Category Archives: Genes and Twins

Gender Identity Disorder and Anorexia Nervosa in Male Monozygotic Twins – Review

This is a fascinating study of identical twins; one had gender dysphoria and one did not. Both twins developed anorexia.

Both twins were feminine in behavior from a young age and both were sexually attracted to men. Both had a difficult childhood with an abusive father.

Both twins were underweight at birth and needed intensive care. Both had developmental delays.

However, one twin considered himself to be a gay man while one identified as a straight woman.

In this case study, gender dysphoria did not cause the eating disorder.

This case highlights the importance of other factors in eating disorders, including genes, hormones, and trauma.

It raises the question; how important is gender identity as a cause of eating disorders?

This case is different from other case studies where gender dysphoria seems to be intimately linked to the eating disorder.

We can’t look at these two patients and conclude that gender dysphoria never contributes to eating disorders. However, this case is a good reminder to be cautious about drawing conclusions from other case studies. Perhaps there are just some people with eating disorders who also have gender dysphoria. Or perhaps there is some other factor which causes both eating disorders and gender dysphoria.

As always, we need more studies.

More about the Patients:

Eating Disorders

Twin A was diagnosed with AN-purging subtype and Twin B was diagnosed with AN-restricting subtype.

Twin B developed an eating disorder at an earlier age, but Twin A was more underweight and had a more disturbed perception of his body. Furthermore, Twin A was hospitalized for his eating disorder and Twin B was not.

Neither twin seems to have been able to maintain a healthy weight.

At age 16 Twin A “was admitted to a children’s hospital because of AN. Later, he was hospitalized in the psychiatric inpatient unit for adolescents. At first, his eating behavior was restrictive. Then he reported intermittent vomiting (AN binge-purge). His weight decreased to 46 kg/1.79 m (body mass index [BMI] ¼ 14.3 kg/m²). His ideal weight was 44 kg according to a BMI of 13.7 kg/m² , which shows his severe disturbance in body perception. During hospitalization, his behavior was sometimes aggressive. He was emotionally unstable, depressed, and was rarely able to engage in stable relationships. Despite strict dietary rules, he achieved a maximal weight of 55 kg (BMI ¼ 17.2 kg/m²). Soon after being discharged, his weight decreased again.”

Twin B’s eating disorder began at a younger age. “In puberty, he developed severe underweight. At the age of 13, he was 42 kg/1.58 m (BMI ¼ 16.8 kg/m² ). When he was referred to our outpatient unit at the age of 18½ years [for gender dysphoria], his weight was 48 kg and his height was 1.76 m (BMI ¼ 15.5 kg/m² ). He denied deliberate dieting, binging, or purging. Although he regarded himself as too slim, he did not manage to gain weight. Further medical checkups revealed no somatic cause for his underweight. An osteodensitometry yielded an osteopenia of the spine.”

Gender Identity

Twin A was a gender non-conforming gay male:

In childhood, he preferred girls’ games and toys (Barbie dolls) and was very close to his twin brother. His sexual feelings were always for males. Although he started cross-dressing at the age of about 16 years, his gender identification was always male. He considered himself to be a homosexual.”

Twin B was a trans woman:

“As far as he could remember, he had felt he was a girl, preferring girls as playmates and had started cross-dressing at nursery school. In gymnastic lessons, he refused to change with the other boys because he was ashamed of his body. Eventually, he refused to attend sports lessons at all. When he was 9 years old, he started to grow his hair. His class mates seemed to accept him as a girl. When he started to work as a hairdresser, he tried to correspond to the male gender role and did not cross-dress. However, at his professional school and in his free time, he continued to cross-dress. His employer, who realized he was transsexual, permitted and encouraged him to cross-dress at work, which consequently allowed him to live as a young woman. Sexually, he was always attracted to men. However, in contrast to his brother, he never considered himself to be homosexual and viewed this attraction as ‘‘heterosexual.’’ Until this point, he had not engaged in sexual relationships either with men or with women.”

Twin B requested hormonal and surgical sex reassignment.

Childhood

The twins grew up together in a small Swiss city without any other siblings. Their childhood was not easy:

“[Their father] was very authoritarian. He could not accept the sexual orientation and the cross-dressing of his sons and threatened them with assault and even with death.

…In family conflicts, [their mother] took a position between her husband and her sons. At a family consultation, she appeared emotionally unstable.”

Birth 

The birth was a difficult one. Both twins were underweight and spent time in intensive care.

“the mother had been admitted to a hospital with hypertension, edema, and proteinuria at 38 weeks of gestation. The vaginal delivery was induced because of maternal preeclampsia. Twin A weighed 2.17 kg at delivery and his Apgar score was 9/9/9. Because of perinatal acidosis and hypotonia, he was kept in the incubator for 3 days. He was diagnosed with a subependymal hemorrhage with ventricular invasion. Twin B’s birth weight at delivery was 1.95 kg and his Apgar score was 7/9/9. Both twins were admitted immediately to the neonatal intensive care unit.”

Developmental Delays

They both had developmental delays:

“In early childhood, Twin A showed a developmental delay in language and motor skills and had deficits in cognitive and verbal skills. He was socially isolated and his behavior was often aggressive.”

