Knowing Neurons
Neuropolicy Paper Competition 2023Science Policy

Gender Dysphoria: What is it and Why Does it Matter?

Policy Brief by Katie Cooke

Introduction

The DSM-5 defines gender dysphoria (GD) as a prolonged incongruence between one’s assigned sex at birth and one’s gender identity (American Psychiatric Association, 2013). Feelings of gender dysphoria are highly correlated with symptoms of major depressive disorder and generalized anxiety disorder (Chodzen et al., 2019) , leading many individuals experiencing GD to consider or attempt suicide (Peterson et al., 2017). To alleviate gender dysphoria, patients will often transition from their birth-assigned sex to the sex that matches their gender identity. Yet, many states have passed laws preventing gender dysphoric youth from receiving gender affirming care, presenting a plethora of possible complications for this population.

federal action must be taken to protect the ability of transgender minors to access gender-affirming care.  

Recently, many states have restricted the access of transgender youth to gender affirming health care. Montana, Idaho, Utah, North Dakota, South Dakota, Iowa, Missouri, Indiana, Kentucky, Mississippi, Florida, Texas, and Tennessee have all fully banned gender affirming medical care for transgender individuals under 18, fundamentally deeming it unlawful to provide gender affirming care for transgender minors who have been diagnosed with gender dysphoria (T.N. Legis. Assemb, 2023). Further, these kinds of laws can introduce the possibility of a felony to health care professionals who provide gender affirming care to minors (N.D. Legis. Assemb, 2023). Though not fully prohibited, gender affirming care is also under major restrictions in Nebraska, Georgia, West Virginia, and Arizona. This trend of severely limiting gender affirming care is widespread. To combat the mental and physical health issues these limitations introduce, federal action must be taken to protect the ability of transgender minors to access gender-affirming care.  

What is Gender-Affirming Care?

When someone feels as if the gender they were assigned at birth does not fit them, they may look to their therapist, psychiatrist, or medical doctor to be evaluated for gender dysphoria.  When patients are diagnosed with gender dysphoria, they are referred to a doctor for medical therapy. Individuals usually begin with taking a puberty blocker known as gonadotropin-releasing hormone agonist (GnRHa) (Van der Loos et al., 2023) that halts the development of sex-specific physical traits by blocking hormones needed to make testosterone and estrogen respectively (Butler et al., 2018). Puberty blockers can reduce anxiety about ongoing sex-specific physical development and allow time and space for identity exploration (Butler et al., 2018). If GD persists, participants typically begin the transition to their desired sex with gender-affirming hormone (GAH) treatment (Van Der Loos et al., 2021) once they are at least 15 years old. For patients transitioning from male to female, testosterone action is blocked, halting the development of male-specific traits. These individuals will take estrogen to trigger the development of female characteristics, such as the development of breast tissue (T’Sjoen et al., 2019). For patients transitioning from female to male, testosterone is taken to stop menstrual cycles and decrease estrogen levels as well as trigger the development of male characteristics, such as facial hair (T’Sjoen et al., 2019). The final step is gender reassignment surgery. This step, only performed when patients are at least 18, aims to align the patient’s physical body with their gender identity through procedures on the face, chest, and/or genitalia (Selvaggi & Bellringer, 2011). All these procedures can help transgender individuals feel more comfortable in their identity through aligning their gender identity with their physical gender presentation (Lee & Rosenthal, 2023). State bans on gender affirming care are based on the notion that children are unable to discern their gender identity before adulthood and, therefore, banning gender affirming health care will protect kids from making a life-altering choice they may regret. However, there is significant evidence that children have a gender identity and that trans children are cognizant of its divergence from their assigned sex as early as six or seven years old (Diamond, 2002). Thus, it is likely that persistent GD would not dissipate and should be treated to prevent mental health complications. 

