ArticlePDF Available

A genetic link between gender dysphoria and sex hormone signalling

September 2018
The Journal of Clinical Endocrinology and Metabolism 104(2)

DOI:10.1210/jc.2018-01105

Authors:

Context There is a likely genetic component to gender dysphoria, but association study data have been equivocal. Objective We explored the specific hypothesis that gender dysphoria in transwomen is associated with variants in sex hormone signalling genes responsible for undermasculinization and/or feminization. Design Subject-control analysis included 380 transwomen and 344 control males. Associations and interactions were investigated between functional variants in 12 sex hormone signalling genes and gender dysphoria in transwomen. Setting Patients were recruited from the Monash Gender Clinic, Monash Health, Melbourne, Australia and the University of California, Los Angeles. Patients Caucasian transwomen, pre- and post-operative diagnosed with transsexualism (DSM-IV) or gender dysphoria (DSM-V) were recruited. Most were receiving hormone treatment at the time of recruitment. Main Outcome Measured Genomic DNA was genotyped for repeat length polymorphisms or SNPs. Results A significant association was identified between gender dysphoria and ERα, SRD5A2 and STS alleles, as well as ERα and SULT2A1 genotypes. Several allele combinations were also over-represented in transwomen, most involving AR (AR-ERβ, AR-PGR, AR-COMT, CYP17-SRD5A2). Over-represented alleles and genotypes are proposed to undermasculinize/feminise based on their reported effects in other disease contexts. Conclusions Gender dysphoria may have an oligogenic component with several genes involved in sex hormone signalling contributing.

Content uploaded by Vincent Harley

Content may be subject to copyright.

A genetic link between gender dysphoria and sex hormone signalling

Madeleine Foreman, Lauren Hare, Kate York, Kara Balakrishnan, Francisco J. Sánchez,

Fintan Harte, Jaco Erasmus, Eric Vilain and Vincent R. Harley

The Journal of Clinical Endocrinology & Metabolism

Endocrine Society

Submitted: May 22, 2018

Accepted: September 18, 2018

First Online: September 21, 2018

Advance Articles are PDF versions of manuscripts that have been peer reviewed and accepted but

not yet copyedited. The manuscripts are published online as soon as possible after acceptance and

before the copyedited, typeset articles are published. They are posted "as is" (i.e., as submitted by

the authors at the modification stage), and do not reflect editorial changes. No

corrections/changes to the PDF manuscripts are accepted. Accordingly, there likely will be

differences between the Advance Article manuscripts and the final, typeset articles. The

manuscripts remain listed on the Advance Article page until the final, typeset articles are posted.

At that point, the manuscripts are removed from the Advance Article page.

DISCLAIMER: These manuscripts are provided "as is" without warranty of any kind, either express

or particular purpose, or non-infringement. Changes will be made to these manuscripts before

publication. Review and/or use or reliance on these materials is at the discretion and risk of the

reader/user. In no event shall the Endocrine Society be liable for damages of any kind arising

references to, products or publications do not imply endorsement of that product or publication.

ADVANCE ARTICLE: THE JOURNAL OF CLINICAL

ENDOCRINOLOGY & METABOLISM

JCEM

Downloaded from https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/jc.2018-01105/5104458 by Biomedical Library user on 25 September 2018

ADVANCE ARTICLE

Gender dysphoria and sex hormone signaling

A genetic link between gender dysphoria and sex hormone signalling

Madeleine Foreman

, Lauren Hare

, Kate York

, Kara Balakrishnan

, Francisco J. Sánchez

Fintan Harte

, Jaco Erasmus

, Eric Vilain

and Vincent R. Harley

Hudson Institute of Research, Melbourne, Australia;

Monash Gender Clinic, Monash Health, Melbourne,

Australia;

University of Missouri, Columbia, MO, USA;

Children’s National Health System, Washington, DC,

USA

ORCiD numbers:

0000-0002-2405-1262

Harley

Vincent

Received 22 May 2018. Accepted 18 September 2018.

Context — There is a likely genetic component to gender dysphoria, but association study

data have been equivocal.

Objective — We explored the specific hypothesis that gender dysphoria in transwomen is

associated with variants in sex hormone signalling genes responsible for

undermasculinization and/or feminization.

Design — Subject-control analysis included 380 transwomen and 344 control males.

Associations and interactions were investigated between functional variants in 12 sex

hormone signalling genes and gender dysphoria in transwomen.

Setting — Patients were recruited from the Monash Gender Clinic, Monash Health,

Melbourne, Australia and the University of California, Los Angeles.

Patients — Caucasian transwomen, pre- and post-operative diagnosed with transsexualism

(DSM-IV) or gender dysphoria (DSM-V) were recruited. Most were receiving hormone

treatment at the time of recruitment.

Main Outcome Measured — Genomic DNA was genotyped for repeat length

polymorphisms or SNPs.

Results — A significant association was identified between gender dysphoria and ER

SRD5A2 and STS alleles, as well as ERα and SULT2A1 genotypes. Several allele

combinations were also over-represented in transwomen, most involving AR (AR-ER

, AR-

PGR, AR-COMT, CYP17-SRD5A2). Over-represented alleles and genotypes are proposed to

undermasculinize/feminise based on their reported effects in other disease contexts.

Conclusions—Gender dysphoria may have an oligogenic component with several genes

involved in sex hormone signalling contributing.

In this study we identified a genetic association between gender dysphoria in transwomen and

polymorphisms in genes involved in sex hormone signalling. .

Introduction

Gender identity—our sense of being male or female—develops early in life. By age 2, most

children are able to identify their own gender, which is typically consistent with the sex they

were at birth (1, 2). Yet, a small percentage of people will report significant clinical distress

because their sex at birth does not reflect their gender identity (3). In extreme cases, patients

ADVANCE ARTICLE: THE JOURNAL OF CLINICAL

ENDOCRINOLOGY & METABOLISM

JCEM

Downloaded from https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/jc.2018-01105/5104458 by Biomedical Library user on 25 September 2018

ADVANCE ARTICLE

will be given the diagnosis of gender dysphoria and may undergo medical treatments to

better align their anatomy and physiology with their gender identity.

Many identity labels may be used among this group of people, with transgender being a

broad, encompassing term for many subtypes. In this report, we focus on transwomen, or

people male at birth and who later transitioned to be female (historically referred to as male-

to-female transsexual). Unlike other people who may be transgender, transwomen take steps

to affirm their gender identity by social and/or physical transitioning from their birth sex to

their experienced gender through cross-hormone treatment and surgery (4).

The aetiology of gender dysphoria is unknown, yet the reported prevalence has been

increasing with most estimates suggesting that as many as 521 in 100,000 males and 265 in

100,000 females experience gender dysphoria (5). Early research into gender dysphoria

focused on the belief that it was a psychological condition and suggested that dysfunctional

family dynamics (6) and traumatic childhood experiences (7) may contribute. However,

recent studies point towards a biological basis involving endocrine, neurobiological and

genetic factors. For instance, an increased prevalence of gender dysphoria was observed

amongst people who experienced atypical prenatal androgen exposure in utero, such as

females with Congenital Adrenal Hyperplasia (8-15). Neuroimaging studies revealed specific

regions in the brains of transwomen that may be more similar to the brains of control women

than that of control men (16,17,18). Heritability studies suggest a genetic component, as 23-

33% of monozygotic twin pairs are concordant for gender dysphoria (19).

Candidate gene association studies have begun to investigate whether functional variants

in sex hormone signalling genes are associated gender dysphoria. It is proposed that

functional variants may alter sex hormone signalling, causing atypical sexual differentiation

of the developing brains for those who will later experience gender dysphoria (20). Some

associations have been identified, including an over-representation of long CAG repeats in

the AR of transwomen (21) and an over-representation of the CYP17 T/C SNP (22, 23), ERβ

CA repeat (24) and ERα Xbal A/G SNP (25) in transgender men. Other studies found no

associations (26-28). Most studies have been limited by small sample sizes and there is a

need to reproduce findings in large, independent cohorts.

We hypothesise that gender dysphoria in transwomen is associated with genetic variants

in sex hormone signalling genes responsible for undermasculinization and/or feminization of

the brain. The aim is to conduct a genetic association study of twelve sex signalling genes

including COMT, CYP11A1, HSD17B6, STS and SULT2A1, which have not previously been

studied in the context of gender dysphoria. Here we determine the allele and genotype

frequencies of variable polymorphic lengths of seven genes and single nucleotide

polymorphisms of five genes in Caucasian transwomen and compared these with Caucasian

male control subjects.