“…Twin B had delays in language and motor development during early childhood. He showed the typical symptoms of attention deficit and hyperactivity disorder. The parents refused further assessment and treatment.”

Other

Twin A was diagnosed with borderline personality disorder and subnormal verbal intelligence.

Twin B was diagnosed with gender dysphoria.

There is no obvious pattern to any of this. Twin A was larger at birth, but had more problems right after birth. Both had developmental delays, and Twin B may have had ADHD as well. Both were feminine in their behavior, but only Twin B developed gender dysphoria. Both were sexually attracted to men. Twin B developed an eating disorder earlier, but Twin A’s eating disorder seems more severe. Twin A has borderline personality disorder and Twin B does not.

Discussion

The authors offer two possible hypotheses about the twins’ gender identity.

Perhaps the twins are on a continuum of gender non-conformity where gender dysphoria is at the extreme end.

Alternatively, perhaps gender dysphoria* in childhood is inherited, but the later development of gender identity is determined by environmental factors and psychiatric comorbidity.

“In childhood, both Twin A and Twin B showed gender atypical behavior and stereotypical feminine traits and interests. In adolescence, their sexual orientation was revealed to be homosexual. Twin A developed effeminate homosexuality with male gender identity, whereas Twin B stabilized his cross-gender identity. Although Twins A and B are concordant for GID in childhood and sexual orientation on a categorical level, they are now discordant for TS. On a more dimensional level, one could argue that Twins A and B show an opposite sex-dimorphic behavior and that they arrived at different points of a continuum. The fact that GID in childhood is a predictor for later homosexuality and TS could support the dimensional view. It could be hypothesized that GID in childhood is mainly hereditary, whereas the development of the later phenotype of the gender identification is determined by environmental factors and psychiatric comorbidity, as any difference between MZ twins provides strong evidence for the role of environmental influences.”

The authors also discuss the relationship between gender and eating disorders. However, they don’t address the fact that the two twins had different gender identities, but both had eating disorders.

Perhaps both gay men and trans women are vulnerable to eating disorders for different reasons, but perhaps genes, hormones, and environment matter more than gender identity.

“Homosexual men seem to have an increased vulnerability to eating disturbance and body dissatisfaction (Williamson & Hartley, 1998), are more dissatisfied with their weight (French, Story, Remafedi, Resnick, & Blum, 1996), and are more concerned about their attractiveness (Siever, 1994). Male AN is associated with disturbed psychosexual and gender identity development, which supports the hypothesis that males with atypical gender role behavior have an increased risk of developing an ED (Fichter & Daser, 1987). Furthermore, feminine gender traits are discussed as a specific risk factor for ED in men and women (Meyer, Blissett, & Oldfield, 2001). Although the role of sexual orientation as a risk factor for ED is well documented, there is hardly any literature about GID and ED. For men with disturbance of gender identity in addition to the aforementioned factors concerning sexual orientation, underweight could be a way to suppress their libido and the expression of their secondary sexual characteristics and, at the same time, correspond to a female ideal of attractiveness (Hepp & Milos, 2002).”

We need more research!

“Further research in eating behavior and body dissatisfaction in patients with GID could provide more insight into the role of gender identity in the development of ED and lead to a better understanding of ED as well as GID.”

 

* In this case, gender non-conformity might be a more fitting phrase. Twin A does not seem to have ever wanted to be a girl.

 

Original Source:

Gender Identity Disorder and Anorexia Nervosa in Male Monozygotic Twins by Urs Hepp, Gabriella Milos, and Hellmuth Braun-Scharm in Int J Eat Disord. 2004 Mar;35(2):239-43.

 

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Identical Reared apart Twins Concordant for Transsexuality – Review

This is a brief article about a case of identical twins reared apart who both had gender dysphoria. Unfortunately, it is based on an interview with only one of the twins. This makes it a suggestive report, but not scientific proof.

In addition, one of the twins was born with an intersex condition. This raises the question of whether his gender dysphoria was caused by genes or the prenatal environment.

The twins were born male and separated at birth and raised in different families. They did not meet each other until they were 15. DNA testing confirmed that they were identical twins.

This is only one case, so the conclusions we can draw are limited.

The main weakness of the report, however, is that it is based on the memories of only one of the twins, LT. The authors were able to interview LT in his 50s.* It is possible that his memories of meeting his twin AT 35 years ago would be incorrect or might exaggerate similarities or differences.

According to LT,

“Prior to meeting, by age 8 years both twins experienced gender discomfort, engaged in cross-dressing, and felt that they should have been born as the other gender. Also prior to meeting, both twins experienced unease with the anticipated and actual secondary sexual development of puberty. Furthermore, unbeknownst to his twin, at age 14 years LT was fully committed to undergoing sex reassignment surgery and so convinced his mother that she took him to see a urologist.”

According to the author of the report, this means that both twins met the criteria for gender dysphoria, “persistent cross-gender identification and a strong desire to change the sexual characteristics to those of the other gender.”

I am not comfortable with diagnosing someone you have not interviewed. Clearly, AT had some issues with his gender, but how did he define himself? Did he want to have surgery? Did the twins continue to have contact and did AT’s gender dysphoria persist into adulthood? Did they influence each other after age 15?