The Neurological Basis of Gender Identity

Research suggests that gender affirming health care significantly improves the mental health of transgender youth, a population at risk for suicidal tendencies. Transgender youth who have received gender-affirming hormone therapy (GAHT) report lower symptoms of depression and are less likely to have attempted suicide in the past year compared with those who wanted GAHT but did not receive it (Green et al., 2022). The well-being of those who received GAHT was similar to or better than youth of their same age from the general population (De Vries et al., 2014). Although opponents of hormone therapy worry this treatment negatively impact the developing brain, data from a longitudinal study on transgender youth reports participants who received puberty suppression before GAH therapy or who began GAH therapy earlier in the pubertal stages show better psychosocial functioning at baseline than those with no puberty suppression or who started GAH therapy later (Chen et al, 2023).This data suggests that the earlier gender affirming care is received, the more likely a transgender individual is to demonstrate better psychological functioning. The worry that hormone therapy may negatively impact the developing brain is not supported by significant scientific evidence, yet it is demonstrated that gender affirming hormone care can improve psychosocial functioning of transgender individuals. Thus, the benefits of gender affirming hormone therapy can be argued to outweigh potential unknown side effects.

This evidence suggests a biological basis for gender dysphoria…

One of the primary arguments against national access to gender affirming health care is the belief that transgender youth are going through a phase and they will no longer want to transition later in life. Yet, there is neurological evidence supporting the hypothesis that differentiation of sexual organs during development in utero appears before the sexual differentiation of the brain, as the brains of these patients match one sex, but their sexual organs match a different sex. There are brain areas that inherently have greater mass in cisgender men compared to cisgender women: the core of the bed nucleus of the stria terminalis (BSTc) and the third interstitial nucleus of the anterior hypothalamus (INAH3) (Bao & Swaab, 2011). The cell counts and volumes of these regions in transgender women match those of cisgender women and are distinct from those of cisgender men, and the volumes and cell counts for transgender men align with those of cisgender men (Garcia-Falgueras & Swaab, 2008). Additionally, evidence of genetic contributions to gender dysphoria has been demonstrated in a study of young twins (Heylens et al., 2012) as well as a study of child and adolescent twins (Coolidge, Thede, & Young, 2002). There is evidence that a mutation in a gene known as CYP17 exists in transmen and elevates levels of oestradiol, progesterone, and testosterone, which are hormones important in sexual differentiation (Bentz et al., 2008; Fernández et al., 2015). Additionally, mutations seen in transwomen seem to lead to a complete loss of function of the androgen receptor gene, which is said to result in a female gender identity (Hare et al., 2009; Henningsson et al., 2005). In transwomen, there is an overrepresentation in genetic variants of estrogen receptors, which influence the signaling of this hormone (Foreman et al., 2019). This evidence suggests a biological basis for gender dysphoria and supports the notion that a transgender identity is not a phase, but instead a natural inclination supported by neurological data.

there are scenarios where the sex of the brain does not match the sex of the body.

Studies support the idea of a fixed gender identity, as both clinical and preclinical work has shown the development of gender identity is biologically programmed and irreversible (Saraswat, Weinand, & Safer, 2015). This is supported by case studies where children have hormonally and socially been raised as the gender opposite their biological sex, yet still had a gender identity that matched their biological sex (Bao & Swaab, 2011). These studies suggest prenatal factors, such as hormone exposure, cause sex-specific brain development that produces sex-specific behavior throughout life. Furthermore, researchers have found preliminary data suggesting sexual differentiation in the brain does not align with the differentiation of sexual organs (Berenbaum & Beltz, 2011).Thus, there is neurological evidence suggesting there are scenarios where the sex of the brain does not match the sex of the body. For individuals who are transgender, this means that their brain aligns with the brain of one sex while their sexual organs align with a different sex. A brain and a body aligning with different sexes may cause developing a gender identity to be difficult and confusing, and it appears natural that these individuals want to orient their body with their brain.   

