterday in The Sunday Times was still a shock.

Give me some days to absorb what you’ve sent me through the link.

For example, girls who are born without or with impaired limbs are forced to wear prostheses when they are still infants, while reliable research has proved that this is detrimental to their identity development and results in more harm than help. Often these children are amputated in order to fit into the prostheses
(Womens Issues:
Disabled Women and the Right to Health Care
By Theresia Degener (degener AT efh-bochum DOT de)
Visiting Professor at UC Berkeley, School of Law
Professor of Law, Administration and Organization at University of Applied Sciences, Bochum, Germany
Presented at Hunter College, June 7th, 2000, New York

I am not sure this is unrelated;

Is Purchasing $700 billion of Toxic Assets the Best Way to Recapitalize the Financial System? No! It is Rather a Disgrace and Rip-Off Benefitting only the Shareholders and Unsecured Creditors of Banks
Nouriel Roubini | Sep 28, 2008

Anonymous said...


Vaknin's PhD is from a non-accredited university (Pacific Western University), which is located in California (and is now called California Miramar University). Because of that, it is questionable whether he can be addressed as "Dr." His other credentials are questionable as well.

I do agree about that truth mixed with lies thing, which makes the whole thing poison soup.

Zoe Brain said...

Poison soup? More like used food. But I won't quibble.

Unknown said...

The think I always don't like about these type of studies is that they class all transsexual MTF or FTM together and then find that they have a distribution similar to that of natals. This completely disregards the possibility that there could be multiple causes. Certainly there is evidence that there are many presentation modes of transsexualism, so that this concept is not far fetched in any way. I have yet to see a study that breaks down those that do match the
genetic variation and see what characterizes their presentation or experiences to try to put it more on an epidemiological basis in terms of defining certain segments of the transsexual population.