This report is also about a tragedy. AT committed suicide at age 35.

The twin’s birth mother had skin cancer and doctors believed she should give one twin up for adoption. AT was therefore put in a state-run institution and then adopted by a less well-to-do family. His parents were “religious, punitive, and rejecting of his cross-gendered behaviors.” (Presumably we know all this from his twin, LT.)

LT was raised by his biological parents. His family was more financially comfortable. His mother and sisters “supported his female identity as it developed and afterward.”

The authors of the study stress the importance of family support in preventing suicide, but there are a number of other factors that might have also influenced AT. Adoptees are more likely to attempt suicide than non-adoptees. It might also be upsetting to learn that you had a twin and your birth parents had kept them, as AT did. Having parents with a lower socio-economic status also increases the risk of suicide. AT was therefore more at risk for suicide to start with, although we also know that family support reduces the risk of suicide for people with gender dysphoria.

An interesting aspect of this study is that LT was a “sickly infant” and had hypospadias, a birth defect in the urethra. The Intersex Society of America lists it as an intersex condition. There is no information in the study as to whether or not AT also had hypospadias or any other intersex condition.

Did the hypospadias contribute to LT’s gender dysphoria? Could having a scar on your penis influence feelings about gender identity?

Could the hypospadias be a sign of something else that also caused LT’s gender dysphoria?

According to Wikipedia, the cause of most cases of hypospadias is unknown, but it may be influenced by: having an older mother, the mother taking progesterone during pregnancy, the fetus not producing enough testosterone or nor responding to it, or genetics. It seems reasonable to ask if these factors might also affect gender identity.

In this case, the mother was 40 when the twins were born, which might have been a factor in LT’s hypospadias. We don’t know about any hormonal factors.

We have no way of knowing what caused LT’s hypospadias, but it does raise the question of whether the twins’ issues with gender were caused by a genetic factor or something to do with the prenatal environment or the genital surgery.

I am frustrated by this study. It seems like a good case for a genetic component to gender dysphoria – twins reared apart are a classic test of genetic effects. Unfortunately, since it is based on the account of one twin, the evidence is not as strong. It might be that the twin who lived developed a narrative to make sense of his twin’s tragic suicide.

In addition, the fact that one twin had an intersex condition at birth might be a sign of something unusual in the twin’s prenatal environment.

Mostly, though, you can’t say you have scientific proof that the twins were alike if you only interview one of the pair of twins.

It is so very hard to get good data on gender dysphoria. People with gender dysphoria are extremely rare and twins with gender dsyphoria are even rarer. Add in a much-too-high suicide rate, and you have even less ability to collect data.

Once again, we need more research in this area. As Heylens et. al said in their review of the literature: “detailed registers of GID twins, preferably on MZ twins discordant for GID and DZ twins are needed, to gain more decisive information about the influence of genetic vs. environmental factors in the development of GID.

Original Case Report:

Identical Reared apart Twins Concordant for Transsexuality by Nancy Segal & Milton Diamond, Letter to the Editor, published in: Journal of Clinical and Experimental Medicine, April 2014 Volume 6, Issue 2, Page 74.

*The article refers to the twins with male pronouns. The article does not make it clear what the twins did when they grew up. LT, if you have transitioned and I am using the wrong pronouns, I apologize.

More about twins and gender dysphoria:

My review of “Gender Identity Disorder in Twins: A Review of the Case Report Literature.”

A review of “Gender Identity Disorder in Twins: A Review of the Case Report Literature”

The data on twins suggests that there is a genetic component to gender dysphoria.

It also suggests that other factors are involved in developing gender dysphoria.

Unfortunately, the data is weak because it is mostly made up of case studies.

In addition, the data on identical twins and the data on fraternal twins were collected in different ways.

It is possible that this review overestimates the influence of genes due to the way the data was collected.

I had thought that writing this review would be quick and easy; genes are involved, but they are not the only factor. The truth is that the data is flawed and we don’t have conclusive proof yet. What we do have is a suggestion that genes are involved in gender dysphoria and a need for more research in this area.

Data on twins with gender dysphoria is hard to collect because it is rare. This review is an important one and it shows that there are good reasons to keep looking for possible genetic links to gender dysphoria. It also shows that there are good reasons to look for non-genetic factors that play a role in developing gender dysphoria.

Now you have the summary of the results, back to the study. Why does it mattter if many of the reports on identical twins came from case studies?

Using case studies means that there is a possibility of selection bias.

People may be more likely to publish interesting cases. For example, the review includes one case study where both identical twins had gender dysphoria, but only one had schizophrenia. In another case study both identical twins had anorexia, but only one had gender dysphoria. These cases are interesting, but they may not be typical.

This can become a more serious problem if therapists are more likely to be interested in cases of twins who are both trans. Alternatively, there could be a selection bias in favor of writing about identical twins where only one twin is trans. Some therapists might unconsciously look for cases of twins that fit their own theory about the cause of gender dysphoria. (Read more about case studies and selection bias here.)

The results of this review suggest that there is a selection bias that favors identical twins over fraternal twins. In other words, people write up and publish cases of identical twins more often than fraternal twins.

