Neurobiological Components of Sexual Identity Development and Epigenetic Effects of Environmental Stressors

Abstract

In this review, we explore the intricate development of sexual identity, drawing insights from genetic, endocrinological, neuroanatomical, and neurophysiological studies. Gender identity, encapsulating an individual's internal perception as male or female, undergoes a nuanced and gradual formation, commencing early in life and progressing through distinct stages. Gender nonconformity delineates behaviors that diverge from culturally prescribed norms, while gender dysphoria encompasses the emotional distress experienced by some individuals due to a mismatch between their gender identity and assigned sex at birth. The genesis of sexual identity involves multifaceted processes spanning numerous years. Human sex differentiation involves the suppression or inactivation of specific genes, a phenomenon illuminated by genetic investigations into gender dysphoria, which have shown comparable rates of genetic variations to the general population. Nevertheless, twin studies suggest an augmented likelihood of transsexuality among family members, hinting at potential environmental influences. Brain sexual differentiation occurs during mid-to-late pregnancy due to the impact of gonadal hormones. The mechanisms underpinning the loss of feminine brain characteristics and subsequent masculinization likely involve a combination of factors, indicating a complex interplay rather than a singular cause. Studies propose that human sexual behavior is not governed by a solitary gene but rather by a network of genes dispersed across the genome. Notably, disparities in brain structures, functionalities between genders, as well as variations in endocrine and serotonin-dopamine levels, are implicated in the etiology of gender dysphoria, contributing to the understanding of this complex phenomenon situated between genders.

Keywords

• Sexual identity
• environmental stress
• neurobiology
• epigenetics

Cinsel Kimlik Gelişiminin Nörobiyolojik Yapıtaşları ve Çevresel Stresörlerin Epigenetik Etkileri

Öz

Bu gözden geçirmede cinsel kimlik gelişimini bu konuda yapılan genetik, endokrinolojik, nöroanatomik, nörofizyolojik çalışmaların ışığında açıklanması hedeflenmiştir. Cinsel kimlik bireyin kendisini öznel olarak kadın ya da erkek olarak algılamasını ifade eder. Cinsel kimlik gelişiminin erken yaşlarda başladığı, uzun yıllar süren aşamalı bir süreç olduğu ve çeşitli aşamalardan geçtiği belirtilmektedir. Cinsiyet uygunsuzluğu kültürel olarak tanımlanan normlara uymayan cinsiyet rol davranışını belirtir. Cinsiyet hoşnutsuzluğu ise, cinsiyet uyumsuzluğu olan bazı bireylerin yaşayabileceği duygusal karmaşa veya sıkıntıyı ifade etmektedir. İnsanlarda cinsiyet farklılaşması bazı genlerin basımlanması ya da inaktivasyonu ile meydana gelmektedir. Cinsiyet hoşnutsuzluğ örneklemlerindeki genetik araştırmalar rutin moleküler karyotiplemede değişiklik oranlarının genel popülasyona benzer olduğunu göstermiştir. Ancak yapılan ikiz çalışmalarında aile üyeleri arasında artan transseksüelite riski paylaşılmış çevrenin de etken olabileceğini düşündürmüştür. İnsanlarda beynin cinsel yönden farklılaşması gonadal hormonlar etkisi ile gebeliğin ortası/sonlarında olmaktadır. Eldeki veriler değerlendirildiğinde beynin dişil özelliklerinin kaybolması ve erkeksileşmesi için olasılıkla birden fazla mekanizmanın rol oynayabileceği düşünülebilir. Yapılan çalışmalar insanlarda cinsel davranışın tek bir gen tarafından belirlenmediğini, tüm genoma yayılmış çoklu genlerce belirlendiğini düşündürmektedir. Erkek ve kadın beyni yapı ve işlevlerin farklı olması, endokrinolojik ve serotonin- dopamin düzeyinde ki farklılıklar cinsiyetler arasında CH etiyolojisinde etkili olabilir.