Gender Dysphoria in Youth

Laws banning health care for transgender youth are reported to have already negatively impacted the mental health of transgender youth (Paley, 2023). Many of the mental health issues experienced by transgender individuals are due to environments in which they experience transphobia, concealment of gender identity, and expectations of rejection and discrimination (Meyer, 2015), all which are likely to increase in prevalence with the passing of the bills. If individuals stop taking gender affirming hormones, they could experience symptoms of withdrawal, such as mood swings, depression, fatigue, and insomnia (Hochberg, Pacak & Chrousos, 2003), as well as hair loss, loss of strength, and loss of muscle (Children’s Hospital of Pittsburgh), all which are a detriment to the physical and mental wellbeing of these individuals.  These laws claim to protect the youth through preventing access to treatments they may regret as an adult. Yet, the prevalence of regret in transgender individuals is low, being less than 1% of FTM patients and 1% of MTF patients (Bustos et al., 2021). Furthermore, these treatments have significant evidence suggesting they significantly improve the well-being of these individuals, and it could be harmful if these treatments were no longer accessible. Thus, the negative consequences of laws restricting access to gender affirming care for transgender youth will likely outweigh any possible prevention of regret in the population. 

Suggested Directions

Concerned members of the public can email their state representatives advocating for the following actions: 

Federal Protection of Transgender Youth

This evidence points to a need for federal protection of gender affirming care for transgender youth. Since there is no evidence indicating long-term negative health outcomes of gender affirming care, states should not be allowed to regulate the access of this care, especially since the short-term benefits of this care have significant supporting scientific evidence. Protection of the rights of transgender youth on a federal level would benefit the mental and physical health of this population and denying it under no substantial basis is unconstitutional as it infringes on the pursuit of life, liberty, and happiness. 

Studies before Regulation

It is difficult to account for the potential harm or benefit of a treatment if there is little to no concrete evidence supporting the claim. It is argued that excessive focus on risk aversion in treatment regulations for medications in general is not helpful to society in achieving maximum health benefit (Eichler et al., 2013). Thus, banning treatments for transgender youth in fear of long-term health consequences when no such evidence exists is more harmful than helpful to this population, as the treatments that alleviate the significant psychological stress associated with gender dysphoria would no longer be accessible. Furthermore, the fourteenth amendment of the constitution states that no state should pass or enforce a law that infringes on the privileges of United States Citizens without due process of the law. Given that there is no “due process,” it is unconstitutional for these laws to be passed and enforced.

Conclusion

The neurological basis of GD is widely miscommunicated and unknown among the general population. Understanding the biological evidence behind the feelings that these individuals or their loved ones are experiencing could increase support for the transgender population. Conversations about topics that have become political are difficult, yet concrete scientific evidence can help bridge the gap. If you or a loved one are struggling with political turmoil over gender identity, my hope is that the evidence presented in this paper can make those conversations a bit easier. 

~~~

Written by Katie Cooke
Edited by Rachel Gilfarb and Zoë Dobler

~~~

Become a Patron!

References

Association AP. Diagnostic and statistical manual of mental disorders (DSM-5®). American

Psychiatric Pub.

Bao, A., & Swaab, D. F. (2011). Sexual differentiation of the human brain: Relation to gender identity, sexual orientation and neuropsychiatric disorders. Frontiers in Neuroendocrinology, 32(2), 214–226. https://doi.org/10.1016/j.yfrne.2011.02.007

Er, B., Kaplan, M., & Naor, Z. (1991). Comparative stimulatory effect of gonadotrophin releasing hormone (GnRH) and GnRH agonist upon pulsatile human chorionic gonadotrophin secretion in superfused placental explants: reversible inhibition by a GnRH antagonist. Human Reproduction, 6(8), 1063–1069. https://doi.org/10.1093/oxfordjournals.humrep.a137485 

Bentz, E., Hefler, L., Kaufmann, U., Huber, J., Kolbus, A., & Tempfer, C. (2008). A polymorphism of the CYP17 gene related to sex steroid metabolism is associated with female-to-male but not male-to-female transsexualism. Fertility and Sterility, 90(1), 56–59. https://doi.org/10.1016/j.fertnstert.2007.05.056

