Skip to main content
SpringerLink
Log in

Genetic Aspects of Gender Identity Development and Gender Dysphoria

  • Chapter
  • First Online:
Gender Dysphoria and Disorders of Sex Development

Part of the book series: Focus on Sexuality Research ((FOSR))

Abstract

The development of gender identity, its variance, and gender dysphoria is thought to be a complex process involving biological and psychosocial factors. Heritability studies have demonstrated a genetic factor for the development of gender dysphoria. The brain is regarded as the anatomical substrate of gender identity, and sex differences of the brain are studied to elucidate the process of gender identity development. Many sex differences have been attributed to hormonal action, and the first genetic studies in transsexuals were focused on sex-steroid-related genes. To this day, a convincing candidate gene has not been identified, and it is now known that sex chromosomes have a direct effect on sex differentiation and that they may play a role in gender identity development. For future studies of the genetic base of gender dysphoria, new techniques, such as genome-wide studies, have become available. In addition, epigenetic studies may provide for a different association perspective of the genetics of gender dysphoria.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Agoulnik, I. U., Tong, X. W., Fischer, D. C., Korner, K., Atkinson, N. E., Edwards, D. P., et al. (2004). A germline variation in the progesterone receptor gene increases transcriptional activity and may modify ovarian cancer risk. Journal of Clinical Endocrinology and Metabolism, 89, 6340–6347.

    Article  PubMed  Google Scholar 

  • Akison, L. K., & Robker, R. L. (2012). The critical roles of progesterone receptor (PGR) in ovulation, oocyte developmental competence and oviductal transport in mammalian reproduction. Reproduction in Domestic Animals, 47(Suppl 4), 288–296.

    Article  PubMed  Google Scholar 

  • Andersson, S., Berman, D. M., Jenkins, E. P., & Russell, D. W. (1991). Deletion of steroid 5 alpha-reductase 2 gene in male pseudohermaphroditism. Nature, 354, 159–161.

    Article  PubMed  Google Scholar 

  • Ao, A., Erickson, R. P., Winston, R. M., & Handyside, A. H. (1994). Transcription of paternal Y-linked genes in the human zygote as early as the pronucleate stage. Zygote, 2, 281–287.

    Article  PubMed  Google Scholar 

  • Arnold, A. P. (1975). The effects of castration on song development in zebra finches (Poephila guttata). The Journal of Experimental Zoology, 191, 261–278.

    Article  PubMed  Google Scholar 

  • Arnold, A. P. (1996). Genetically triggered sexual differentiation of brain and behavior. Hormones and Behavior, 30, 495–505.

    Article  PubMed  Google Scholar 

  • Arnold, A. P. (1997). Sexual differentiation of the zebra finch song system: Positive evidence, negative evidence, null hypotheses, and a paradigm shift. Journal of Neurobiology, 33, 572–584.

    Article  PubMed  Google Scholar 

  • Arnold, A. P. (2009a). Mouse models for evaluating sex chromosome effects that cause sex differences in non-gonadal tissues. Journal of Neuroendocrinology, 21, 377–386.

    Article  PubMed  Google Scholar 

  • Arnold, A. P. (2009b). The organizational-activational hypothesis as the foundation for a unified theory of sexual differentiation of all mammalian tissues. Hormones and Behavior, 55, 570–578.

    Article  PubMed  Google Scholar 

  • Arnold, A. P., & Burgoyne, P. S. (2004). Are XX and XY brain cells intrinsically different? Trends in Endocrinology and Metabolism, 15, 6–11.

    Article  PubMed  Google Scholar 

  • Ascenzi, P., Bocedi, A., & Marino, M. (2006). Structure-function relationship of estrogen receptor alpha and beta: Impact on human health. Molecular Aspects of Medicine, 27, 299–402.

    Article  PubMed  Google Scholar 

  • Auchus, R. J., & Miller, W. L. (2012). Defects in androgen biosynthesis causing 46, XY disorders of sexual development. Seminars in Reproductive Medicine, 30, 417–426.

    Article  PubMed  Google Scholar 

  • Bailey, J. M., Dunne, M. P., & Martin, N. G. (2000). Genetic and environmental influences on sexual orientation and its correlates in an Australian twin sample. Journal of Personality and Social Psychology, 78, 524–536.

    Article  PubMed  Google Scholar 

  • Becker, J. (2008). Sex differences in the brain: From genes to behavior. Oxford: Oxford University Press.

    Google Scholar 

  • Belgorosky, A., Guercio, G., Pepe, C., Saraco, N., & Rivarola, M. A. (2009). Genetic and clinical spectrum of aromatase deficiency in infancy, childhood and adolescence. Hormones and Research, 72, 321–330.