Anahtar Kelimeler

• cinsel kimlik
• çevresel stres
• nörobiyloji
• epigenetik

Kaynakça

1. Agana M, Greydanus D, Indyk J, Calles J, Kushner J, Leibowitz S et al. (2019) Caring for the transgender adolescent and young adult: Current concepts of an evolving process in the 21st century. Dis Mon, 65:303-356.
2. Akdemir A, Güriz O, Örsel S, Karaoğlan A (2006) Erkek pseudohermafroditizmi: Bir olgu sunumu. Klinik Psikiyatri Dergisi, 9:49-52.
3. APA (2013) Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5). Washington DC, American Psychiatric Association.
4. Arnoldussen M, Rooy FB, DeVries AL, Miesen AI, Popma A, Steensma TD(2022) Demographics and gender-related measures in younger and older adolescents presenting to a gender service. Eur Child Adolesc Psychiatry, doi: 10.1007/s00787-022-02082-8.
5. Avcı A,Önder Z, Sezgin F, Yüksel B (1996) Konjenital adrenal hiperplazide cinsel kimlik karmaşası: bir olgu sunumu. PsychoMed, 2:152-154.
6. Baba T, Endo T, Honnma H, Kitajima Y, Hayashi T, Ikeda Het al. (2007) Association between polycystic ovary syndrome and female-to-male transsexuality. Hum Reprod, 22:1011-1016.
7. Bailey JM, Dunne MP, Martin NG (2000) Genetic and environmental ınfluences on sexual orientation and ıts correlates in an australian twin sample. J Pers Soc Psychol, 78:524-536.
8. Beatrice A, Sumana K, Mengade MG (2019) Juvenile autoimmune hypothyroidism and gender dysphoria:a causal relationship or a casual coincidence?.Indian J Endocrinol Metab, 23:166-167.