Methods and Materials

Participants

Three hundred and eighty Caucasian transwomen, pre- and post-operative diagnosed with

transsexualism (DSM-IV) or gender dysphoria (DSM-V) were recruited from the Monash

Medical Centre (MMC), Victoria, Australia (n = 222) and the University of California, Los

Angeles (UCLA) (n = 158). Most were receiving hormone treatment at the time of

recruitment. Three hundred and forty-four Caucasian male control subjects without gender

dysphoria were also recruited from Monash Medical Centre (n = 281) and UCLA (n = 63).

All transwomen and non-transgender male controls were determined to be Caucasian, based

upon their surname if ethnicity was not specified (29). Subjects who identified themselves as

non-caucasian were excluded. Ethics approval for this study were obtained from Monash

ADVANCE ARTICLE: THE JOURNAL OF CLINICAL

ENDOCRINOLOGY & METABOLISM

JCEM

Downloaded from https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/jc.2018-01105/5104458 by Biomedical Library user on 25 September 2018

ADVANCE ARTICLE

Medical Centre and UCLA, and consent procedures adhered to the tenets of the Declaration

of Helsinki.

Genotyping

Genomic DNA was extracted from whole blood (30) or saliva (Oragene

) samples.

Androgen receptor (AR) exon 1 CAG repeat, estrogen receptor α (ERα)

promoter region TA

repeat, estrogen receptor β (ERβ) intron 5 CA repeat cytochrome P450 family 11 subfamily A

member 1 (Cyp11a1) promoter region TTTTTA repeat, aromatase (Cyp19) intron 5 TTTA

repeat and progesterone receptor CA repeat fragment lengths were amplified by polymerase

chain reaction (PCR) and sized by automated capillary electrophoresis (21). Steroid 5-

α reductase 2 3’untranslated region (UTR) TA repeat was genotyped by PCR directly

followed by gel electrophoresis (31). Single nucleotide polymorphisms (SNP) in catechol-O-

methyltransferase (exon 3 G/A SNP), cytochrome P450 17α-hydroxylase/17,20-lyase

(5’UTR T/C SNP), 17β hydroxysteroid dehydrogenase 6 (intron 1 T/C SNP), steroid

sulfatase (intron 2 A/G SNP) and sulfotransferase (3’UTR T/C SNP) were determined by

agarose gel electrophoresis, following PCR and restriction enzyme digestion (31-34).

Oligonucleotide pairs, restriction enzymes and optimal annealing temperatures used are

shown in Supplementary Table 1. Genotyping data was removed if the subject was

determined to be non-Caucasian or have a DSD post-genotyping or if a sample had a

genotype failure rate greater than 20%, the removed samples are shown in Supplementary

Table 2. Each gene was successfully genotyped, with n numbers ranging from 320 – 343

transwomen and 259 – 283 non-transgender male controls (> 90% of the sample cohort).

Statistics

To evaluate the repeat length polymorphism data for possible associations with transwomen,

the distribution of repeat lengths of AR, ERα, ERβ, CYP11A1, CYP19 and PGR were

analysed using the non-parametric Mann-Whitney U test. Repeat lengths were divided into

short or long alleles based upon the median repeat length of the male control group. Allele

and genotype frequencies of all twelve genes (stratified repeat length polymorphisms and

SNPs) were compared using the chi-square test for independence. Binary logistic regression

was used to measure of the strength of the associations with gender dysphoria and evaluate

possible interactions between the twelve genes. Analyses were performed using SPSS 23.0. A

p value < .05 was considered significant.

Results

Polymorphic fragments lengths were obtained for 320-343 transwomen and 269-283 male

controls. The number of repeats identified for each allele is shown in Supplementary Table 3.

Median values were calculated from 24 repeat length distributions. A difference in median

repeat length was identified, with transwomen having a significantly shorter median repeat

length (16 TA repeats) for ERα when compared to male controls (17 TA repeats) (p = 0.03)

(Table 1).

Allele frequencies were determined for the five SNPs (COMT, CYP17, HSD17B6,

SULT2A1 and STS) and the dichotomous SRD5A2 repeat length polymorphism (Table 2). A

difference between transwomen and male control allele frequencies was identified in two of

the six genes. Specifically, in transwomen compared to male controls, there was an over-

representation of both the TA(9) repeat in SRD5A2 (12.3% compared to 8.5%, p = 0.030) and

the G allele in STS (91.2% compared to 85.9%, p = 0.015).

To compare genotypes repeat lengths were assigned to “short” or “long” allele groups

based upon the median repeat length of the control population for the six repeat length

polymorphism genes (AR short ≤22, long >22; CYP11A1 short ≤4, long >4; CYP19 short ≤7,

long >7; ERα short ≤17, long >17; ERβ short ≤23, long >23; PGR short ≤18, long >18). The

ADVANCE ARTICLE: THE JOURNAL OF CLINICAL

ENDOCRINOLOGY & METABOLISM

JCEM

Downloaded from https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/jc.2018-01105/5104458 by Biomedical Library user on 25 September 2018

ADVANCE ARTICLE

genotypes of CYP11A1, CYP19, ERα, ERβ and PGR polymorphisms for all individuals were

determined as SS (two short alleles), SL (one short and one long allele) or LL (two long

alleles). As the AR gene is located on the X chromosome it is hemizygous and the allele and

genotype frequencies are equivalent.

Genotype frequencies of the stratified repeat length polymorphisms (in CYP11A1,

CYP19, ERα, ERβ, PGR, SRD5A2) and of the SNPs (in COMT, CYP17, HSD17B6, STS,

SULT2A1) were analysed using binary logistic regression. An association was identified

between transwomen and the SULT2A1 homozygous TC genotype (p = 0.009) and the ERα

SS genotype (p = 0.035) when compared to male controls (Table 3). The odds ratios indicate

that within this population, the likelihood of being transgender increases by 1.61 times (95%

CI 1.13-2.31) if an individual possesses the SULT2A1 TC genotype and increases by 1.65

times (95% CI 1.04 - 2.63) if an individual possesses the ERα SS genotype.

Of possible two-locus gene interactions modelled using binary logistic regression, four

interactions were over-represented in transwomen when compared to male controls: AR-

ERβ, AR-PGR, AR-COMT, CYP17-SRD5A2 (Table 4). Notably, three of the four interactions

involve the long CAG repeats of the AR.

Discussion

To date, this is the largest study of gender dysphoria conducted, examining 12 genes.

Variants within COMT, CYP11A1, HSD17B6, STS and SULT2A1 have not previously been

studied in transgender men or women. In addition, this is the first of three studies to identify

an association between TA repeats in ERα and gender dysphoria. This study did not

reproduce the independent associations between ERβ and gender dysphoria in transwomen

reported by Henningson et al. (35) or the association with long CAG repeats in AR,

previously identified in a subset of this cohort (21). However, both ERβ and AR were

identified to be overrepresented in transwomen when in combination with other genes,

supporting their involvement in the development of gender dysphoria.

Associations were identified between genetic variants in ERα, SRD5A2, STS and

SULT2A1 and this cohort of transwomen. These genetic variants are suspected to be

functional which permits us to examine the predicted functional effects of the specific

polymorphism over-represented in transwomen. In ERα, for example, short TA repeats

overrepresented in transwomen are also associated with low bone mineral density in women

(36). Therefore, we speculate that estrogen signalling, is reduced (37). In SULT2A1, the

heterozygous TC genotype is overrepresented in transwomen. The minor, C allele of

SULT2A1 is associated with elevated sex hormone-binding globulin (38), a glycoprotein that

regulates circulatory sex steroid bioavailability and is present within fetal male blood during

early gestation (39). In transwomen with the TC SNP, we speculate that fetal sex hormone

binding globulin levels are increased which may reduce the effects of circulating hormones.

Polymorphisms in two genes were over-represented in transwomen by allele analysis but not

by the (more stringent) genotype analysis. First, TA(9) of SRD5A2 is associated with reduced

prostate cancer risk likely due to reduced DHT (40), suggesting that levels of the potent

androgen DHT could be reduced among transwomen. Second, the G allele in STS is

associated with reduced enzyme levels, mostly among studies of ADHD (41), a condition

with 5-fold increased incidence of gender dysphoria (42), suggesting a possible overlap in

aetiology.