    Article  Google Scholar 

  • Benbow, C. P., Lubinski, D., Shea, D. L., & Eftekhari-Sanjani, H. (2000). Sex differences in mathematical reasoning ability at age 13: Their status 20 years later. Psychological Science, 11, 474–480.

    Article  PubMed  Google Scholar 

  • Bentz, E. K., Hefler, L. A., Kaufmann, U., Huber, J. C., Kolbus, A., & Tempfer, C. B. (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, 56–59.

    Article  PubMed  Google Scholar 

  • Bentz, E. K., Schneeberger, C., Hefler, L. A., van Trotsenburg, M., Kaufmann, U., Huber, J. C., et al. (2007). A common polymorphism of the SRD5A2 gene and transsexualism. Reproductive Science, 14, 705–709.

    Article  Google Scholar 

  • Berstein, L. M., Imyanitov, E. N., Suspitsin, E. N., Grigoriev, M. Y., Sokolov, E. P., Togo, A., et al. (2001). CYP19 gene polymorphism in endometrial cancer patients. Journal of Cancer Research and Clinical Oncology, 127, 135–138.

    Article  PubMed  Google Scholar 

  • Blecher, S. R., & Erickson, R. P. (2007). Genetics of sexual development: A new paradigm. American Journal of Medical Genetics, 143A, 3054–3068.

    Article  PubMed  Google Scholar 

  • Boraska, V., Jeroncic, A., Colonna, V., Southam, L., Nyholt, D. R., Rayner, N. W., et al. (2012). Genome-wide meta-analysis of common variant differences between men and women. Human Molecular Genetics, 21, 4805–4815.

    Article  PubMed  Google Scholar 

  • Brinkmann, A. O., Klaasen, P., Kuiper, G. G., van der Korput, J. A., Bolt, J., de Boer, W., et al. (1989). Structure and function of the androgen receptor. Urological Research, 17, 87–93.

    Article  PubMed  Google Scholar 

  • Budefeld, T., Grgurevic, N., Tobet, S. A., & Majdic, G. (2008). Sex differences in brain developing in the presence or absence of gonads. Developmental Neurobiology, 68, 981–995.

    Article  PubMed  Google Scholar 

  • Budefeld, T., Jezek, D., Rozman, D., & Majdic, G. (2009). Initiation of steroidogenesis precedes expression of cholesterologenic enzymes in the fetal mouse testes. Anatomia, Histologia, Embryologia, 38, 461–466.

    Article  PubMed  Google Scholar 

  • Burri, A., Cherkas, L., Spector, T., & Rahman, Q. (2011). Genetic and environmental influences on female sexual orientation, childhood gender typicality and adult gender identity. PLoS One, 6, e21982.

    Article  PubMed  Google Scholar 

  • Carey, A. H., Waterworth, D., Patel, K., White, D., Little, J., Novelli, P., et al. (1994). Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17. Human Molecular Genetics, 3, 1873–1876.

    Article  PubMed  Google Scholar 

  • Cargill, M., Altshuler, D., Ireland, J., Sklar, P., Ardlie, K., Patil, N., et al. (1999). Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nature Genetics, 22, 231–238.

    Article  PubMed  Google Scholar 

  • Carruth, L. L., Reisert, I., & Arnold, A. P. (2002). Sex chromosome genes directly affect brain sexual differentiation. Nature Neuroscience, 5, 933–934.

    Article  PubMed  Google Scholar 

  • Chen, X., Watkins, R., Delot, E., Reliene, R., Schiestl, R. H., Burgoyne, P. S., et al. (2008). Sex difference in neural tube defects in p53-null mice is caused by differences in the complement of X not Y genes. Developmental Neurobiology, 68, 265–273.

    Article  PubMed  Google Scholar 

  • Chung, B. C., Picado-Leonard, J., Haniu, M., Bienkowski, M., Hall, P. F., Shively, J. E., et al. (1987). Cytochrome P450c17 (steroid 17 alpha-hydroxylase/17,20 lyase): Cloning of human adrenal and testis cDNAs indicates the same gene is expressed in both tissues. Proceedings of the National Academy of Sciences of the United States of America, 84, 407–411.

    Article  PubMed  Google Scholar 

  • 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, 251–257.

    Article  PubMed  Google Scholar 

  • Davis-Dao, C. A., Tuazon, E. D., Sokol, R. Z., & Cortessis, V. K. (2007). Male infertility and variation in CAG repeat length in the androgen receptor gene: A meta-analysis. Journal of Clinical Endocrinology and Metabolism, 92, 4319–4326.

    Article  PubMed  Google Scholar 

  • De Vivo, I., Huggins, G. S., Hankinson, S. E., Lescault, P. J., Boezen, M., Colditz, G. A., et al. (2002). A functional polymorphism in the promoter of the progesterone receptor gene associated with endometrial cancer risk. Proceedings of the National Academy of Sciences of the United States of America, 99, 12263–12268.

