Abstract :

These days, the rate of gender dysphoria among transgender individuals has increased drastically. Gender dysphoria is a significant issue affecting every aspect of individuals’ daily activities. It induces significant stress and might eventually cause an impairment. Historically, the etiology of gender dysphoria solely focused on the anatomical aspect, mentioning that men’s and women’s brains are distinct. However, it is now believed to be multifactorial, and emerging researchers are trying to shed light on both brain structures and genes that might contribute to gender dysphoria. To explore the possible etiologies of gender dysphoria, this paper reviews the evidence of how epigenetics contributes to gender dysphoria. The basis includes the role of sex-determining genes, anatomical differences among various populations, epigenetics, and mutation of the RYR3 gene. Epigenetics focuses solely on CpGs methylation. Thus far, these mechanisms could not wholly explain the exact mechanism causing gender dysphoria; therefore, additional research is required to disclose this information. Ultimately, understanding the mechanism of gender dysphoria will promote a better quality of life for individuals experiencing gender dysphoria.

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Keywords :

Epigenetics, Gender dysphoria, Neurostimulation Differences, RYR3, Sexual Differentiation.

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References :

1. W. Byne et al., “Gender dysphoria in adults: an overview and primer for psychiatrists,” Transgender Health, vol. 3, no. 1, pp. 57-A3, 2018.
2. L. A. Kilpatrick, M. Holmberg, A. Manzouri, and I. Savic, “Cross sex hormone treatment is linked with a reversal of cerebral patterns associated with gender dysphoria to the baseline of cisgender controls,” European Journal of Neuroscience, vol. 50, no. 8, pp. 3269-3281, 2019.
3. M. Holmberg, S. Arver, and C. Dhejne, “Supporting sexuality and improving sexual function in transgender persons,” Nature Reviews Urology, vol. 16, no. 2, pp. 121-139, 2019.
4. Z. Davy and M. Toze, “What is gender dysphoria? A critical systematic narrative review,” Transgender health, vol. 3, no. 1, pp. 159-169, 2018.
5. F. J. O. Boucher and T. I. Chinnah, “Gender dysphoria: a review investigating the relationship between genetic influences and brain development,” Adolescent health, medicine and therapeutics, vol. 11, p. 89, 2020.
6. D. W. Riggs, R. Pearce, C. A. Pfeffer, S. Hines, F. White, and E. Ruspini, “Transnormativity in the psy disciplines: Constructing pathology in the Diagnostic and Statistical Manual of Mental Disorders and Standards of Care,” American Psychologist, vol. 74, no. 8, p. 912, 2019.
7. K. del Valle Ramírez et al., “Implications of the estrogen receptor coactivators SRC1 and SRC2 in the biological basis of gender incongruence,” Sexual Medicine, vol. 9, no. 3, p. 100368, 2021.
8. R. Fernández et al., “An Analysis of the Implication of Estrogens and Steroid Receptor Coactivators in the Genetic Basis of Gender Incongruence,” Oxytocin and Health, p. 99, 2021.
9. R. Fernández, K. Ramírez, E. Delgado-Zayas, E. Gómez-Gil, A. Guillamon, and E. Pásaro, “The Biological Basis of Gender Incongruence,” 2022.
10. D. Glintborg, G. T’Sjoen, P. Ravn, and M. S. Andersen, “Management of endocrine disease: Optimal feminizing hormone treatment in transgender people,” European journal of endocrinology, vol. 185, no. 2, pp. R49-R63, 2021.
11. K. Ramirez et al., “Epigenetics is implicated in the basis of gender incongruence: an epigenome-wide association analysis,” Frontiers in Neuroscience, p. 1074, 2021.
12. J. Ristori et al., “Brain sex differences related to gender identity development: Genes or hormones?,” International Journal of Molecular Sciences, vol. 21, no. 6, p. 2123, 2020.
13. D. F. Swaab, S. E. C. Wolff, and A.-M. Bao, “Sexual differentiation of the human hypothalamus: Relationship to gender identity and sexual orientation,” Handbook of Clinical Neurology, vol. 181, pp. 427-443, 2021.
14. H. B. Nguyen, J. Loughead, E. Lipner, L. Hantsoo, S. L. Kornfield, and C. N. Epperson, “What has sex got to do with it? The role of hormones in the transgender brain,” Neuropsychopharmacology, vol. 44, no. 1, pp. 22-37, 2019.
15. M. N. Skorska et al., “A multi-modal MRI analysis of cortical structure in relation to gender dysphoria, sexual orientation, and age in adolescents,” Journal of clinical medicine, vol. 10, no. 2, p. 345, 2021.
16. S. F. Witelson, “Neuroanatomical Bases of Hemispheric Functional Specialization in the Human Brain: Possible Developmental Factors1,” in Hemispheric communication: Mechanisms and models: Routledge, 2020, pp. 61-84.
17. C. Bello-Alvarez and I. Camacho-Arroyo, “Impact of sex in the prevalence and progression of glioblastomas: the role of gonadal steroid hormones,” Biology of sex Differences, vol. 12, no. 1, pp. 1-13, 2021.
18. T. Beking et al., “Testosterone effects on functional amygdala lateralization: A study in adolescent transgender boys and cisgender boys and girls,” Psychoneuroendocrinology, vol. 111, p. 104461, 2020.