Berenbaum, S. A., & Beltz, A. M. (2011). Sexual differentiation of human behavior: Effects of prenatal and pubertal organizational hormones. Frontiers in Neuroendocrinology, 32(2), 183–200. https://doi.org/10.1016/j.yfrne.2011.03.001

Bustos, V. P., Bustos, S. S., Mascaró, A., Del Corral, G., Forte, A. J., Ciudad, P., Kim, E. A., Langstein, H. N., & Manrique, O. J. (2021). Regret after Gender-affirmation Surgery: A Systematic Review and Meta-analysis of Prevalence. Plastic and Reconstructive Surgery. Global Open, 9(3), e3477. https://doi.org/10.1097/gox.0000000000003477

Butler, G., De Graaf, N. M., Wren, B., & Carmichael, P. (2018). Assessment and support of children and adolescents with gender dysphoria. Archives of Disease in Childhood, archdischild-314992. https://doi.org/10.1136/archdischild-2018-314992

Chen, D., Berona, J., Chan, Y., Ehrensaft, D., Garofalo, R., Hidalgo, M. A., Rosenthal, S. M., Tishelman, A. C., & Olson-Kennedy, J. (2023). Psychosocial Functioning in Transgender Youth after 2 Years of Hormones. The New England Journal of Medicine, 388(3), 240–250. https://doi.org/10.1056/nejmoa2206297

Children’s Hospital of Pittsburgh. (n.d.). Patient Information for Feminizing Hormone Therapy. In Children’s Hospital of Pittsburgh. https://www.chp.edu/-/media/chp/departments-and-services/adolescent-and-young-adult-medicine/documents/gender-and-sexual-development/feminizing-hormone-therapy.pdf?la=en#:~:text=If%20you%20stop%20taking%20hormones,you%20hadn’t%20taken%20hormones.&text=You%20may%20lose%20muscle%20and%20strength%20in%20your%20upper%20body.&text=Your%20skin%20may%20become%20softer,body%20will%20make%20less%20testosterone.

Chodzen, G., Hidalgo, M. A., Chen, D., & Garofalo, R. (2019). Minority stress factors associated with depression and anxiety among transgender and Gender-Nonconforming youth. Journal of Adolescent Health, 64(4), 467–471. https://doi.org/10.1016/j.jadohealth.2018.07.006

Coolidge, F. L., Thede, L. L., & Young, S. E. (2002). The heritability of gender identity disorder in a child and adolescent twin sample. Behavior Genetics, 32(4), 251–257.  https://doi.org/10.1023/a:1019724712983

De Vries, A. L., Doreleijers, T. a. H., Steensma, T. D., & Cohen-Kettenis, P. T. (2011). Psychiatric comorbidity in gender dysphoric adolescents. Journal of Child Psychology and Psychiatry, 52(11), 1195–1202. https://doi.org/10.1111/j.1469-7610.2011.02426.x

De Vries, A. L., McGuire, J. K., Steensma, T. D., Wagenaar, E. C. F., Doreleijers, T. a. H., & Cohen-Kettenis, P. T. (2014). Young Adult Psychological outcome after puberty suppression and gender reassignment. Pediatrics, 134(4), 696–704. https://doi.org/10.1542/peds.2013-2958

Diamond, M. (2002). Sex and Gender are Different: Sexual Identity and Gender Identity are Different. Clinical Child Psychology and Psychiatry, 7(3), 320–334. https://doi.org/10.1177/1359104502007003002 

Eichler, H., Bloechl-Daum, B., Brasseur, D., Breckenridge, A., Leufkens, H. G. M., Raine, J., Salmonson, T., Schneider, C. K., & Rasi, G. (2013). The risks of risk aversion in drug regulation. Nature Reviews Drug Discovery, 12(12), 907–916. https://doi.org/10.1038/nrd4129