Four significant two-locus interactions were identified by binary logistic regression

modelling; AR-ERβ, AR-PGR, AR-COMT and CYP17-SRD5A2. Of these, three involved long

CAG repeats of the AR. While long CAG repeats in AR alone may not have an independent

effect on the development of gender dysphoria, this AR polymorphism may interact with

other genes to increase the likelihood of being transgender. This is consistent with a previous

ADVANCE ARTICLE: THE JOURNAL OF CLINICAL

ENDOCRINOLOGY & METABOLISM

JCEM

Downloaded from https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/jc.2018-01105/5104458 by Biomedical Library user on 25 September 2018

ADVANCE ARTICLE

finding by Hare et al. (21) who identified an increased proportion of long AR repeat lengths

within a subset of the population of transwomen in this study. Long CAG repeats reduce AR

signalling (43-45). Similarly, long repeats in ERβ have been associated with decreased ERβ

signalling (36), potentially reducing the influence of ERβ on the defeminization of the male

brain (46). In combination, both genotypes appear to have additive effects on the

development of gender dysphoria. In contrast, the interaction of AR and COMT is unclear

where the Met

158

homozygous genotype is known to reduce COMT activity (47), affecting

estrogen catechol metabolism. Also, the functional effect of the PGR polymorphism is

unclear in transwomen. Interaction analysis also identified the specific combination of

SRD5A2 and CYP17 polymorphism, the former associated with reduced levels of DHT (48)

while the latter is known to increase sex steroid precursor production (49). It seems plausible

that together, these polymorphisms may increase the production of precursor steroids and

testosterone, but not of DHT, the more potent androgen form.

A limitation of the study is that patients and controls were obtained from 2 sites, in

Australia and the USA, and therefore likely to represent genetically different populations.

Another limitation of this study is the use of Caucasian surnames as a selection criteria.

Future and more detailed genetic analyses such as GWAS, would give insight into the

ethnicity of the cohort, obviating the need for selection criteria based upon ethnicity.

In summary, our study of transwomen supports the hypothesis that gender dysphoria has

a polygenic basis, involving interactions between multiple genes and polymorphisms that

may alter the sexual differentiation of the brain in utero, contributing to the development of

gender dysphoria in transwomen. However, while discordance rates for gender dysphoria

suggest that genetics plays a role, it is not the sole determinant of gender identity. GWAS,

genome and methylome approaches especially when coupled with neuroimaging or sex

steroid measurements should be undertaken to allow a better understanding of how genetic

variants contribute to gender dysphoria.

Transgender people continue to be subjected to high rates of gender-based discrimination

when seeking medical care, employment and education (50, 51). Although people’s civil

rights should not hinge on science to validate their individuality and lived experience,

determining what biological factors contribute to gender dysphoria may influence public

opinion and public policies related to the transgender community. More importantly, such

knowledge can be used to improve diagnosis and treatment for transgender people (e.g.,

differentiating which children with gender dysphoria will persist into adulthood versus

remit). Therefore, there is a clinical need to investigate further the genetic and biological

basis of gender dysphoria.

Acknowledgements

This work was supported by the National Health and Medical Research Council (NHMRC,

Australia) Program Grant 1074258 (to V.R.H.) and the Victorian Government’s Operational

Infrastructure Support Program. V.R.H. is the recipient of the NHMRC (Australia) Research

Fellowship 441102. We also thank the individuals who voluntarily participated and who are

an integral part of this research. The authors have no conflicts of interest to declare.

FUNDING: This work was supported by the National Health and Medical Research Council

(NHMRC, Australia) Program Grant 1074258 (to V.R.H.) and the Victorian Government’s

Operational Infrastructure Support Program. V.R.H. is the recipient of the NHMRC

(Australia) Research Fellowship 441102.

National Health and Medical Research Council

http://dx.doi.org/10.13039/501100000925, 1074258, Vincent Harley; National Health

ADVANCE ARTICLE: THE JOURNAL OF CLINICAL

ENDOCRINOLOGY & METABOLISM

JCEM

Downloaded from https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/jc.2018-01105/5104458 by Biomedical Library user on 25 September 2018

ADVANCE ARTICLE

and Medical Research Council http://dx.doi.org/10.13039/501100000925, 441102,

Vincent Harley

Corresponding Author: Vincent Harley, Hudson Instiutte of Medical Research,

Vincent.harley@hudson.org.au, +61 3 8572 2527

DISCLOSURE STATEMENT:

The authors have nothing to disclose.

References

1. Byne W, Bradley SJ, Coleman E, Eyler AE, Green R, Menvielle EJ, et al. (2012):

Report of the American Psychiatric Association Task Force on Treatment of Gender Identity

Disorder. Arch Sex Behav. 41:759-796.

2. American Psychiatric Association DSMTF (2013): Diagnostic and statistical manual

of mental disorders : DSM-5. 5th ed. ed. Arlington, VA: Arlington, VA : American

Psychiatric Association.

3. Zucker KJ, Lawrence AA, Kreukels BP (2016): Gender Dysphoria in Adults. Annu

Rev Clin Psychol. 12:217-247.

4. (2012): Standards of Care for the Health of Transsexual, Transgender, and Gender-

Nonconforming People, Version 7. International Journal of Transgenderism. 13:165-232.

5. Collin L, Reisner SL, Tangpricha V, Goodman M (2016): Prevalence of Transgender

Depends on the “Case” Definition: A Systematic Review. The journal of sexual medicine.

13:613-626.

6. Loeb L, Shane M (1982): The resolution of a transsexual wish in a five-year-old boy.

Journal of the American Psychoanalytic Association. 30:419-434.

7. Devor H (1994): Transsexualism, Dissociation,and Child Abuse. Journal of

Psychology & Human Sexuality. 6:49-72.

8. Fisher AD, Ristori J, Fanni E, Castellini G, Forti G, Maggi M (2016): Gender

identity, gender assignment and reassignment in individuals with disorders of sex

development: a major of dilemma. J Endocrinol Invest. 39:1207-1224.

9. Furtado PS, Moraes F, Lago R, Barros LO, Toralles MB, Barroso U, Jr. (2012):

Gender dysphoria associated with disorders of sex development. Nat Rev Urol. 9:620-627.

10. Jürgensen M, Kleinemeier E, Lux A, Steensma TD, Cohen-Kettenis PT, Hiort O, et

al. (2013): Psychosexual Development in Adolescents and Adults with Disorders of Sex

Development—Results from the German Clinical Evaluation Study. The Journal of Sexual

Medicine. 10:2703-2714.

11. Mattila AK, Fagerholm R, Santtila P, Miettinen PJ, Taskinen S (2012): Gender

identity and gender role orientation in female assigned patients with disorders of sex

development. J Urol. 188:1930-1934.

12. Mendonca BB (2014): Gender assignment in patients with disorder of sex

development. Curr Opin Endocrinol Diabetes Obes. 21:511-514.

13. Meyer-Bahlburg HF, Baratz Dalke K, Berenbaum SA, Cohen-Kettenis PT, Hines M,

Schober JM (2016): Gender Assignment, Reassignment and Outcome in Disorders of Sex

Development: Update of the 2005 Consensus Conference. Horm Res Paediatr. 85:112-118.

14. Sandberg DE, Gardner M, Cohen-Kettenis PT (2012): Psychological aspects of the

treatment of patients with disorders of sex development. Semin Reprod Med. 30:443-452.

15. Yang JH, Baskin LS, DiSandro M (2010): Gender identity in disorders of sex

development: review article. Urology. 75:153-159.

16. Kreukels BP, Guillamon A (2016): Neuroimaging studies in people with gender

incongruence. Int Rev Psychiatry. 28:120-128.

ADVANCE ARTICLE: THE JOURNAL OF CLINICAL

ENDOCRINOLOGY & METABOLISM

JCEM

Downloaded from https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/jc.2018-01105/5104458 by Biomedical Library user on 25 September 2018

ADVANCE ARTICLE

17. Cerasa A, Cherubini A, Quattrone A, Gioia MC, Tarantino P, Annesi G, et al. (2010):

Met158 variant of the catechol-O-methyltransferase genotype is associated with thicker

cortex in adult brain. Neuroscience. 167:809-814.

18. Zubiaurre-Elorza L, Junque C, Gómez-Gil E, Segovia S, Carrillo B, Rametti G, et al.

(2013): Cortical Thickness in Untreated Transsexuals. Cerebral Cortex. 23:2855-2862.