9. Bentz EK, Hefler AL, Kaufmann U, Huber JC, Kolbus A, TempferCB (2008) A Polymorphism of the cyp17 gene related to sex steroid metabolism ıs associated with female-to-male but not male-to-female transsexualism. Fertil Steril, 90:56-59.
10. Blanchard R, Zucker KJ, Bradley SJ, Hume CS (1995) Birth order and sibling sex ratio in homosexual male adolescents and probably prehomosexual feminine boys. Dev Psychol, 31:22-30.
11. Carrel L, Willard HF (2005) X-ınactivation profile reveals extensive variability in X-linked gene expression in females.Nature, 434:400-404.
12. Cohen-Kettenis PT, Owen A, Kaijser VG, Bradley SJ, Zucker KJ (2003) Demographic characteristics, social competence, and behavior problems in children with gender identity disorder:a cross-national, cross-clinic comparative analysis. J Abnorm Child Psychol, 31:41-53.
13. Coolidge FL, Thede LL, Young SE (2002) The heritability of gender ıdentity disorder in a child and adolescent twin sample. Behav Genet, 32:251-257.
14. Daae E, Feragen KB, Waehre A, Nermoen I, Falhammar H(2020) Sexual orientation in individuals with congenital adrenal hyperplasia:a systematic review. Front Behav, 14:38.
15. Davies W, Isles AR, Burgoyne PS, Wilkinson LS (2006) X-linked imprinting: Effects on brain and behaviour. Bioessays, 28:35-44.
16. Diamond LM, and Butterworth M (2008) Questioning gender and sexual identity: Dynamic links over time. Sex Roles, 59:365-376.
17. Egan SK, Perry DG (2001) Gender identity: A multidimensional analysis with implications for psychosocial adjustment. Dev Psychol, 37:451-463.
18. Ellis L, Cole-Harding S (2001) The effects of prenatal stress, and of prenatal alcohol and nicotine exposure, on human sexual orientation. Physiol Behav, 74:213-226.
19. Fagot BI (1977) Teachers’ reinforcement of sex-preferred behaviors in Dutch preschools.Psychol Rep, 41:1249-1250.
20. Galambos NL, Almeida DM, Petersen AC (1990) Masculinity, femininity, and sex role attitudes in early adolescence:exploring gender ıntensification. Child Dev, 61:1905-1914.
21. Ganna A, Verweij KJ, Nivard MG, Maier R, Wedow R, Busch AS et al. (2019) Large-scale GWAS reveals insights into the genetic architecture of same-sex sexual behavior. Science, 365:112-114.
22. Gómez-Gil E, Esteva I, Almaraz MC, Pasaro E, Segovia S, Guillamon A (2009) Familiality of gender identity disorder in non-twin siblings. Arch Sex Behav, 39:546-552.
23. Gooren L(1990) The endocrinology of transsexualism:a review and commentary. Psychoneuroendocrinology, 15:3-14.
24. Green R (1976) One-hundred ten feminine and masculine boys:behavioral contrasts and demographic similarities. Arch Sex Behav, 5:425-446.
25. Green Rand Keverne EB (2000) The disparate maternal aunt-uncle ratio in male transsexuals:an explanation invoking genomic imprinting. J Theor Biol, 202:55-63.
26. Green R (2000) Family cooccurrence of ‘gender dysphoria’: ten sibling or parent–child pairs. Arch Sex Behav, 29:499-507.
27. Güneş H (2010)Demographic characteristics and behavior problems of childrens with gender identity problems and child rearing practices, marital and sexual adjustment and gender roles of their parents [Postgraduate thesis]. Istanbul, Istanbul University.
28. Hammack-Aviran C, Eilmus A, Diehl C, Gottlieb KG, Gonzales G, Davis LK et al. (2022) LGBTQ+ Perspectives on conducting genomic research on sexual orientation and gender identity. Behav Genet, 52:246-267.
29. Hengstschläger M, Trotsenburg MV, Repa C, Marton E, Huber JC, BernaschekG (2003) Sex chromosome aberrations and transsexualism. Fertil Steril, 79:639-640.
30. Henningsson S, Westberg L, Nilsson S, Lundström B, Ekselius L, Bodlund O et al. (2005) Sex steroid-related genes and male-to-female transsexualism. Psychoneuroendocrinology, 30:657-664.
31. Hill JP, Lynch ME (1983) The intensification of gender-related role expectations during early adolescence. In Girls at Puberty (Ed JB Gunn, AC Petersen):201-228. Boston, MA, Springer.
32. Hines M (2020) Neuroscience and sex/gender:looking back and forward. J Neurosci, 40:37-43.
33. Hines M, Ahmed SF, Hughes IA (2003) Psychological outcomes and gender-related development in complete androgen ınsensitivity syndrome. Arch Sex Behav, 32:93-101.
34. Holmes L, Watts-Overall TM, Slettevold E, Gruia DC, Raines J, Rieger G (2021) Sexual orientation, sexual arousal, and finger length ratios in women.Arch Sex Behav, 23:14-16.