This is not because trans people don’t have fraternal twins; the studies that reviewed clinic records found 19 sets of fraternal same-sex twins and only 7 sets of identical twins. Only 27% of the twins in this group were identical twins. This is not surprising; fraternal twins are more common than identical twins in the general public.

The other studies, in contrast, reported on 16 sets of identical twins and only 2 sets of fraternal twins. A whopping 89% of the twins in this group were identical twins.

The key to figuring out if gender dysphoria is genetic is to compare identical twins and fraternal twins. If identical twins are more likely to both have gender dysphoria than fraternal twins, you have a good case for a genetic contribution. So if the sets of identical twins are chosen in a different way from the sets of fraternal twins, you have a problem.

In fact, for this study most of the data on identical twins is coming from case reports; there might be a selection bias involved there. Almost all of the data on fraternal twins, however, is coming from comprehensive reviews of clinic records.

Reviews of case studies include a number of other problems.

You can’t be sure people are being diagnosed in the same way; you may not be looking at the same phenomenon. This review looked at people diagnosed by different therapists in at least ten different countries.* The dates of the studies ranged from 1956 to 2011. Some of the twins were children or teens, some were adults.

There may also be cultural or environmental differences that are relevant. For example, one of the case studies is of a pair of identical twins in Iran. Both twins are trans. We know that many people feel pressured to transition in Iran; what if that is a factor in this particular case? What if in another country, only one of the twins would have transitioned?

The era of the study might also affect gender dysphoria. For example, the Belgian clinic noticed that two of the fraternal twins with gender dysphoria they found had been born after in vitro fertilization. If IVF is a factor in gender dysphoria, it will only affect later cases.**

The data in case studies is not uniform; this makes it hard to compare. For example, one study discussed birth weights while another focused on relationships with parents.

This review of studies did include three sets of twins who were found in a method that did not have a selection bias or problems with inconsistent collection of data.

1) Zucker looked at the records of 561 patients who went to a Canadian clinic for gender dysphoria between 1976 and 2011 and found 25 sets of twins. The patients were all under 12 years old.

They found no cases where both twins had gender dysphoria.

2) Heylens and De Cuypere looked at 3 sets of adult twins from the 450 patients who went to a Belgian gender clinic between 1985-2011 plus 3 sets of non-adult twins who went to the Belgian gender clinic for children and teenagers.

They found only one case where both of the twins had gender dysphoria: a set of identical twins who were female-to-male transgender (FtM).

3) Vujovic et al reviewed all the cases of gender dysphoria who were treated at a Serbian clinic between 1987 and 2006. Out of 147 people, one trans man and one trans woman had a fraternal twin. Neither of their twins had gender dysphoria.

If we exclude case studies because of possible bias, we end up with no genetic component to gender dysphoria in trans women. None of the clinics found pairs of male twins who both had gender dysphoria.

The problem with this approach is that identical twins who are both male-to-female transsexuals exist. They just didn’t show up at these three clinics. Presumably, they are very rare.

Using the clinic studies for trans men we would have one set of identical Belgian twins who both had gender dysphoria, and one set of identical Canadian twins who did not. In addition, we would have three sets of fraternal twins where only one twin had gender dysphoria. This is not enough data.

So it makes sense to look at the data from individual case studies; we just need to be cautious about interpreting it. It is possible that it would over or underestimate the genetic component to gender dysphoria.

What was the data, then?

The authors searched the literature and put their data from the three clinics together with data from 17 different case reports and studies.***

They found:

FtMs with identical twins

3 sets of identical twins who both had gender dysphoria (37.5%)

5 sets of identical twins where only one of the twins had gender dysphoria (62.5%)

FtMs with fraternal twins

5 sets of fraternal twins where only one of the twins had gender dysphoria (100%)

MtFs with identical twins

6 sets of identical twins where both twins had gender dysphoria (40%)

9 sets of identical twins where only one twin had gender dysphoria (60%)

MtFs with fraternal twins

16 sets of fraternal twins where only one twin had gender dysphoria (100%)

Based on this data, identical twins with gender dysphoria are more likely than fraternal twins or the general public to have a twin with gender dysphoria. This suggests a genetic component to gender dysphoria.

However, most of the time, only one identical twin has gender dysphoria. This suggests other factors are involved in gender dysphoria.

At this point, we have no idea what the other factors involved might be. The case reports don’t give enough information on the twins to figure it out. The information they give is inconsistent; one study reported on the age of the first period while another talked about whether or not the mother was domineering. In addition, we may be comparing apples and oranges; for example, one study looked at an adult male American Indian in 1976, another looked at 13 year old American females in 1992.

The authors of the review conclude:

“The etiology of GID is a complex process of biopsychosocial components with unexplained interactions. Twin literature on GID supports the contribution of genetic factors to the development of gender identity with a higher tendency in males than in females.****

Since sample size is still limited and genotype studies are lacking, conclusions must be drawn with caution.

Therefore, detailed registers of GID twins, preferably on MZ twins discordant for GID and DZ twins are needed, to gain more decisive information about the influence of genetic vs. environmental factors in the development of GID.

The authors of the study combine the data from studies of MtF and FtM twins for the statistical analysis. This gives them 9 pairs of identical twins where both twins had gender dysphoria (39%) and 14 pairs of identical twins where only one twin had gender dysphoria (61%). This is contrasted with 21 sets of fraternal twins where only one twin had gender dysphoria (100%). The difference is statistically significant.