19. Diamond M (2013): Transsexuality Among Twins: Identity Concordance, Transition,

Rearing, and Orientation. International Journal of Transgenderism. 14:24-38.

20. Gooren L (1990): The endocrinology of transsexualism: a review and commentary.

Psychoneuroendocrinology. 15:3-14.

21. Hare L, Bernard P, Sánchez FJ, Baird PN, Vilain E, Kennedy T, et al. (2009):

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

transsexualism. Biol Psychiatry. 65:93-96.

22. Bentz EK, Hefler LA, Kaufmann U, Huber JC, Kolbus A, Tempfer CB (2008): A

polymorphism of the CYP17 gene related to sex steroid metabolism is associated with

female-to-male but not male-to-female transsexualism. Fertil Steril. 90:56-59.

23. Fernandez R, Cortes-Cortes J, Esteva I, Gomez-Gil E, Almaraz MC, Lema E, et al.

(2015): The CYP17 MspA1 Polymorphism and the Gender Dysphoria. J Sex Med. 12:1329-

1333.

24. Fernandez R, Esteva I, Gomez-Gil E, Rumbo T, Almaraz MC, Roda E, et al. (2014):

The (CA)n polymorphism of ERbeta gene is associated with FtM transsexualism. J Sex Med.

11:720-728.

25. Cortes-Cortes J, Fernandez R, Teijeiro N, Gomez-Gil E, Esteva I, Almaraz MC, et al.

(2017): Genotypes and Haplotypes of the Estrogen Receptor alpha Gene (ESR1) Are

Associated With Female-to-Male Gender Dysphoria. J Sex Med. 14:464-472.

26. Ujike H, Otani K, Nakatsuka M, Ishii K, Sasaki A, Oishi T, et al. (2009): Association

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

Neuropsychopharmacol Biol Psychiatry. 33:1241-1244.

27. Fernandez R, Esteva I, Gomez-Gil E, Rumbo T, Almaraz MC, Roda E, et al. (2014):

Association study of ERbeta, AR, and CYP19A1 genes and MtF transsexualism. J Sex Med.

11:2986-2994.

28. Lombardo F, Toselli L, Grassetti D, Paoli D, Masciandaro P, Valentini F, et al.

(2013): Hormone and genetic study in male to female transsexual patients. J Endocrinol

Invest. 36:550-557.

29. King TE, Ballereau SJ, Schurer KE, Jobling MA (2006) Genetic signatures of

coancestry with surnames. Genome Biology 16: 384-388

30. Miller SA, Dykes DD, Polesky HF (1988): A simple salting out procedure for

extracting DNA from human nucleated cells. Nucleic Acids Res. 16:1215.

31. Bharaj B, Scorilas A, Giai M, Diamandis EP (2000): TA repeat polymorphism of the

5alpha-reductase gene and breast cancer. Cancer epidemiology, biomarkers & prevention : a

publication of the American Association for Cancer Research, cosponsored by the American

Society of Preventive Oncology. 9:387-393.

32. Lajin B, Alachkar A (2011): Detection of catechol-O-methyltransferase (COMT)

Val158Met Polymorphism by a New Optimized PCR-RFLP Method. Am J Biomed Sci.

3:170-175.

33. Letonja M, Peterlin B, Bregar D, Petrovic D (2005): Are the T/C polymorphism of the

CYP17 gene and the tetranucleotide repeat (TTTA) polymorphism of the CYP19 gene

genetic markers for premature coronary artery disease in Caucasians? Folia biologica. 51:76.

34. Ju R, Wu W, Fei J, Qin Y, Tang Q, Wu D, et al. (2015): Association analysis between

the polymorphisms of HSD17B5 and HSD17B6 and risk of polycystic ovary syndrome in

Chinese population. European journal of endocrinology. 172:227-233.

ADVANCE ARTICLE: THE JOURNAL OF CLINICAL

ENDOCRINOLOGY & METABOLISM

JCEM

Downloaded from https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/jc.2018-01105/5104458 by Biomedical Library user on 25 September 2018

ADVANCE ARTICLE

35. Henningsson S, Westberg L, Nilsson S, Lundstrom B, Ekselius L, Bodlund O, et al.

(2005): Sex steroid-related genes and male-to-female transsexualism.

Psychoneuroendocrinology. 30:657-664.

36. Gennari L, Merlotti D, De Paola V, Calabrò A, Becherini L, Martini G, et al. (2005):

Estrogen Receptor Gene Polymorphisms and the Genetics of Osteoporosis: A HuGE Review.

American Journal of Epidemiology. 161:307-320.

37. Westberg L, Eriksson E (2008): Sex steroid–related candidate genes in psychiatric

disorders. Journal of Psychiatry & Neuroscience : JPN. 33:319-330.

38. Utriainen P, Laakso S, Jääskeläinen J, Voutilainen R (2012): Polymorphisms of POR,

SULT2A1 and HSD11B1 in children with premature adrenarche. Metabolism. 61:1215-1219.

39. Hammond GL (2011): Diverse Roles for Sex Hormone-Binding Globulin in

Reproduction. Biology of Reproduction. 85:431-441.

40. Li X, Huang Y, Fu X, Chen C, Zhang D, Yan L, et al. (2011): Meta-analysis of three

polymorphisms in the steroid-5-alpha-reductase, alpha polypeptide 2 gene (SRD5A2) and

risk of prostate cancer. Mutagenesis. 26:371-383.

41. Brookes KJ, Hawi Z, Park J, Scott S, Gill M, Kent L (2010): Polymorphisms of the

Steroid Sulfatase [STS] Gene are Associated With Attention Deficit Hyperactivity Disorder

and Influence Brain Tissue mRNA Expression. American Journal of Medical Genetics.

153B:1417-1424.

42. Strang JF, Kenworthy L, Dominska A, Sokoloff J, Kenealy LE, Berl M, et al. (2014):

Increased gender variance in autism spectrum disorders and attention deficit hyperactivity

disorder. Arch Sex Behav. 43:1525-1533.

43. Kazemi-Esfarjani P, Trifiro MA, Pinsky L (1995): Evidence for a repressive function

of the long polyglutamine tract in the human androgen receptor: possible pathogenetic

relevance for the (CAG)n-expanded neuronopathies. Human molecular genetics. 4:523-527.

44. Westberg L, Baghaei F, Rosmond R, Hellstrand M, Landen M, Jansson M, et al.

(2001): Polymorphisms of the androgen receptor gene and the estrogen receptor beta gene are

associated with androgen levels in women. The Journal of clinical endocrinology and

metabolism. 86:2562-2568.

45. Choong CS, Wilson EM (1998): Trinucleotide repeats in the human androgen

receptor: a molecular basis for disease. Journal of molecular endocrinology. 21:235-257.

46. Kudwa AE, Bodo C, Gustafsson JA, Rissman EF (2005): A previously

uncharacterized role for estrogen receptor beta: defeminization of male brain and behavior.

Proc Natl Acad Sci U S A. 102:4608-4612.

47. Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, Melhem S, et al. (2004):

Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on

mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet. 75:807-

821.

48. Francis A, Sarkar S, Pooja S, Surekha D, Rao DR, Rao L, et al. (2014): SRD5A2 gene

polymorphisms affect the risk of breast cancer. The Breast. 23:137-141.

49. Feigelson HS, Shames LS, Pike MC, Coetzee GA, Stanczyk FZ, Henderson BE

(1998): Cytochrome P450c17alpha gene (CYP17) polymorphism is associated with serum

estrogen and progesterone concentrations. Cancer research. 58:585-587.

50. Grant J, Mottet L, Tanis J, Herman J, Harrison J, Keisling M (2010): National

Transgender Discrimination Survery Report on Health and Health Care. Findings of a Study

by the National Center for Transgender Equality and the National Gay and Lesbian Task

Force. US: National Center for Transgender Equality and the National Gay and Lesbian Task

Force.

ADVANCE ARTICLE: THE JOURNAL OF CLINICAL

ENDOCRINOLOGY & METABOLISM

JCEM

Downloaded from https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/jc.2018-01105/5104458 by Biomedical Library user on 25 September 2018

ADVANCE ARTICLE

51. Schoning S, Engelien A, Bauer C, Kugel H, Kersting A, Roestel C, et al. (2010):

Neuroimaging differences in spatial cognition between men and male-to-female transsexuals

before and during hormone therapy. J Sex Med. 7:1858-1867.