19. S. Gülgöz et al., “Similarity in transgender and cisgender children’s gender development,” Proceedings of the National Academy of Sciences, vol. 116, no. 49, pp. 24480-24485, 2019.
20. Á. Gómez et al., “Effects of adult male rat feminization treatments on brain morphology and metabolomic profile,” Hormones and behavior, vol. 125, p. 104839, 2020.
21. G. Spizzirri et al., “Grey and white matter volumes either in treatment-naïve or hormone-treated transgender women: a voxel-based morphometry study,” Scientific reports, vol. 8, no. 1, pp. 1-10, 2018.
22. G. Perrotta, “Sexual orientations: a critical review of psychological, clinical and neurobiological profiles. Clinical hypothesis of homosexual and bisexual positions,” International Journal of Sexual and Reproductive Health Care, vol. 3, no. 1, pp. 027-041, 2020.
23. A. El-Osta, “Distinguishing transgender DNA methylation,” vol. 14, ed: BioMed Central, 2022, pp. 1-3.
24. R. Fernández and S. M. Burke, “Research in Transgender Healthcare: what have we learned and where are we going?,” Frontiers in endocrinology, vol. 12, 2021.
25. K. d. V. Ramirez Olivero, “Análisis del perfil de metilación CpG del ADN genómico de una población con incongruencia de género,” 2021.
26. B. Spurny-Dworak et al., “Effects of sex hormones on brain GABA and glutamate levels in a cis-and transgender cohort,” Psychoneuroendocrinology, vol. 138, p. 105683, 2022.
27. J. G. Theisen et al., “The use of whole exome sequencing in a cohort of transgender individuals to identify rare genetic variants,” Scientific reports, vol. 9, no. 1, pp. 1-11, 2019.
28. F. M. G. Enjamio, “TRABAJO DE FIN DE MÁSTER,” 2021.
29. Y. Nagamura et al., “PLEKHA5 regulates the survival and peritoneal dissemination of diffuse-type gastric carcinoma cells with Met gene amplification,” Oncogenesis, vol. 10, no. 3, pp. 1-14, 2021.
30. L. B. Jilaveanu et al., “PLEKHA5 as a Biomarker and Potential Mediator of Melanoma Brain MetastasisRole of PLEKHA5 in Melanoma Brain Metastasis,” Clinical Cancer Research, vol. 21, no. 9, pp. 2138-2147, 2015.
31. S. C. Eisele, C. M. Gill, G. M. Shankar, and P. K. Brastianos, “PLEKHA5: A Key to Unlock the Blood–Brain Barrier? Role of PLEKHA5 in CNS Homing,” Clinical Cancer Research, vol. 21, no. 9, pp. 1978-1980, 2015.
32. M. A. Mahajan and H. H. Samuels, “Nuclear receptor coactivator/coregulator NCoA6 (NRC) is a pleiotropic coregulator involved in transcription, cell survival, growth and development,” Nuclear receptor signaling, vol. 6, no. 1, pp. nrs-06002, 2008.
33. Q. Li and J. Xu, “Identification and characterization of the alternatively spliced nuclear receptor coactivator-6 isoforms,” International Journal of Biological Sciences, vol. 7, no. 5, p. 505, 2011.
34. J. Kawagoe et al., “Nuclear receptor coactivator-6 attenuates uterine estrogen sensitivity to permit embryo implantation,” Developmental cell, vol. 23, no. 4, pp. 858-865, 2012.
35. R. Fernández et al., “Gender-affirming hormone therapy modifies the CpG methylation pattern of the ESR1 gene promoter after six months of treatment in transmen,” The Journal of Sexual Medicine, vol. 17, no. 9, pp. 1795-1806, 2020.
36. R. Shepherd et al., “Gender-affirming hormone therapy induces specific DNA methylation changes in blood,” Clinical epigenetics, vol. 14, no. 1, pp. 1-19, 2022.
37. R. Fernandez and S. Burke, “Research in Transgender,” 2022.
38. L. Liguori et al., “The metallophosphodiesterase Mpped2 impairs tumorigenesis in neuroblastoma,” Cell cycle, vol. 11, no. 3, pp. 569-581, 2012.
39. E. C. Délot and E. Vilain, “Towards improved genetic diagnosis of human differences of sex development,” Nature Reviews Genetics, vol. 22, no. 9, pp. 588-602, 2021.
40. C. E. Roselli, “Neurobiology of gender identity and sexual orientation,” Journal of neuroendocrinology, vol. 30, no. 7, p. e12562, 2018.
41. D. F. Deegan and N. Engel, “Sexual dimorphism in the age of genomics: how, when, where,” Frontiers in Cell and Developmental Biology, vol. 7, p. 186, 2019.
42. M. R. Binder, “Neuronal hyperexcitability: The elusive but modifiable instigator of disease,” AJCEM, vol. 10, no. 1, pp. 1-7, 2022.
43. F. Pallotti et al., “Epigenetic Effects of Gender-Affirming Hormone Treatment: A Pilot Study of the ESR2 Promoter’s Methylation in AFAB People,” Biomedicines, vol. 10, no. 2, p. 459, 2022.
44. A. Gualerzi, F. Capirone, C. Schettini, and F. Bert, “Gender dysphoria and psychiatric comorbid-ity: a ten-years descriptive study.”
45. E. Durcan et al., “Fertility Desire and Motivation Among Individuals with Gender Dysphoria: A Comparative Study,” Journal of Sex & Marital Therapy, pp. 1-15, 2022.
46. S. Tenugu and B. Senthilkumaran, “Sexual plasticity in bony fishes: Analyzing morphological to molecular changes of sex reversal,” Aquaculture and Fisheries, 2022.
47. M. A. Simonson, “Genome-wide association study (GWAS),” Encyclopedia of Behavioral Medicine, pp. 936-939, 2020.