    Article  PubMed  Google Scholar 

  • De Vries, A. L. C., Doreleijers, T. A. H., & Cohen-Kettenis, P. T. (2007). Disorders of sex development and gender identity outcome in adolescence and adulthood: Understanding gender identity development and its clinical implications. Pediatric Endocrinology Reviews, 4, 343–351.

    PubMed  Google Scholar 

  • De Vries, G. J., Rissman, E. F., Simerly, R. B., Yang, L. Y., Scordalakes, E. M., Auger, C. J., et al. (2002). A model system for study of sex chromosome effects on sexually dimorphic neural and behavioral traits. Journal of Neuroscience, 22, 9005–9014.

    PubMed  Google Scholar 

  • Dewing, P., Chiang, C. W. K., Sinchak, K., Sim, H., Fernagut, P. O., Kelly, S., et al. (2006). Direct regulation of adult brain function by the male-specific factor SRY. Current Biology, 16, 415–420.

    Article  PubMed  Google Scholar 

  • Dunning, A. M., Healey, C. S., Pharoah, P. D., Teare, M. D., Ponder, B. A., & Easton, D. F. (1999). A systematic review of genetic polymorphisms and breast cancer risk. Cancer Epidemiology, Biomarkers and Prevention, 8, 843–854.

    PubMed  Google Scholar 

  • Fan, Y. S., Sasi, R., Lee, C., Winter, J. S., Waterman, M. R., & Lin, C. C. (1992). Localization of the human CYP17 gene (cytochrome P450(17 alpha)) to 10q24.3 by fluorescence in situ hybridization and simultaneous chromosome banding. Genomics, 14, 1110–1111.

    Article  PubMed  Google Scholar 

  • Feigelson, H. S., Shames, L. S., Pike, M. C., Coetzee, G. A., Stanczyk, F. Z., & Henderson, B. E. (1998). Cytochrome P450c17alpha gene (CYP17) polymorphism is associated with serum estrogen and progesterone concentrations. Cancer Research, 58, 585–587.

    PubMed  Google Scholar 

  • Fiddler, M., Abdel-Rahman, B., Rappolee, D. A., & Pergament, E. (1995). Expression of SRY transcripts in preimplantation human embryos. American Journal of Medical Genetics, 55, 80–84.

    Article  PubMed  Google Scholar 

  • Ford, C. E., Jones, K. W., Polani, P. E., De Almeida, J. C., & Briggs, J. H. (1959). A sex-chromosome anomaly in a case of gonadal dysgenesis (Turner’s syndrome). Lancet, 1, 711–713.

    Article  PubMed  Google Scholar 

  • Fuqua, S. A., Hill, S. M., Chamness, G. C., Benedix, M. G., Greene, G. L., O’Malley, B. W., et al. (1991). Progesterone receptor gene restriction fragment length polymorphisms in human breast tumors. Journal of the National Cancer Institute, 83, 1157–1160.

    Article  PubMed  Google Scholar 

  • Garcia-Falgueras, A., & Swaab, D. F. (2008). A sex difference in the hypothalamic uncinate nucleus: Relationship to gender identity. Brain, 131, 3132–3146.

    Article  PubMed  Google Scholar 

  • Gatewood, J. D., Wills, A., Shetty, S., Xu, J., Arnold, A. P., Burgoyne, P. S., et al. (2006). Sex chromosome complement and gonadal sex influence aggressive and parental behaviors in mice. Journal of Neuroscience, 26, 2335–2342.

    Article  PubMed  Google Scholar 

  • Giangrande, P. H., Pollio, G., & McDonnell, D. P. (1997). Mapping and characterization of the functional domains responsible for the differential activity of the A and B isoforms of the human progesterone receptor. Journal of Biological Chemistry, 272, 32889–32900.

    Article  PubMed  Google Scholar 

  • Goldstein, J. M., Seidman, L. J., Horton, N. J., Makris, N., Kennedy, D. N., Caviness, V. S., Jr., et al. (2001). Normal sexual dimorphism of the adult human brain assessed by in vivo magnetic resonance imaging. Cerebral Cortex, 11, 490–497.

    Article  PubMed  Google Scholar 

  • Graupp, M., Wehr, E., Schweighofer, N., Pieber, T. R., & Obermayer-Pietsch, B. (2011). Association of genetic variants in the two isoforms of 5alpha-reductase, SRD5A1 and SRD5A2, in lean patients with polycystic ovary syndrome. European Journal of Obstetrics, Gynecology, and Reproductive Biology, 157, 175–179.

    Article  PubMed  Google Scholar 

  • Green, R., & Keverne, E. B. (2000). The disparate maternal aunt-uncle ratio in male transsexuals: An explanation invoking genomic imprinting. Journal of Theoretical Biology, 202, 55–63.