Table 1 Comparison of repeat length distributions of AR, ERα, ERβ, CYP11A1, CYP19 and

PGR repeat length polymorphisms

Gene

Male Control

Transgender Women

Mann

Whitney U Test p

value

Median

AR 289 22 327 22 0.31

ERα 567 17 640 16 0.03*

ERβ 580 23 668 23 0.70

CYP11A1 546 4 668 4 0.55

CYP19 580 7 658 7 0.21

PGR 562 18 676 18 0.20

* denotes a significant p-value < 0.05.

Table 2 Allele frequencies of the COMT, CYP17, HSD17B6, SRD5A2, STS and SULT2A1

single nucleotide or dichotomous polymorphisms

Gene Allele Male Controls Transgender women P-value

COMT G 303 58.7 356 54.1 0.11

A 213 41.3 302 45.9

CYP17 T 354 63.7 384 58.9 0.090

C 202 36.3 268 41.1

HSD17B6 T 366 65.6 406 60.2 0.053

C 192 34.3 268 39.8

SRD5A2 TA(0) 516 91.5 598 87.7 0.030*

TA(9) 48 8.5 84 12.3

STS G 238 85.9 302 92.1 0.015*

A 39 14.1 26 7.9

SULT2A1 T 419 80.9 504 77.5 0.16

C 99 19.1 146 22.5

The p-value was calculated using the chi-square test. *denotes the p-value is significant (<0.05).

Table 3 Genotype analysis of the COMT, CYP11A1, CYP17, CYP19, ERα, ERβ, HSD17B6,

PGR, SRD5A2 and SULT2A1 polymorphisms

Gene

Genotype

Male Control

Transgender Women

value

(

OR, 95% CI)

COMT GG 85 32.8 100 30.4 0.06 (1.59, 0.98 - 2.58)

GA 135 52.1 156 47.4

AA 39 15.1 73 22.2

CYP11A1 SS 89 33.1 124 37.1 0.24 (0.81, 0.57 - 1.15)

SL 138 51.3 155 46.4

LL 42 15.6 55 16.5

CYP17 TT 112 40.3 109 33.2 0.097 (1.34, 0.95 - 1.91)

TT 130 46.8 170 51.8

CC 36 12.9 85 14.9

CYP19 SS 86 30.3 83 25.2 0.20 (1.36, 0.85 - 2.16)

SL 142 50.2 174 52.9

LL 55 19.4 72 21.9

ERα SS 75 27 103 32.2 0.035* (1.65, 1.04 - 2.63)

SL 138 49.6 163 50.9

LL 65 23.4 54 16.9

ERβ SS 186 65.7 216 64.7 0.81 (1.04, 0.74 - 1.45)

SL 85 30 103 30.8

LL 12 4.2 15 4.5

HSD17B6 TT 122 43.7 123 36.5 0.091 (1.53, 0.93 - 2.51)

TC 122 43.7 160 47.5

CC 35 12.5 54 16

PGR SS 81 29.3 106 31.4 0.35 (0.80, 0.50 - 1.27)

SL 135 48.9 169 50

LL 60 21.7 63 18.6

ADVANCE ARTICLE: THE JOURNAL OF CLINICAL

ENDOCRINOLOGY & METABOLISM

JCEM

Downloaded from https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/jc.2018-01105/5104458 by Biomedical Library user on 25 September 2018

ADVANCE ARTICLE

SRD5A2 TA(0)/(0) 238 84.4 269 78.4 0.12 (1.42 0.92 - 2.18)

TA(0)/(9) 40 14.2 64 18.7

TA(9)/(9) 4 1.4 10 2.9

SULT2A1 TT 175 67.6 192 58.9 0.009* (1.61, 1.13 - 2.31)

TC 69 26.6 122 37.4

CC 15 5.8 12 3.7

S = short alleles L = long alleles. P-values, odds ratios (OR) and 95% confidence intervals (CI) were calculated

using binary logistic regression. ORs greater than 1 indicate an increased likelihood of being transgender

compared to the reference allele. ORs less than one indicate a decreased likelihood of being transgender

compared to the reference allele. *denotes statistical significance (p<0.05).

Table 4 Odd’ ratios and 95% confidence intervals of significant two-locus gene interactions

determined by binary logistic regression modelling.

Two

locus gene interactions

95% CI

value

Lower

Upper

AR (L) – ERβ (SL) 2.78 1.15 6.70 0.023

AR (L) – PGR (LL) 5.68 1.63 17.95 0.006

AR (L) – COMT (AA) 3.88 1.2 12.56 0.024

CYP17 (A1A2) – SRD5A2(TA(0)/TA(9)) 4.09 1.19 14.03 0.025

The interacting genotypes for each gene are shown in brackets. Fragment length alleles polymorphisms were

analysed as dichotomous short (S) or long (L) variables. The odds ratio (OR), 95% confidence interval (CI) and

p-value were computed using binary logistic regression. n = 233 transgender women and 195 male controls.

ADVANCE ARTICLE: THE JOURNAL OF CLINICAL

ENDOCRINOLOGY & METABOLISM

JCEM

Downloaded from https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/jc.2018-01105/5104458 by Biomedical Library user on 25 September 2018

The genetics and hormonal basis of human gender identity

Article

Full-text available

Nov 2024

Gender identity refers to one's psychological sense of their own gender. Establishing gender identity is a complex phenomenon, and the diversity of gender expression challenges simplistic or unified explanations. For this reason, the extent to which it is determined by nature (biological) or nurture (social) is still debatable. The biological basis of gender identity cannot be modeled in animals and is best studied in people who identify with a gender that is different from the sex of their genitals such as transgender people and people with disorders/differences of sex development. Numerous research studies have delved into unraveling the intricate interplay of hormonal, neuroanatomic/neurofunctional, and genetic factors in the complex development of core gender identity. In this review, we explore and consolidate existing research that provides insights into the biological foundations of gender identity, enhancing our understanding of this intriguing human psychological trait. Keywords Gender identity; transgender; sex steroids; genetics; sex development

Comparison of Sexual Identity in Identical Twins: A Systematic Review

Preprint

Full-text available

May 2024

Objective The aim and scope of this systematic review was to provide a comprehensive assessment of the impact nature and nurture have in influencing sexual identity, with a specific focus on the concordance or discordance of sexuality in identical twins. Design Systematic literature review. Methods Utilizing the National University Library, Google Scholar, Credo Reference, and National Institutes of Health (NIH), twenty-three articles were collected for review. Inclusion criteria: (a) peer-reviewed texts from 1990 to 2023; (b) quantitative and qualitative studies and educational pieces categorized: Alluded to Genetics, Alluded to Environment, Nature Versus Nurture Interplay, and Human Biology, Sexuality, Behavior and History (c) written in English; descriptive details (e.g., title, data source, sample size, type of siblings, age); and core aspects (e.g., main findings, limitations, conclusion). Results Strong allusion, particularly to genetics, is made regarding the origin(s) of sexual identity. However, due to its multifaceted nature, conclusive evidence has not been established. Even identical twins raised in the same environment may develop different sexual identities due to individual differences (e.g,, IQ, reactions, social circles, hobbies, preferences, and beliefs). Conclusion Further exploratory research, quantitative analysis, methodological improvements, and integrated collaboration will provide knowledge to facilitate more impactful interventions, destigmatization initiatives, and policy development aimed at fostering equality and well-being for individuals of all identities (e.g., educational programs and training, human rights advocacy, community outreach, funding allocations, and support services).

A genderkérdés pszichiátriai vonatkozásai – áttekintés

Article

Jan 2025

Lajos Simon

A közlemény áttekinti a biológiai nem (sex) és a társadalmi nem (gender) fogalmak kialakulásának meghatározó szempontjait, és bemutatja a transzneműség fogalmának megjelenését a pszichiátriai diskurzusban. A tanulmány továbbá áttekinti a transzállapotok medikalizálódását, a diagnosztikai kategóriák változásait és a depatologizálás felé irányuló jelenlegi helyzetet. Összefoglalja a nemi inkongruencia és nemi diszfória pszichiátriai vonatkozásait, a transznemű személyek mentális segítésének lehetőségeit a mentális egészség, az érzelmi stabilitás, az életminőség javítása céljából a jóllét erősítése érdekében.