This might be problematic since the mechanism that causes gender dysphoria in trans women is probably different from the mechanism that causes gender dysphoria in trans men. The genes are also probably different.

On the other hand the question here is whether or not gender dysphoria is inheirited, so perhaps this works.

Another problem is the possibility of selection bias. It looks like people are over-reporting cases involving identical twins. This might affect comparisons between identical twins and fraternal twins.

In addition, the total size of the group used in their statistical analysis is small and includes disparate groups – males and females, adults and children, people in different countries, and people living in different eras.

In the end, we’re left with weak evidence for a genetic component to gender dysphoria. We can’t prove it, but there is an excellent case for doing more studies in this area.

There is also an excellent case for future studies looking at what factors make one identical twin have gender dysphoria and one not. This seems to be the more common outcome than for both twins to have gender dysphoria.*****

Original Review:

Gender Identity Disorder in Twins: A Review of the Case Report Literature by Heylens G, De Cuypere G, Zucker KJ, Schelfaut C, Elaut E, Vanden Bossche H, De Baere E, T’Sjoen G in J Sex Med. 2012 Mar;9(3):751-7.

 

*Authors of the studies were from Belgium, Canada, Germany, Iran, Israel, the Netherlands, Serbia, Switzerland, the United Kingdom, and the United States. In addition, one author seemed to be from Scandinavia, possibly either Norway or Sweden.

**Using IVF means that the parents were infertile. It might be that the parents were older or that they had something wrong with their reproductive systems. It could be that the parent’s age or fertility problems affected the children rather than the IVF procedure.

***In some cases, it is hard to tell from the title if an article was a study or case report or an article on gender dysphoria that includes information on a case. Then again, the sub-title of this study is “A review of the case report literature,” so maybe they were all case reports.

**** I think the idea that there is a higher tendency in males than females is overstated. There were only 8 pairs of identical FtM twins and I doubt the 2.5% difference in the frequency of FtM versus MtF identical twin pairs who both have gender dysphoria is significant.

***** There may be selection bias in the cases of identical twins from the case reports. However, the clinic studies did find six sets of identical twins. In five of these six pairs, only one twin had gender dysphoria. Specifically, they found four pairs of identical male twins where only one twin had gender dysphoria, one pair of identical female twins where only one twin had gender dysphoria, and one pair of identical twins who were both FtM. So it looks like it is more common for only one identical twin to have gender dysphoria.

Emphases added are mine, including in the quote from the original review of the literature.

Study of Gay Brothers Suggests Genetic Basis of Male Homosexuality – Discovery Magazine Article

An interesting and important piece from Discovery magazine.

“Are people born gay or is it a choice? A new study of gay brothers, the largest to date, adds more scientific evidence that there’s a genetic basis for homosexuality.

A genetic analysis of over 409 pairs of gay brothers found that two areas of the human genome, a portion of the X chromosome and a portion of chromosome 8, were associated with the men’s sexual orientation. The findings gel with a smaller study conducted in 1993 that implicated the same area of the X chromosome.”

You can read the rest of the article at Discovery magazine.

So why is this important for research on gender dysphoria?

1) If sexual orientation is influenced by genes, then researchers looking for genes related to gender identity need to control for sexual orientation.

Trans men (born female) are usually attracted to women and about half of trans women (born male) are attracted to men, so they might share genes with cis lesbians or gay men.

Future studies of genes and gender dysphoria need to include cis gay men and lesbians in the control groups.

2) The genes that may be involved in male homosexual orientation were found on the X chromosome and chromosome 8. The researchers looked at the whole genome for 409 pairs of homosexual brothers.

Studies of genes for gender dysphoria have focused on genes known to be related to sex hormones and the X and Y chromosomes (read more in Genes and Gender Dysphoria). This makes sense if you are looking at behavior that is related to sex differences, but perhaps the genes are somewhere else.

So far, researchers have had not luck finding genes related to gender dysphoria in trans women and only some luck finding genes related to gender dysphoria in trans men. Perhaps the genes for gender dysphoria and the mechanism involved are not what we expect.

A whole genome scan for genes related to gender dysphoria would be a great study for someone to do.

Genes and Gender Dysphoria

Twin and family studies suggest that there may be a genetic component to gender dysphoria. Researchers have naturally been trying to find genes linked to gender dysphoria.

Most of the research has focused on genes that are known to be related to sex hormones in some way.

I. Researchers may have found genes related to gender dysphoria in trans men (born female).

A large Spanish study found an association between the gene for Estrogen Receptor β and gender dysphoria, but a medium-sized Japanese study did not.

A small Austrian study found an association between gender dysphoria and a different gene related to converting progesterone into androgens. Nobody else has looked at this gene.

A possible flaw with the Austrian study is that the control females were seeking help with perimenopausal issues; it may be that their genes were different from the general public.

Both of these results need to be replicated.

It is also possible that the genes were related to sexual orientation.

In the Spanish study, all of the trans men were attracted to women; it is likely that 95% of the control women were attracted to men.

The Austrian study does not talk about sexual orientation, but typically most trans men are attracted to women and most women are not.