Fernández, R., Cortés-Cortés, J., Esteva, I., Gómez-Gil, E., Almaraz, M. C., Lema, E., Rumbo, T., Haro-Mora, J. J., Cortés-Cortés, J., Esteva, I., Gómez-Gil, E., Almaraz, M. C., Lema, E., Rumbo, T., Haro-Mora, J. J., Roda, E., Guillamon, A., & Pásaro, E. (2015). The CYP17 MspA1 Polymorphism and the Gender Dysphoria. The Journal of Sexual Medicine, 12(6), 1329–1333. https://doi.org/10.1111/jsm.12895

Foreman, M., Hare, L. M., York, K., Balakrishnan, K., Sánchez, F. J., Harte, F., Erasmus, J., Vilain, E., & Harley, V. R. (2018). Genetic link between gender dysphoria and sex hormone signaling. The Journal of Clinical Endocrinology and Metabolism, 104(2), 390–396. https://doi.org/10.1210/jc.2018-01105

Foreman, M., Hare, L. M., York, K., Balakrishnan, K., Sánchez, F. J., Harte, F., Erasmus, J., Vilain, E., & Harley, V. R. (2018). Genetic link between gender dysphoria and sex hormone signaling. The Journal of Clinical Endocrinology and Metabolism, 104(2), 390–396. https://doi.org/10.1210/jc.2018-01105

Green, A. E., DeChants, J., Price-Feeney, M., & Davis, C. K. (2022). Association of Gender-Affirming hormone therapy with depression, thoughts of suicide, and attempted suicide among transgender and nonbinary youth. Journal of Adolescent Health, 70(4), 643–649. https://doi.org/10.1016/j.jadohealth.2021.10.036

Hare, L. M., Bernard, P., Sánchez, F. J., Baird, P. N., Vilain, E., Kennedy, T., & Harley, V. R. (2009). Androgen Receptor Repeat Length Polymorphism Associated with Male-to-Female Transsexualism. Biological Psychiatry, 65(1), 93–96. https://doi.org/10.1016/j.biopsych.2008.08.033 

H.B. 1254, 2023 Biennium, 2023 Reg. Sess. (N. Dak. 2023). https://www.ndlegis.gov/assembly/68-2023/regular/documents/23-0869-04000.pdf 

Henningsson, S., Westberg, L., Nilsson, S., Lundström, B., Ekselius, L., Bodlund, O., Lindström, E., Hellstrand, M., Rosmond, R., Eriksson, E., & Landén, M. (2005). Sex steroid-related genes and male-to-female transsexualism. Psychoneuroendocrinology, 30(7), 657–664. https://doi.org/10.1016/j.psyneuen.2005.02.006 

Heylens, G., De Cuypere, G., Zucker, K. J., Schelfaut, C., Elaut, E., Vanden Bossche, H., De Baere, E., & T’Sjoen, G. (2012). Gender Identity Disorder in Twins: A Review of the Case Report literature. The Journal of Sexual Medicine, 9(3), 751–757. https://doi.org/10.1111/j.1743-6109.2011.02567.x 

Hochberg, Z., Pacak, K., & Chrousos, G. P. (2003). Endocrine withdrawal syndromes. Endocrine Reviews, 24(4), 523–538. https://doi.org/10.1210/er.2001-0014

Klink, D., & Heijer, M. D. (2013). Genetic aspects of gender identity development and gender dysphoria. In Springer eBooks (pp. 25–51). https://doi.org/10.1007/978-1-4614-7441-8_2

Lee, J. Y., & Rosenthal, S. M. (2023). Gender-Affirming Care of Transgender and Gender-Diverse Youth: Current Concepts. Annual Review of Medicine, 74(1), 107–116. https://doi.org/10.1146/annurev-med-043021-032007

Meyer, I. H. (2015). Resilience in the study of minority stress and health of sexual and gender minorities. Psychology of Sexual Orientation and Gender Diversity, 2(3), 209–213. https://doi.org/10.1037/sgd0000132 

NCI Dictionary of Cancer Terms. (n.d.). National Cancer Institute. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/gnrha