LGBTQ: Sex Differences

Chapter

Feb 2025

Izabela Pawłowska

LGBTQ (lesbian, gay, bisexual, transgender, queer) individuals are people of various sexual orientations and gender identities. Sexual orientation can be described as “an enduring pattern of or disposition to experience sexual or romantic desires for, and relationships with, people of one’s same sex, the other sex, or both sexes” (The Health of Lesbian, Gay, Bisexual, and Transgender People: Building a Foundation for Better Understanding, 2011). In turn, gender identity is “a person’s basic sense of being a man or boy, a woman or girl, or another gender” (The Health of Lesbian, Gay, Bisexual, and Transgender People: Building a Foundation for Better Understanding, 2011, p. 25). Gender identity can be consistent with one’s sex assigned at birth (cisgender) or not (transgender; Mauvais-Jarvis et al., 2020). Sex is defined as the biological and physical characteristics that define women, men, and those with intersex identities (Mauvais-Jarvis et al., 2020). Sex is often perceived as a binary construct consisting of two categories: male and female. However, this perspective excludes the experiences of intersex individuals. In response to this reductive stance, the idea of sexual diversity was born. It sees sex as a spectrum (Štrkalj & Pather, 2021). Gender, on the other hand, is a social construct consisting of norms that determine and impose social roles, relationships, and power dynamics and is not a binary term (Mauvais-Jarvis et al., 2020). It is understood that people can possess both masculine and feminine characteristics, as well as identify outside of that spectrum. Gender roles are behavioral norms applied to men and women that influence everyday actions and expectations. They can affect individuals’ diet, health, disease susceptibility, and expression of feelings (Mauvais-Jarvis et al., 2020). The current entry concerns sex differences between LGBTQ individuals in the context of genetic differences, identity, and outness, community and activism, relationships, experiences of discrimination and heterosexism, as well as mental and physical health.

Genetic Analyses on Transgender Individuals: Impact on Physician Attitudes and Surgical Decision‐Making

Article

Full-text available

Jan 2025

Purpose Genetic studies on the transgender and gender diverse (TGD) community have started to appear in the literature. However, there are limited studies on how genetic data will impact attitudes and perspectives toward TGD individuals. In this study, we investigated the impact of genetic alterations on physicians' attitudes toward TGD individuals and on physicians' decisions concerning gender confirmation surgery (GCS). In this context, we intended to highlight a number of strategies to reduce the inequalities that the TGD community is exposed to in accessing health‐care services. Method An online survey including the Turkish version of the Attitudes Toward Transgendered Individuals Scale (ATTIS) was completed by 224 physicians from relevant specialties. Scheffé and least significant difference (LSD) post hoc analysis methods were used to determine physicians' perspectives on whether genetic findings would cause TGD individuals to feel validated/invalidated. Multivariate multinomial logistic regression analysis was employed to assess their responses concerning the decision to perform GCS when genetic alterations had been identified. Results More than half of the physicians expressed the view that genetic analyses for TGD individuals would confer benefits (67.1%). Those who thought that the presence of gender–diversity‐related genetic alterations would have a “positive impact” on their GCS‐related decision to operate were found to have less positive attitudes toward TGD individuals (Bonferroni corrected p < 0.001). Multivariate multinomial logistic regression analysis revealed that age, presenting the odds ratio as the strongest factor, distinguished the “no impact” group from the reference “positive impact” group, particularly among those aged ≤ 35 years (3.299, 95% CI: 1.355–8.033; p = 0.009). Conclusion Although genetic analysis of TGD individuals is predicted to have a positive effect on physicians' attitudes toward them and on the GCS decision‐making process, it should be emphasized that the benefits for TGD individuals must outweigh the potential harm. The results showed that physicians need “early and continuing education” to develop a comprehensive perspective on gender identity. The most appropriate approach for genetic testing would be to include the TGD community in decision‐making processes and to develop guidelines for the interpretation of genetic data.

Gender Reassignment and the Role of the Laboratory in Monitoring Gender-Affirming Hormone Therapy

Article

Full-text available

Aug 2024

Indra Ramasamy

Transgender people experience distress due to gender incongruence (i.e., a discrepancy between their gender identity and sex assigned at birth). Gender-affirming hormone treatment (GAHT) is a part of gender reassignment treatment. The therapeutic goals of the treatment are to develop the physical characteristics of the affirmed gender as far as possible. Guidelines have been developed for GAHT, which recommend dosage as well as different formulations of oestrogen and testosterone for treatment. Questions arise about the metabolic side effects of hormone treatment. Establishing reference ranges for common analytes in transgender individuals remains a task for laboratory medicine. It has been suggested once GAHT is commenced, the reference ranges for affirmed gender are reported for red blood cells, haemoglobin and haematocrit. For transgender assigned-female-at-birth (AFAB) people, testosterone concentrations are recommended to be within the reference interval established for cisgender men and for transgender assigned-male-at-birth (AMAB) people, estradiol concentrations are within the reference range for cisgender women. Sex-specific reference ranges are available for certain laboratory tests, and these may be organ (e.g., heart)-specific. Transgender-specific reference ranges may be a requirement for such tests. Laboratories may need to make decisions on how to report other tests in the transgender population, e.g., eGFR. Interpretation of further tests (e.g., reproductive hormones) can be individualized depending on clinical information. Electronic medical record systems require fields for gender identity/biological sex at birth so that laboratory results can be flagged appropriately. In this review, we aim to summarise the current position of the role of the laboratory in the clinical care of the transgender individual. Prior to the review, we will summarise the genetics of sex determination, the aetiology of gender incongruence, and the recommendations for GAHT and monitoring for the transgender population.

Care of Transgender and Gender Diverse Youth

Chapter

Dec 2024

In many parts of the world, increasing numbers of transgender and gender diverse (TGD) youth are seeking medical services to enable the development of physical characteristics aligned with their gender identities. Such medical services include use of agents to pause endogenous puberty as early as Tanner stage 2 with subsequent use of gender-affirming sex hormones and are based on longitudinal studies, demonstrating that those individuals who were first identified as gender dysphoric in early or middle childhood and continue to meet the mental health criteria for gender incongruence at early puberty are likely to persist in their gender identities as adults. This chapter addresses terms and definitions applicable to TGD youth, studies that shed light on the biologic underpinnings of gender identity, outcomes and potential complications of current treatment models, gaps in knowledge, and priorities for research.

O DIREITO À IDENTIDADE DE GÊNERO E O USO DO NOME SOCIAL: UM COMPARATIVO BRASIL E ARGENTINA"THE RIGHT TO GENDER IDENTITY AND THE USE OF SOCIAL NAME: A COMPARISON BETWEEN BRAZIL AND ARGENTINA"

Article

Full-text available

Sep 2024

Omar Luiz da Costa Júnior

The study aims to compare the legal frameworks of Brazil and Argentina regarding the right to gender identity and the use of a preferred name. The methodology employed consisted of a bibliographic review, consulting books, journals, articles, legal doctrine, and case law to provide the necessary foundation for the development of this study. The conclusion of this comparative analysis on the right to gender identity and the use of a preferred name in Brazil and Argentina highlights significant progress, particularly in Argentine legislation, which has proven to be more progressive and inclusive. Argentina’s Gender Identity Law, enacted in 2012, stands as a milestone in guaranteeing rights for trans individuals, allowing for the change of name and gender on official documents without the need for judicial authorization or medical diagnoses, thus ensuring greater autonomy and dignity for individuals. In Brazil, while the use of a preferred name has advanced, especially with the CNJ Resolution No. 270 and the 2018 Supreme Court decision recognizing the right to amend name and gender without surgery, challenges remain. The lack of comprehensive legislation, like Argentina’s, creates legal uncertainties and inequalities in accessing these rights. Moreover, cultural and social barriers persist, hindering the full acceptance and respect for preferred names and gender identity in everyday life.