Many control women also had the genetic variations found in trans men. Some other genes or environmental factors must also be involved.

These results need to be replicated. The Austrian study was relatively small and possibly flawed while the Spanish and Japanese studies contradict each other.

II. Researchers thought they had found genes related to gender dysphoria in trans women (born male), but larger studies did not replicate the results. It is possible, however, that the genes related to gender dysphoria are different in different populations.

Four studies looked at genes related to sex hormones, specifically genes for estrogen receptor β, androgen receptor, and CYP19A1. CYP19A1 encodes aromatase, an enzyme involved in turning androgens into estrogens.

None of the studies found a relationship between gender dysphoria and the gene for CYP19A1.

Three studies found no difference in the gene for estrogen receptor β; the study that found a difference was much smaller than the others.

Three studies found no difference in the gene for androgen receptor, including one study of over 400 trans women.

III. An Italian study that looked at the Y chromosome found no differences between trans women and control males.

IV. An Austrian study that looked at sex chromosomes in trans women and trans men found no significant abnormalities.

V. A Japanese study that looked at genes related to estrogen receptor alpha and progesterone receptor found no differences between the genes of male to female transsexuals and male controls or the genes of female to male transsexuals and female controls. This study also looked at estrogen receptor β, androgen receptor, and CYP19A1 and found no differences for those genes either; this is one of the studies discussed above.

VI. An Austrian study of a gene related to steroid 5-alpha reductase (SRD5A2) found no differences between trans women, trans men, and male and female controls. SRD5A2 is involved in the conversion of testosterone to dihydrotestosterone.

It is important to remember that there may be some other genetic variations that are linked to gender dysphoria in trans women, something that we haven’t studied yet.

At this point, however, we do not seem to have found genes related to gender dysphoria in trans women.

Recommendations for future research:

Look at genes other than the ones related to sex hormones or sex chromosomes. Perhaps the cause of gender dysphoria is different from what we expect.

Control for sexual orientation by including some cis lesbians and gay men in the study.

Study trans people with African ancestry – and other groups that have not yet been studied. Studies so far have looked at people from Spain, Italy, Japan, Austria, America and Australia (Caucasian only), and Sweden.

For more details on the studies, see the links and comments below.

STUDIES OF TRANS MEN (Born female)

2014:

The (CA)n Polymorphism of ERβ Gene is Associated with
FtM Transsexualism – This Spanish study compared the genes of 273 female to male transsexuals and 371 control females. As in the study of trans women below, they focused on three variable regions of genes: estrogen receptor β (ERβ), androgen receptor, and CYP19A1 which encodes aromatase, an enzyme involved in turning androgens into estrogens.

They found no connection between the genes related to androgen receptors or aromatase, but they did find an association between the ERβ gene and gender dysphoria in trans men.

“The repeat numbers in ERβ were significantly higher in FtMs than in control group, and the likelihood of developing transsexualism was higher (odds ratio: 2.001 [1.15-3.46]) in the subjects with the genotype homozygous for long alleles.”

Three caveats:

All the trans men participating in the study had gender dysphoria that began before puberty and were attracted to women (i.e. members of their biological sex). The control females were probably 95% straight. It is possible that the genetic difference they found is related to sexual orientation, not gender identity.

This is not an absolute difference, it is a difference in frequency – 69% of the trans men had the long allele for ERβ, but so did 59% of the control women. Some other genes or environmental factors must also be involved in gender dysphoria (or sexual orientation).

The study below found different results; however, this study was larger.

note: All participants in the study were of Spanish origin.

2009:

Association study of gender identity disorder and sex hormone-related genes.

This Japanese study compared 74 male-to-female transsexuals, 168 female-to-male transsexuals, 106 male controls, and 169 female controls. They looked at genes for androgen receptor, estrogen receptors alpha and beta, aromatase, and progesterone receptor.

They found no differences between the genes of male to female transsexuals and male controls or the genes of female to male transsexuals and female controls. 

“The present findings do not provide any evidence that genetic variants of sex hormone-related genes confer individual susceptibility to MTF or FTM transsexualism.”

The abstract does not provide any information on the demographics of the trans women and trans men.

The results of this study for ERβ contradict the results of the Spanish study. The Spanish study looked at 273 trans men while this study only looked at 74, so it is unlikely that the Spanish study is simply wrong.

It may be, however, that this study is still right, at least in Japan. People in different countries have different genes; they may have different genes for gender dysphoria.

It is possible that cultural differences or medical policies may mean that clinics in different countries are looking at groups of people with different problems.

Finally, gender dysphoria might be caused by different factors or combinations of factors in different cultures. Japanese trans men may be different from Spanish trans men in some important way.

2008:

A polymorphism of the CYP17 gene related to sex steroid metabolism is associated with female-to-male but not male-to-female transsexualism.

This Austrian study compared 102 male to female transsexuals to 756 male controls and 49 female to male transsexuals to 915 female controls.

A possible flaw in this study is that the females controls were women seeking help with perimenopausal disorders; they may have had genes that were different from the general population. The male controls, on the other hand, were “participating in a health prevention program.”

Since the results found that the frequency of a particular mutation was different in female controls from all of the other groups, it matters a great deal if the control females are significantly different in some other way from the other participants.