35. Huser N, Hulswit BB,Koeller DR, Yashar BM (2022) Improving gender-affirming care in genetic counseling:Using educational tools that amplify transgender and/or gender non-binary community voices. J Genet Couns, 31:1102-1112.
36. Imperato-McGinley J, Guerrero L, Gautier T, Peterson RE (1974) Steroid 5alpha-reductase deficiency in man:An ınherited form of male pseudohermaphroditism. Science, 186:1213-1215.
37. Kassis W, Aksoy D, Favre AC, Artz ST(2021) Multidimensional and ıntersectional gender ıdentity and sexual attraction patterns of adolescents for quantitative research. Front Psychol, 12:112-114.
38. Knafo A, Spinath FM (2011) Genetic and environmental influences on girls’ and boys’ gender-typed and gender-neutral values. Dev Psychol, 47:726-731.
39. Kraemer B, Noll T, Delsignore A, Milos G, Schnyder U, Hepp U (2009) Finger length ratio (2D:4D) in adults with gender ıdentity disorder. Arch Sex Behav, 38:359-363.
40. Kruijver FP, Zhou JN, Pool CW, X Hofman MA, Gooren LJ, Swaab DF (2000) Male-to-female transsexuals have female neuron numbers in a limbic nucleus. J Clin Endocrinol Metab, 85:2034-2041.
41. Kruijver FP, Fernández-Guasti A, Fodor M, Kraan EM, Swaab DF (2001) Sex differences in androgen receptors of the human mamillary bodies are related to endocrine status rather than to sexual orientation or transsexuality. J Clin Endocrinol Metab, 86:818-827.
42. Kudwa AE, Michopoulos V, Gatewood JF, Rissman EF (2006) Roles of estrogen receptors alpha and beta in differentiation of mouse sexual behavior. Neuroscience, 138:921-928.
43. Leibowitz S, Chen D, Hidalgo MA (2016) Gender dysphoria and nonconformity. In Dulcan’s Textbook of Child and Adolescent Psychiatry: (Ed MK Dulcan): 585-602. Washington DC, American Psychiatric Publishing.
44. Leibowitz S, DeVries AL (2016) Gender dysphoria in adolescence. Int Rev Psychiatry, 28:21-35.
45. Manning, JT, Scutt D, Wilson J, Lewis-Jones DI (1998) The ratio of 2nd to 4th digit length: a predictor of sperm numbers and concentrations of testosterone, luteinizing hormone and oestrogen. Hum Reprod, 13:3000-3004.
46. Marantz S, Coates S (1991) Mothers of boys with gender ıdentity disorder:a comparison of matched controls. J Am Acad Child Adolesc Psychiatry, 30:310-315.
47. McKee EA (1976) Transsexualism: a selective review. South Med J, 69:185-187.
48. Mello Z, Worrell FC (2008) Gender variation in extracurricular activity participation and perceived life chances in Trinidad and Tobago adolescents. Psykhe (Santiago), 17:91-102.
49. Meyer-Bahlburg HF, Gruen RS, New MI, Bell JJ, Morishima A, Shimshi M, et al. (1996) Gender change from female to male in classical congenital adrenal hyperplasia. Horm Behav, 30:319-32.
50. Pagnotta FP (2022) Gender identity ın the contemporary age: it is often a suffered conquest. Psychiatr Danub, 34:112-114.
51. Pang KC, Feldman D, Oertel R, Telfer M (2018) Molecular karyotyping in children and adolescents with gender dysphoria. Transgender Health, 3:147-153.
52. Ramírez KD, Fernández R, Delgado-Zayas E, Gómez-Gil E, Esteva I, Guillamon A, et al. (2021) Implications of the estrogen receptor coactivators SRC1 and SRC2 in the biological basis of gender ıncongruence. Sex Med, 9:100368.
53. Reale C, Invernizzi F, Panteghini C, Garavaglia B (2021) Genetics, sex, and gender. J Neurosci Res, 34:112-114.
54. Reisner SL, Poteat T, Keatley JA, Cabral M, Mothopeng T, Dunham E et al. (2016) Global health burden and needs of transgender populations: A review. Lancet,388:412-436.
55. Rekers GA, Mead SL, Rosen AC, Brigham SL (1983) Family correlates of male childhood gender disturbance. J Genet Psychol, 142:31-42.
56. Rekers GA, Crandall BF, Rosen AC, Bentler PM (1979) Genetic and physical studies of male children with psychological gender disturbances. Psychol Med, 9:373-375.
57. Ristori J, Cocchetti C, Romani A, Mazzoli F, Vignozzi L, Maggi M et al. (2020) Brain sex differences related to gender identity development:genes or hormones? Int J Mol Sci, 21:112-114.
58. Romeo RD, McCarthy JM, Wang A, Milner TA, McEwen BS (2005) Sex differences in hippocampal estradiol-induced N-methyl-d-aspartic acid binding and ultrastructural localization of estrogen receptor-alpha. Neuroendocrinology, 81:391-399.