Estrogen receptor signaling and targets: Bones, breasts and brain (Review)

Article

Full-text available

Jun 2024

Estrogens are involved in a number of physiological functions, including in the development of the brain, growth, reproduction and metabolism. The biological actions of estrogens are achieved by binding to estrogen receptors (ERs) in numerous types of tissues. ERα and ERβ belong to the nuclear receptor superfamily and the G‑protein coupled ER1 (GPER1) is a membrane receptor. The primary biologically active estrogen, 17β‑estradiol demonstrates a high affinity for ERs. Mechanistically, estrogens bind to the ERs in the nucleus, and the complex then dimerize and bind to estrogen response elements (EREs) located in the promoter regions of the target genes. This is referred to as the genomic mechanism of ERs' function. Furthermore, ERs can also act through kinases and other molecular interactions leading to specific gene expression and functions, referred to as the non‑genomic mechanism. While ERα and ERβ exert their functions via both genomic and non‑genomic pathways, GPER1 exerts its function primarily via the non‑genomic pathways. Any aberrations in ER signaling can lead to one of a number of diseases such as disorders of growth and puberty, fertility and reproduction abnormalities, cancer, metabolic diseases or osteoporosis. In the present review, a focus is placed on three target tissues of estrogens, namely the bones, the breasts and the brain, as paradigms of the multiple facets of the ERs. The increasing prevalence of breast cancer, particularly hormone receptor‑positive breast cancer, is a challenge for the development of novel antihormonal therapies other than tamoxifen and aromatase inhibitors, to minimize toxicity from the long treatment regimens in patients with breast cancer. A complete understanding of the mechanism of action of ERs in bones may highlight options for novel targeted treatments for osteoporosis. Likewise, the aging of the brain and related diseases, such as dementia and depression, are associated with a lack of estrogen, particularly in women following menopause. Furthermore, gender dysphoria, a discordance between experienced gender and biological sex, is commonly hypothesized to emerge due to discrepancies in cerebral and genital sexual differentiation. The exact role of ERs in gender dysphoria requires further research.

Analysis of single nucleotide polymorphisms of the metabotropic glutamate receptors in a transgender population

Article

Full-text available

Jun 2024

Introduction Gender incongruence (GI) is characterized by a marked incongruence between an individual’s experienced/expressed gender and the assigned sex at birth. It includes strong displeasure about his or her sexual anatomy and secondary sex characteristics. In some people, this condition produces a strong distress with anxiety and depression named gender dysphoria (GD). This condition appears to be associated with genetic, epigenetics, hormonal as well as social factors. Given that L-glutamate is the major excitatory neurotransmitter in the central nervous system, also associated with male sexual behavior as well as depression, we aimed to determine whether metabotropic glutamate receptors are involved in GD. Methods We analyzed 74 single nucleotide polymorphisms located at the metabotropic glutamate receptors (mGluR1, mGluR3, mGluR4, mGluR5, mGluR7 and mGluR8) in 94 transgender versus 94 cisgender people. The allele and genotype frequencies were analyzed by c2 test contrasting male and female cisgender and transgender populations. The strength of the associations was measured by binary logistic regression, estimating the odds ratio (OR) for each genotype. Measurement of linkage disequilibrium, and subsequent measurement of haplotype frequencies were also performed considering three levels of significance: P ≤ 0.05, P ≤ 0.005 and P ≤ 0.0005. Furthermore, false positives were controlled with the Bonferroni correction (P ≤ 0.05/74 = 0.00067). Results After analysis of allele and genotypic frequencies, we found twenty-five polymorphisms with significant differences at level P ≤ 0.05, five at P ≤ 0.005 and two at P ≤ 0.0005. Furthermore, the only two polymorphisms (rs9838094 and rs1818033) that passed the Bonferroni correction were both related to the metabotropic glutamate receptor 7 (mGluR7) and showed significant differences for multiple patterns of inheritance. Moreover, the haplotype T/G [OR=0.34 (0.19–0.62); P<0.0004] had a lower representation in the transgender population than in the cisgender population, with no evidence of sex cross-interaction. Conclusion We provide genetic evidence that the mGluR7, and therefore glutamatergic neurotransmission, may be involved in GI and GD.

Genotypes and Haplotypes of the Estrogen Receptor α Gene (ESR1) Are Associated With Female-to-Male Gender Dysphoria

Article

Full-text available

Jan 2017

Introduction: Gender dysphoria, a marked incongruence between one's experienced gender and biological sex, is commonly believed to arise from discrepant cerebral and genital sexual differentiation. With the discovery that estrogen receptor β is associated with female-to-male (FtM) but not with male-to-female (MtF) gender dysphoria, and given estrogen receptor α involvement in central nervous system masculinization, it was hypothesized that estrogen receptor α, encoded by the ESR1 gene, also might be implicated. Aim: To investigate whether ESR1 polymorphisms (TA)n-rs3138774, PvuII-rs2234693, and XbaI-rs9340799 and their haplotypes are associated with gender dysphoria in adults. Methods: Molecular analysis was performed in peripheral blood samples from 183 FtM subjects, 184 MtF subjects, and 394 sex- and ethnically-matched controls. Main outcome measures: Genotype and haplotype analyses of the (TA)n-rs3138774, PvuII-rs2234693, and XbaI-rs9340799 polymorphisms. Results: Allele and genotype frequencies for the polymorphism XbaI were statistically significant only in FtM vs control XX subjects (P = .021 and P = .020). In XX individuals, the A/G genotype was associated with a low risk of gender dysphoria (odds ratio [OR] = 0.34; 95% CI = 0.16-0.74; P = .011); in XY individuals, the A/A genotype implied a low risk of gender dysphoria (OR = 0.39; 95% CI = 0.17-0.89; P = .008). Binary logistic regression showed partial effects for all three polymorphisms in FtM but not in MtF subjects. The three polymorphisms were in linkage disequilibrium: a small number of TA repeats was linked to the presence of PvuII and XbaI restriction sites (haplotype S-T-A), and a large number of TA repeats was linked to the absence of these restriction sites (haplotype L-C-G). In XX individuals, the presence of haplotype L-C-G carried a low risk of gender dysphoria (OR = 0.66; 95% CI = 0.44-0.99; P = .046), whereas the presence of haplotype L-C-A carried a high susceptibility to gender dysphoria (OR = 3.96; 95% CI = 1.04-15.02; P = .044). Global haplotype was associated with FtM gender dysphoria (P = .017) but not with MtF gender dysphoria. Conclusions: XbaI-rs9340799 is involved in FtM gender dysphoria in adults. Our findings suggest different genetic programs for gender dysphoria in men and women. Cortés-Cortés J, Fernández R, Teijeiro N, et al. Genotypes and Haplotypes of the Estrogen Receptor α Gene (ESR1) Are Associated With Female-to-Male Gender Dysphoria. J Sex Med 2017;14:464-472.

Gender Dysphoria in Adults

Article

Full-text available

Jan 2016
ANNU REV CLIN PSYCHO

Gender dysphoria (GD), a term that denotes persistent discomfort with one's biologic sex or assigned gender, replaced the diagnosis of gender identity disorder in the Diagnostic and Statistical Manual of Mental Disorders in 2013. Subtypes of GD in adults, defined by sexual orientation and age of onset, have been described; these display different developmental trajectories and prognoses. Prevalence studies conclude that fewer than 1 in 10,000 adult natal males and 1 in 30,000 adult natal females experience GD, but such estimates vary widely. GD in adults is associated with an elevated prevalence of comorbid psychopathology, especially mood disorders, anxiety disorders, and suicidality. Causal mechanisms in GD are incompletely understood, but genetic, neurodevelopmental, and psychosocial factors probably all contribute. Treatment of GD in adults, although largely standardized, is likely to evolve in response to the increasing diversity of persons seeking treatment, demands for greater patient autonomy, and improved understanding of the benefits and limitations of current treatment modalities. Expected final online publication date for the Annual Review of Clinical Psychology Volume 12 is March 28, 2016. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.

Neuroimaging studies in people with gender incongruence

Article

Full-text available

Jan 2016
INT REV PSYCHIATR

The current review gives an overview of brain studies in transgender people. First, we describe studies into the aetiology of feelings of gender incongruence, primarily addressing the sexual differentiation hypothesis: does the brain of transgender individuals resemble that of their natal sex, or that of their experienced gender? Findings from neuroimaging studies focusing on brain structure suggest that the brain phenotypes of trans women (MtF) and trans men (FtM) differ in various ways from control men and women with feminine, masculine, demasculinized and defeminized features. The brain phenotypes of people with feelings of gender incongruence may help us to figure out whether sex differentiation of the brain is atypical in these individuals, and shed light on gender identity development. Task-related imaging studies may show whether brain activation and task performance in transgender people is sex-atypical. Second, we review studies that evaluate the effects of cross-sex hormone treatment on the brain. This type of research provides knowledge on how changes in sex hormone levels may affect brain structure and function.