Olson, K. R., Durwood, L., DeMeules, M., & McLaughlin, K. A. (2016). Mental health of transgender children who are supported in their identities. Pediatrics, 137(3). https://doi.org/10.1542/peds.2015-3223 

Paley, A. (2023, January 1). 2022 national survey on LGBTQ Youth Mental Health. The Trevor Project. https://www.thetrevorproject.org/survey-2022/

Peterson, C. M., Matthews, A., Copps-Smith, E., & Conard, L. a. E. (2016). Suicidality, Self-Harm, and Body Dissatisfaction in Transgender Adolescents and Emerging Adults with Gender Dysphoria. Suicide and Life Threatening Behavior, 47(4), 475–482. https://doi.org/10.1111/sltb.12289

Phoenix, C. H., Goy, R. W., Gerall, A. A., & Young, W. C. (1959). ORGANIZING ACTION OF PRENATALLY ADMINISTERED TESTOSTERONE PROPIONATE ON THE TISSUES MEDIATING MATING BEHAVIOR IN THE FEMALE GUINEA PIG1. Endocrinology, 65(3), 369–382. https://doi.org/10.1210/endo-65-3-369

Saraswat, A., Weinand, J. D., & Safer, J. D. (2015). Evidence supporting the biologic nature of gender identity. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists, 21(2), 199–204. https://doi.org/10.4158/EP14351.RA 

S.B. 0001, 2023 Biennium, 2023 Reg. Sess. (Ten. 2023). https://wapp.capitol.tn.gov/apps/billinfo/default.aspx?BillNumber=sb0001

Selvaggi, G., & Bellringer, J. (2011). Gender reassignment surgery: an overview. Nature Reviews Urology, 8(5), 274–282. https://doi.org/10.1038/nrurol.2011.46

Slattery, J., & Kurz, X. (2020). Assessing strength of evidence for regulatory decision making in licensing: What proof do we need for observational studies of effectiveness? Pharmacoepidemiology and Drug Safety, 29(10), 1336–1340. https://doi.org/10.1002/pds.5005

T’Sjoen, G., Arcelus, J., Gooren, L., Klink, D., & Tangpricha, V. (2019). Endocrinology of Transgender Medicine. Endocrine Reviews, 40(1), 97–117. https://doi.org/10.1210/er.2018-00011

Van Der Loos, M. a. T. C., Hellinga, I., Vlot, M., Klink, D., Heijer, M. D., & Wiepjes, C. M. (2021). Development of hip bone geometry during Gender‐Affirming hormone therapy in transgender adolescents resembles that of the experienced gender when pubertal suspension is started in early puberty. Journal of Bone and Mineral Research, 36(5), 931–941. https://doi.org/10.1002/jbmr.4262

Van Der Loos, M. a. T. C., Klink, D., Hannema, S., Bruinsma, S., Steensma, T. D., Kreukels, B. P., Cohen-Kettenis, P. T., De Vries, A. L., Heijer, M. D., & Wiepjes, C. M. (2023). Children and adolescents in the Amsterdam Cohort of Gender Dysphoria: trends in diagnostic- and treatment trajectories during the first 20 years of the Dutch Protocol. The Journal of Sexual Medicine, 20(3), 398–409. https://doi.org/10.1093/jsxmed/qdac029 

Author

  • Katie Cooke

    Katie is starting her junior year of her bachelor's in Neuroscience at Belmont University. She plans to pursue a Ph.D. in Molecular Pharmacology or Behavioral Neuroscience. Currently, she works in a lab at Vanderbilt studying therapeutic treatments for Rett Syndrome. Katie is passionate about using scientific data for advocacy.

Katie Cooke

Katie is starting her junior year of her bachelor's in Neuroscience at Belmont University. She plans to pursue a Ph.D. in Molecular Pharmacology or Behavioral Neuroscience. Currently, she works in a lab at Vanderbilt studying therapeutic treatments for Rett Syndrome. Katie is passionate about using scientific data for advocacy.