This study looked at a different gene from the other studies, CYP17. CYP17 encodes cytochrome, an enzyme involved in converting progesterone and pregnenolone into androgens.

The authors found that a particular mutation of this gene, CYP17 −34 T>C, was associated with female to male transsexualism, but not male to female transsexualism.

They also found that, “the CYP17 −34 T>C allele distribution was gender-specific among controls. The MtF transsexuals had an allele distribution equivalent to male controls, whereas the 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.” 

In other words, trans men and trans women were similar to male controls and not female controls.

They point out, however, that there were women without gender dysphoria who had the mutant allele as well as women with gender dysphoria who did not have it. “Thus, carriage of the mutant CYP17 T−34C SNP C allele is neither necessary nor sufficient for developing transsexualism.”

In other words, there must be other genetic or environmental factors involved.

They do not discuss the sexual orientation of the participants in the study. As discussed above, it is possible that most of the trans men were attracted to women and that this genetic mutation is related to sexual orientation, not gender identity.*

Finally, I keep coming back to the female control group. What if converting progesterone to androgens is related in some way to perimenopausal symptoms? What if the mutant gene protects against problems in menopause somehow and so the female control group includes fewer people with this gene?

2007:

A common polymorphism of the SRD5A2 gene and transsexualism. This Austrian study compared 100 trans women, 47 trans men, 755 control men, and 915 control women. They looked at a mutation of the steroid 5-alpha reductase gene (SRD5A2); this gene produces an enzyme that catalyzes the conversion of testosterone to dihydrotestosterone.

They found no differences between any of the groups. The mutant allele was not associated with transsexualism and its distribution was not gender specific among controls.

This study has the same flaw as the 2008 study listed above; the control females were all seeking help for problems with perimenopause.

2002:

Sex chromosome aberrations and transsexualism. This Austrian study looked at the chromosomes of 30 trans women and 31 trans men. They did not find significant abnormalities, although they suggested further investigation might be worthwhile.

“We could not detect any chromosomal aberrations with the exception of one balanced translocation 46,XY,t(6;17)(p21.3;q23). Importantly, no sex chromosomal aberrations, which would be detectable on the G-banded chromosome level, have been observed.”

They conclude:

“The data described here provide evidence that genetic aberrations detectable on the chromosome level are not significantly associated with transsexualism. In addition, molecular-cytogenetic FISH analyses did not reveal deletions of the androgen receptor gene locus on chromosome Xq12 or of the SRY locus on chromosome Yp11.3. Multiplex PCR analyses demonstrated one AZF deletion in a male-to-female transsexual.”

but:

“However, the detection of one carrier of a Y chromosome microdeletion out of 30 male-to-female transsexuals could argue for further investigations. This is of special interest in light of the recent discussion of gamete banking before hormonal and sex reassignment surgery of transsexuals.”

 

STUDIES OF TRANS WOMEN (Born male)

The Y Chromosome:

2013

Hormone and genetic study in male to female transsexual patients. This Italian study looked at six areas on the Y chromosomes of 30 trans women. They found no abnormalities.

“This gender disorder does not seem to be associated with any molecular mutations of some of the main genes involved in sexual differentiation.”

The trans women were aged 24-39 and had already begun hormone therapy. A little over half of them had already had sex reassignment surgery and the rest were waiting for it.

2002:

Sex chromosome aberrations and transsexualism. This Austrian study looked at the chromosomes of 30 trans women and 31 trans men. They did not find significant abnormalities, although they suggested further investigation might be worthwhile.

For further details, see the description above under trans men.

Genes Related to Sex Hormones:

2007:

A common polymorphism of the SRD5A2 gene and transsexualism. This Austrian study looked at a mutation of the steroid 5-alpha reductase gene (SRD5A2. They found no differences related to gender or gender identity. For more details, see the description above in the section on studies of trans men.

The following studies looked at the same areas of genes related to sex hormones.

Initially, a small Swedish study of trans women (born male) found a difference in the length of the estrogen receptor β repeat polymorphism, but none of the other studies did.

Similarly, an American-Australian study found that trans women had longer repeat lengths for the androgen receptor allele, but none of the other studies did.

It looks like these genes do not affect gender dysphoria in trans women, although it is possible that different genes affect people in different countries.

2014:

Association Study of ERβ, AR, and CYP19A1 Genes and MtF Transsexualism – This Spanish study compared the genes of 442 trans women and 473 control males. They focused on three variable regions of genes: estrogen receptor β, androgen receptor, and CYP19A1 which encodes aromatase, an enzyme involved in turning androgens into estrogens.

They found no connection between these genes and gender dysphoria.

Interestingly, 98% of the trans women had chromosomes that were 46,XY, i.e. normal, but 2% of the group showed aneuploidy, or abnormal chromosomal numbers. This is slightly higher than usual.

The abstract does not go into detail, but presumably the aneuploidies were cases of Klinefelter syndrome; a condition where a person typically has one Y chromosome and two X chromosomes. Most people with Klinefelter’s syndrome identify as male, but there may be a higher than usual occurrence of gender dysphoria among people with Klinefelter’s.