Transsexuality Among Twins: Identity Concordance, Transition, Rearing, and Orientation

Article

Full-text available

Jan 2013

Milton Diamond

The relative contributions of genetic and environmental factors to the development of gender identity have been debated. Twins were studied that are concordant or discordant for gender identity status in order to provide clarification of this issue. An extensive library search yielded reports of 27 male and 16 female sets concordant or discordant for transsexuality. An Internet bulletin board search and clinical contact requests for participants in a survey of twins in which one or both transitioned located 69 new twin pairs. In addition to asking about matters associated with gender, these new twins were asked about their transition, rearing, and sexual practices. Combining data from the present survey with those from past-published reports, 20% of all male and female monozygotic twin pairs were found concordant for transsexual identity. This was more frequently the case for males (33%) than for females (23%). The responses of our twins relative to their rearing, along with our findings regarding some of their experiences during childhood and adolescence show their identity was much more influenced by their genetics than their rearing.

A Polymorphism of the CYP17 Gene Related to Sex Steroid Metabolism is Associated With Female-to-Male But Not Male-to-Female Transsexualism

Article

Dec 2008

Transsexualism is a rare condition. Although its etiology is unknown, it has been speculated that sex steroids may play an important role during early brain development. There may be a genetic component based on reports of an association between male to female (MtF) transsexualism and a CA repeat polymorphism in the estrogen receptor beta gene. CYP17 A2 T>C is a functional single nucleotide polymorphism (SNP) of the common cytochome P-450 that is associated with elevated serum and plasma levels of estradiol (E2), progesterone, and testosterone. The authors hypothesized that CYP17 A2 T>C is associated with transsexualism and that mutant alleles would be overrepresented among individuals with this condition. This case-control study assesses the association between transsexualism and allele and genotype frequencies of CYP17 A2 T>C SNP in a series of Caucasian transsexuals compared with controls. The participants were 102 male-to-female (MtF) and 49 female-to-male (FtM) transsexuals, 756 male controls, and 915 female controls. The mean age at presentation of FtM transsexuals was 33.2 and that of MtF transsexuals was 41.8 years. CYP17 A2 T>C SNP allele frequencies were statistically significantly different between FtM transsexuals and female controls (CYP17 T: 56% and CYP17 C: 44% versus CYP17 T: [69%] and CYP17 C: [31%], respectively). Genotype distributions were also different between FtM transsexuals and female controls. In contrast, no statistically significantly differences between MtF transsexuals and male controls were found in the CYP17 A2 T>C allele and genotype distributions. The allele distribution of CYP17 A2 T>C was gender-specific among male and female controls in that a higher mutant C allele frequency occurred in the male controls (CYP17 C: males; [40%] versus females [31%]), respectively; P ≤ .001. Allele distribution in the MtF transsexuals was equivalent to male controls. In contrast, FtM transsexuals did not follow the gender-specific allele distribution of female controls but instead had an allele distribution equivalent to MtF transsexuals and male controls. The overrepresentation of CYP17 A2 T>C SNP among FtM transsexuals but not MtFs supports this polymorphism as a candidate gene of FtM transsexualism. The loss of a female-specific CYP17 A2 T>C allele distribution pattern may predispose women to become transsexuals.

A simple salting out procedure for extracting DNA for human nucleated cells

Article

Jan 1988

Gender identity, gender assignment and reassignment in individuals with disorders of sex development: a major of dilemma

Article

Jun 2016
J ENDOCRINOL INVEST

Introduction Disorders of Sex Development (DSD) are a wide range of congenital conditions characterized by an incongruence of components involved in sexual differentiation, including gender psychosexual development. The management of such disorders is complex, and one of the most crucial decision is represented by gender assignment. In fact, the primary goal in DSD is to have a gender assignment consistent with the underlying gender identity in order to prevent the distress related to a forthcoming Gender Dysphoria. Historically, gender assignment was based essentially on surgical outcomes, assuming the neutrality of gender identity at birth. This policy has been challenged in the past decade refocusing on the importance of prenatal and postnatal hormonal and genetic influences on psychosexual development. Aims (1) to update the main psychological and medical issues that surround DSD, in particular regarding gender identity and gender assignment; (2) to report specific clinical recommendations according to the different diagnosis. Methods A systematic search of published evidence was performed using Medline (from 1972 to March 2016). Review of the relevant literature and recommendations was based on authors’ expertise. Results A review of gender identity and assignment in DSD is provided as well as clinical recommendations for the management of individuals with DSD. Conclusions Given the complexity of this management, DSD individuals and their families need to be supported by a specialized multidisciplinary team, which has been universally recognized as the best practice for intersexual conditions. In case of juvenile GD in DSD, the prescription of gonadotropin-releasing hormone analogues, following the World Professional Association for Transgender Health and the Endocrine Society guidelines, should be considered. It should always be taken into account that every DSD person is unique and has to be treated with individualized care. In this perspective, international registries are crucial to improve the understanding of these challenging conditions and clinical practice, in providing a better prediction of gender identity.

Prevalence of Transgender Depends on the “Case” Definition: A Systematic Review

Article

Apr 2016
J SEX MED

Introduction: A systematic review and meta-analysis was conducted to evaluate how various definitions of transgender affect prevalence estimates. Aims: To evaluate the epidemiology of transgender and examine how various definitions of transgender affect prevalence estimates and to compare findings across studies that used different methodologies, in different countries, and over different periods. Methods: PubMed, EMBASE, and Medline were searched to identify studies reporting prevalence estimates of transgender in a population. All studies were grouped based on the case definition applied to the numerator. Summary estimates were derived using a random-effects model for total prevalence of transgender and for male-to-female and female-to-male subgroups. Overall and stratum-specific meta-prevalence estimates (mPs) and 95% confidence intervals (CIs) were accompanied by tests for heterogeneity and meta-regressions to assess sources of heterogeneity. Main outcome measures: The main outcome measure was population prevalence of transgender. Secondary outcomes included gender-specific prevalence estimates for male-to-female and female to male subgroups. Results: Thirty-two studies met the inclusion criteria for systematic review. Of those, 27 studies provided necessary data for a meta-analysis. Overall mP estimates per 100,000 population were 9.2 (95% CI = 4.9-13.6) for surgical or hormonal gender affirmation therapy and 6.8 (95% CI = 4.6-9.1) for transgender-related diagnoses. Of studies assessing self-reported transgender identity, the mP was 871 (95% CI = 519-1,224); however, this result was influenced by a single outlier study. After removal of that study, the mP changed to 355 (95% CI = 144-566). Significant heterogeneity was observed in most analyses. Conclusion: The empirical literature on the prevalence of transgender highlights the importance of adhering to specific case definitions because the results can range by orders of magnitude. Standardized and routine collection of data on transgender status and gender identity is recommended.

Gender Assignment, Reassignment and Outcome in Disorders of Sex Development: Update of the 2005 Consensus Conference

Article

Jan 2016

Background: Societal changes are increasingly moving the conceptualization of gender from a set of binary categories towards a bimodal continuum, which along with the cautious conclusions resulting from the 2005 Consensus Conference influences gender-related clinical work with patients with disorders of sex development. Objective: This article provides an update of these developments over the past decade along with an overview of pertinent new data. Conclusion: Considerably more research is needed on larger sample sizes with systematic long-term follow-up to ground the emerging trends in clinical management of the highly diverse disorders of sex development syndromes in a solid empirical basis.

A Simple salting out procedure for extracting DNA from Human Nucleated Cells

Article

Jan 1988
NUCLEIC ACIDS RES

We investigate the contribution of the Iberian bat fauna to the cryptic diversity in Europe using mitochondrial (cytb and ND1) and nuclear (RAG2) DNA sequences. For each of the 28 bat species known for Iberia, samples covering a wide geographic range within Spain were compared to samples from the rest of Europe. In this general screening, almost 20% of the Iberian species showed important mitochondrial discontinuities (K2P distance values > 5%) either within the Iberian or between Iberian and other European samples. Within Eptesicus serotinus and Myotis nattereri, levels of genetic divergence between lineages exceeded 16%, indicating that these taxa represent a complex of several biological species. Other well-differentiated lineages (K2P distances between 5–10%) appeared within Hypsugo savii, Pipistrellus kuhlii and Plecotus auritus, suggesting the existence of further cryptic diversity. Most unsuspected lineages seem restricted to Iberia, although two have crossed the Pyrenees to reach, at leas...

A genetic link between gender dysphoria and sex hormone signalling

Abstract

Recommended publications

From transsexualism to gender dysphoria: Conceptual clustering or confusion - Du transsexualisme à l...

Recommendations for Revision of the DSM Diagnoses of Gender Identity Disorders: Consensus Statement...

Changing models of Transsexualism

Psychological functions in male-to-female transsexual people before and after surgery