59. Ruigrok AN, Salimi-Khorshidi G, Lai MG, Baron-Cohen S, Lombardo MV, Tait RJ et al. (2014) A meta-analysis of sex differences in human brain structure. Neurosci Biobehav Rev, 39:34-50.
60. Sabuncuoglu O (2017) Towards a further understanding of prenatal thyroid theory of homosexuality:autoimmune thyroiditis, polycystic ovary syndrome, autism and low birth weight. Ment Illn, 9:7325.
61. Schwarz JM, McCarthy MM (2008) The role of neonatal nmda receptor activation in defeminization and masculinization of sex behavior in the rat. Horm Behav, 54:662-668.
62. Serbin LA, Poulin-Dubois D, Colburne KA, Sen MG, EichstedtJA (2001) Gender stereotyping in infancy:Visual preferences for and knowledge of gender-stereotyped toys in the second year. Int J Behav, 25:7-15.
63. Shumer DE, Nokoff NJ, Spack NP (2016) Advances in the care of transgender children and adolescents.Adv Pediatr, 63:79-102.
64. Slabbekoorn D, VanGoozen SH, Sanders G, Gooren LJ, Cohen-Kettenis PT (2000) The dermatoglyphic characteristics of transsexuals:ıs there evidence for an organizing effect of sex hormones. Psychoneuroendocrinology, 25:365-375.
65. Smolko AE, Shapiro-Kulnane L, Salz HK (2020) An autoregulatory switch in sex-specific phf7 transcription causes loss of sexual identity and tumors in the Drosophila female germline. Development, 147: dev192856.
66. Solbes-Canales I, Valverde-Montesino S, Herranz-Hernández P (2020) Socialization of gender stereotypes related to attributes and professions among young Spanish school-aged children. Front Psychol, 11:609.
67. Steensma TD, Kreukels BP, DeVries AL, Cohen-Kettenis PT (2013) Gender identity development in adolescence. Horm Behav, 64:288-297.
68. Swaab DF, Garcia-Falgueras A (2009) Sexual differentiation of the human brain in relation to gender identity and sexual orientation.Funct Neurol, 24:17-28.
69. Tetel MJ, Auger AP, Charlier TD (2009) Who’s in charge? Nuclear receptor coactivator and corepressor function in brain and behavior. Front Neuroendocrinol, 30:328-342.
70. Thomsen AH, Gaml-Sørensen A, Brix N, Ernst A, Lunddorf LL, Strandberg-Larsen K et al. (2022) Gender incongruence and timing of puberty:A population-based cohort study. Fertil Steril, 118:938-945.
71. Turan MT, Eşel E, Dündar M, Candemir Z, Baştürk M, Sofuoğlu S et al. (2000) Female-to-male transsexual with 47,XXX karyotype. Biol Psychiatry, 48:1116-1117.
72. Wallien MS, Quilty LC, Steensma TD, Singh D, Lambert SL, Leroux A et al. (2009) Cross-national replication of the gender identity interview for children. J Pers Assess, 91:545-552.
73. Wallien MS, Zucker KJ, Steensma TD, Cohen-Kettenis PT (2008) 2D:4D finger-length ratios in children and adults with gender identity disorder. Horm Behav, 54:450-454.
74. Wick JY, Zanni GR (2008) Hypochondria: the worried well. Consult Pharm, 23:192-208.
75. Wisniewski AB, Migeon CJ, Meyer-Bahlburg HF, Gearhart JP, Berkovitz GD, Brown TR et al. (2000) Complete androgen insensitivity syndrome:long-term medical, surgical, and psychosexual outcome. J Clin Endocrinol Metab, 85:2664-2669.
76. Wolfe SM (1990) Psychopathology and psychodynamics of parents of boys with a gender identity disorder of childhood (Doctoral thesis). New York, City University of New York.
77. Wright CL, Burks SR, McCarthy MM (2008) Identification of prostaglandin E2 receptors mediating perinatal masculinization of adult sex behavior and neuroanatomical correlates. Dev Neurobiol, 68:1406-1419.
78. Wu JB, Chen K, Li Y, Lau YC, Shih JC (2009) Regulation of monoamine oxidase A by the SRY gene on the Y chromosome. FASEB J, 23:4029-4038.
79. Zechner U, Wilda M, Kehrer-Sawatzki H, Vogel W, Fundele R, Hameister H (2001) A high density of X-linked genes for general cognitive ability: A run-away process shaping human evolution? Trends Genet, 17:697-701.
80. Zhou, JN, Hofman MA, Gooren LJ, Swaab DF (1995) A Sex difference in the human brain and ıts relation to transsexuality. Nature, 378:68-70.
81. Zosuls KM, Ruble DN , Tamis-Lemonda CS, Shrout PE, Bornstein MH, Greulich FK (2009) The acquisition of gender labels in infancy: Implications for gender-typed play. Dev Psychol, 45:688-701.
82. Zucker KJ, Green R, Coates S, Zuger B, Cohen-Kettenis PT, Zecca GMet al. (1997) Sibling sex ratio of boys with gender identity disorder. J Child Psychol Psychiatry, 38:543-551.
83. Zucker KJ (2017) Epidemiology of gender dysphoria and transgender identity. Sex Health, 14:404-411.