There are no details on the trans women in the abstract; however, the same researchers did a very similar study of trans men (see above). It may be that the participants in the two studies were screened in the same way.

2009:

Association study of gender identity disorder and sex hormone-related genes.

This Japanese study compared 74 male-to-female transsexuals, 168 female-to-male transsexuals, 106 male controls, and 169 female controls. They looked at genes for androgen receptor, estrogen receptors alpha and beta, aromatase, and progesterone receptor.

They found no differences between the genes of male to female transsexuals and male controls or the genes of female to male transsexuals and female controls. 

“The present findings do not provide any evidence that genetic variants of sex hormone-related genes confer individual susceptibility to MTF or FTM transsexualism.”

The abstract does not provide any information on the demographics of the trans women and trans men.

Androgen receptor repeat length polymorphism associated with male-to-female transsexualism.

This Australian and American study compared 112 male to female transsexuals to 258 control males. They looked at genes for androgen receptor, estrogen receptor beta, and aromatase. No differences were found for the estrogen receptor or aromatase, but transsexuals had longer repeat lengths for the androgen receptor allele.

“This study provides evidence that male gender identity might be partly mediated through the androgen receptor.”

This result was not found in the Spanish study or the Japanese study above. The Spanish study was larger than this one. Thus, this result has not been replicated.

However, it is possible that this genetic variation is connected to gender dysphoria for Caucasian trans women in America and Australia, but not in Spain or Sweden and not for Japanese trans women.

It is also possible that the genetic difference found here is related to sexual orientation, not gender identity. The researchers in this study only knew the sexual orientation for about 40% of the participants in the study, but people with gender dysphoria are much more likely to be attracted to people of the same biological sex than people without gender dysphoria.

As in the Spanish, study above, this is not an absolute difference, it is a relative one. There were also cis men who had long AR repeat lengths (Figure 1). Again, some other genes or environmental factors must also be involved in gender dysphoria (or sexual orientation).

The trans women in this study were all Caucasian; 76 of them were from an Australian clinic and 36 of them were from UCLA in America. Almost all of them were on hormones. Some of them had gender dysphoria in childhood. “The sexuality is only known for approximately 40% of patients, because some patients did not wish to discuss or disclose this information or the patient’s sexuality was flexible and not easily classified.”

2005:

Sex steroid-related genes and male-to-female transsexualism.

This Swedish study compared the genes of 24 male to female transsexuals and 229 male controls. They looked at specific areas in the androgen receptor gene, the aromatase gene, and the estrogen receptor β gene.

They did not find a difference between male-to-female transsexuals and men for the first two genes, but they did find a difference related to the gene for estrogen receptor β. “Transsexuals differed from controls with respect to the mean length of the ERβ repeat polymorphism.”

In addition, “binary logistic regression analysis revealed significant partial effects for all three polymorphisms, as well as for the interaction between the AR and aromatase gene polymorphisms, on the risk of developing transsexualism.” 

The study was very small, however, and as the authors said, “results should be interpreted with the utmost caution.”

The three more recent studies above did not replicate the findings of this study. The other studies were much larger than this one, so it is possible that these results were a fluke.

It is also possible, that the genes linked to gender dysphoria in Sweden are different from the genes linked to it in other countries.

The authors of the American-Australian study described above say, “Our sample size was approximately four times larger than that of the Swedish study, so it is possible that the former study was underpowered to detect a false positive. Alternatively, there might be differences between Swedish and non-Swedish populations in this polymorphism. In the Swedish study, the long repeat occurred in 51.8% of control subjects and 67.1% of transsexuals, whereas in the present study the long repeat occurred in 36.5% of control subjects and 44.1% of transsexuals. Thus, although there was a trend in the same direction in both studies, there are major differences in prevalence of these long repeats between the two populations.”

The only data we have on the participants in the study are that the trans women were Caucasian and the vast majority of the controls were also Caucasian. Again, it is likely that there was a higher percentage of people attracted to male in the group of trans women than the general population; this might have affected the results.

As the authors point out, “the gene variants investigated in this study are relatively common, none of the studied variants could hence be assumed to be the primary cause of this condition.” Rather, genes might increase or decrease the chance of developing gender dysphoria.

So, if the results of this study are not a fluke, we are still left with the questions of what other factors contribute to developing gender dysphoria and is this a gene related to gender dysphoria or sexual orientation in Sweden?

The end result of all this:

We have a couple of possible candidates for genetic variations related to gender dysphoria in trans men, but we need further studies. We need to replicate the results and to control for sexual orientation. In the case of the CYP 17 gene, we need to compare trans men to healthy control females instead of women with perimenopausal issues.

We don’t have any strong candidates for genetic variations related to gender dysphoria in trans women. Future studies might do well to look for genes that are not related to sex hormones. As always, they should control for sexual identity. (This should be done by adding lesbians and gay men without gender dysphoria, not by excluding trans women who are attracted to women from the studies. See my rants in articles on brain sex.)

 

*A group of trans women would include many more people attracted to men than a group of control males, but typically about half of trans women are attracted to women while most trans men are attracted to women. Thus this could be a comparison of two groups (control males and trans men) where a large majority of the people are sexually attracted to women, one group where half the people are attracted to women (trans women), and a group where about 5% of the people are attracted to women (control females).