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)
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.
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.
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?
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.
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."
"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:
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.
For further details, see the description above under trans men.
Genes Related to Sex Hormones:
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.
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.
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."
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).
This entry was posted in Genes and Twins and tagged androgen receptor, aromatase, Australia, Austria, estrogen receptor, gay, gender dysphoria, gender identity, genes, genetics, hormones, Italy, Japan, Klinefelter syndrome, lesbian, sex hormones, sexual orientation, Spain, Sweden, trans kids, trans men, Trans women, USA on November 14, 2014 by George Davis.
Ability of an orally administered lactobacilli preparation to improve the quality of the neovaginal microflora in male to female transsexual women – Review and a possible health benefit
This is a very cool study that found that trans women could improve the microflora in their neovaginas by taking lactobacilli orally.
Trans women might need to keep taking the lactobacilli pills to maintain the good microflora in their neovaginas.
Why would you want to do this?
Well in addition to other benefits, mostly for digestion, lactobacilli can help to treat bacterial infections in the vagina and it may help prevent urinary tract infections.
According to the authors of the study, many trans women don't have enough lactobacilli in their neovagina.
"The microflora of male to female transsexual women is a complex symbiosis of aerobic and anaerobic species with a very limited number of lactobacilli. It has substantial similarity to the abnormal vaginal microflora characteristic of bacterial vaginosis (BV) [1,2]. Weyers et al. reported that, although transsexual women show serum oestradiol levels comparable to those of postmenopausal women taking oestrogen replacement therapy, their neovaginal environment does not support the growth of lactobacilli [1]. In one study [1], only one of thirty transsexual women had neovaginal colonisation with lactobacilli. Another study of transsexual women, the same authors [2] found a neovaginal lactobacilli colonisation rate of 4%."
In this study, the authors found a higher rate of neovaginal lactobacilli colonisation, however, everyone who took the lactobacilli improved their scores.
The study was a good, randomized test of whether or not the lactobacilli worked, using 60 trans women split into two groups (one taking the lactobacilli, one not).
The bottom line – Post-op trans women should talk to their doctors about whether they should take lactobacilli.
Their discussion of their results:
"The results of this prospective randomised controlled study show that oral administration of L. crispatus, L. rhamnosus, L. jensenii and L. gasseri significantly improved the neovaginal microflora and reduced the Nugent score in a group of transsexual women. Also, the microflora was significantly enriched with lactobacilli after oral supplementation compared to placebo. The combination of Lactobacillus spp. used in this study is the only one published as the physiologic mixture of female vaginal lactobacilli microflora [15]. We used an innovative probiotic lactobacilli composition containing four of the most common lactobacilli isolated from the microflora of healthy women's vaginas [15] for treatment of 7 days' duration. Weyers et al. reported that colonisation of the neovagina of transsexual women with lactobacilli is minimal [1,2]. According to Nugent, an intermediate vaginal microflora is defined by a reduction and BV by an absence of lactobacilli with the presence of Gram negative bacteria in both cases [14]. The small number of publications on the standard neovaginal microflora and the near lack of evidence of lactic acid bacteria in the transsexual genital tract area are a challenge for investigations in this population. While transsexual women have normal female anatomy, there is no uterus and no connection of the neovagina to the pelvic cavity, which is why the risk of pelvic inflammatory disease is low. We were therefore able to include all transsexual women without clinical signs of infection, including those with asymptomatic BV. To our knowledge, this is the first study to allow a direct assessment of the comparative effect of oral probiotic lactobacilli and placebo on BV.
The gastrointestinal tract plays an important role as a reservoir for the vaginal colonisation by Lactobacillusspp. [4], [5] and [6]. Both vaginal and oral applications of lactobacilli have been shown to improve the vaginal microflora of both pre- and post-menopausal women [3], [9], [10] and [11]. The results of this study indicate that oral lactobacilli have a similar effect on the neovaginal flora of transsexual women. Descriptive analyses of the difference in Nugent score showed a reduction of −0.18 in the intervention group and an increase of +0.92 in the control group.
We found a significant improvement in the Nugent score in 48.5% of women in the intervention group, compared with only 14.8% in the control group. Lactobacilli concentrations assessed by culture and real-time PCR were 5–6 times higher in the intervention than in the control group, with these differences being statistically significant.
The sample size calculation in this study was based on neovaginal lactobacilli colonization rates of up to 4% reported in the literature [1] and [2]. In the present study, however, 30% of the women in both the intervention and control groups had a normal lactobacillus microflora (Nugent score ≤3). This was an unexpected finding contrasting with the current literature [1] and [2]. Because oral lactobacillus supplementation cannot be expected to change a neovaginal microflora dominated by lactobacilli, this unexpectedly high proportion of women with a normal lactobacillus flora may have led to an underestimation of the treatment effect. We therefore carried out a subgroup analysis including only women with a baseline Nugent score above 4, corresponding to either an intermediate microflora or BV. Even then, after 7 days of treatment with oral lactobacilli, we found an improvement in the Nugent score in the intervention group and no change in the control group. The results of this subgroup analysis are comparable with the results of one of our earlier studies on the effect of lactobacilli on postmenopausal women, which showed an improvement in Nugent scores [11]. In contrast to the previous study with a lactobacilli treatment duration of 14 days, however, the improvement in the current was already seen after 7 days of oral lactobacilli. The renewed increase of the Nugent score two weeks after the end of oral therapy indicates that extended oral probiotic therapy may be necessary to maintain a lactobacilli-dominated microbiota.
This study had several limitations. With a specific study group of male to female transsexual women and very limited number of patients visiting our clinic we could observe only a small sample size in our study. The therapy duration was limited to 7 days: we assume that longer treatment with probiotics could obtain a better outcome. Microbiology analyses of CFU's and c/ml were presented only for presumptive lactobacilli. In the next step we will include other bacteria with similar colony characteristics, such as Gardnerella vaginalis and Atopobium vaginae to present more detailed data. This study is first to observe male to female transsexual women using probiotics and we are aware of our initial oversights.
In summary, this first study on the effect of oral probiotics on the neovaginal microflora of transsexual women found that oral administration of lactobacilli resulted in a significant improvement in the Nugent score and a change of the neovaginal microflora. These observations are consistent with previous results obtained in pre- and post-menopausal women. The increase of the Nugent score two weeks after the end of oral therapy provides a possible need for extended oral probiotic therapy for maintenance of a lactobacilli-dominated microbiota. In addition, this study shows that even asymptomatic BV may be improved to a normal microflora by 7 days of oral supplementation of lactobacilli."
Original Aritcle:
Ability of an orally administered lactobacilli preparation to improve the quality of the neovaginal microflora in male to female transsexual women by Ulrike Kaufmann, Konrad J. Domig, Christina I. Lippitsch, Manuel Kraler, Julian Marschalek, Wolfgang Kneifel, Herbert Kiss, Ljubomir Petricevic in European Journal of Obstetrics & Gynecology and Reproductive Biology, Volume 172, January 2014, Pages 102–105.
This entry was posted in Gender Reassignment Surgery, Treatment and tagged Austria, gender reassignment surgery, neovagina, study review, Trans women on August 16, 2014 by George Davis.