    Article  PubMed  Google Scholar 

  • Gu, M., Dong, X., Zhang, X., & Niu, W. (2012). The CAG repeat polymorphism of androgen receptor gene and prostate cancer: A meta-analysis. Molecular Biological Reproduction, 39, 2615–2624.

    Article  Google Scholar 

  • Gurney, M. E., & Konishi, M. (1980). Hormone-induced sexual differentiation of brain and behavior in zebra finches. Science, 208, 1380–1383.

    Article  PubMed  Google Scholar 

  • Haiman, C. A., Hankinson, S. E., Spiegelman, D., De Vivo, I., Colditz, G. A., Willett, W. C., et al. (2000). A tetranucleotide repeat polymorphism in CYP19 and breast cancer risk. International Journal of Cancer, 87, 204–210.

    Article  Google Scholar 

  • Hare, L., Bernard, P., Sanchez, F. J., Baird, P. N., Vilain, E., Kennedy, T., et al. (2009). Androgen receptor repeat length polymorphism associated with male-to-female transsexualism. Biological Psychiatry, 65, 93–96.

    Article  PubMed  Google Scholar 

  • Hayek, A., Riccardi, V., Atkins, L., & Hendren, H. (1971). 49, XXXXY chromosomal anomaly in a neonate. Journal of Medical Genetics, 8, 220–221.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • Heylens, G., De Cuypere, G., Zucker, K. J., Schelfaut, C., Elaut, E., Vanden Bossche, H., et al. (2012). Gender identity disorder in twins: A review of the case report literature. The Journal of Sexual Medicine, 9, 751–757.

    Article  PubMed  Google Scholar 

  • Ikeda, Y., Shen, W. H., Ingraham, H. A., & Parker, K. L. (1994). Developmental expression of mouse steroidogenic factor-1, an essential regulator of the steroid hydroxylases. Molecular Endocrinology, 8, 654–662.

    Article  PubMed  Google Scholar 

  • Jacobs, P. A., & Strong, J. A. (1959). A case of human intersexuality having a possible XXY sex-determining mechanism. Nature, 183, 302–303.

    Article  PubMed  Google Scholar 

  • Jaenisch, R., & Bird, A. (2003). Epigenetic regulation of gene expression: How the genome integrates intrinsic and environmental signals. Nature Genetics, 33(Suppl), 245–254.

    Article  PubMed  Google Scholar 

  • Kagimoto, M., Winter, J. S., Kagimoto, K., Simpson, E. R., & Waterman, M. R. (1988). Structural characterization of normal and mutant human steroid 17 alpha-hydroxylase genes: Molecular basis of one example of combined 17 alpha-hydroxylase/17,20 lyase deficiency. Molecular Endocrinology, 2, 564–570.

    Article  PubMed  Google Scholar 

  • Knafo, A., Iervolino, A. C., & Plomin, R. (2005). Masculine girls and feminine boys: Genetic and environmental contributions to atypical gender development in early childhood. Journal of Personality and Social Psychology, 88, 400–412.

    Article  PubMed  Google Scholar 

  • Kos, M., Reid, G., Denger, S., & Gannon, F. (2001). Minireview: Genomic organization of the human ERalpha gene promoter region. Molecular Endocrinology, 15, 2057–2063.

    Article  PubMed  Google Scholar 

  • Kuiper, G. G., Enmark, E., Pelto-Huikko, M., Nilsson, S., & Gustafsson, J. A. (1996). Cloning of a novel receptor expressed in rat prostate and ovary. Proceedings of the National Academy of Sciences of the United States of America, 93, 5925–5930.

    Article  PubMed  Google Scholar 

  • Kurian, J. R., Olesen, K. M., & Auger, A. P. (2010). Sex differences in epigenetic regulation of the estrogen receptor-alpha promoter within the developing preoptic area. Endocrinology, 151, 2297–2305.

    Article  PubMed  Google Scholar 

  • Labrie, F., Sugimoto, Y., Luu-The, V., Simard, J., Lachance, Y., Bachvarov, D., et al. (1992). Structure of human type II 5 alpha-reductase gene. Endocrinology, 131, 1571–1573.

    Article  PubMed  Google Scholar 

  • Law, M. L., Kao, F. T., Wei, Q., Hartz, J. A., Greene, G. L., Zarucki-Schulz, T., et al. (1987). The progesterone receptor gene maps to human chromosome band 11q13, the site of the mammary oncogene int-2. Proceedings of the National Academy of Sciences of the United States of America, 84, 2877–2881.

    Article  PubMed  Google Scholar 

  • Li, J., Coates, R. J., Gwinn, M., & Khoury, M. J. (2010). Steroid 5-{alpha}-reductase Type 2 (SRD5a2) gene polymorphisms and risk of prostate cancer: A HuGE review. American Journal of Epidemiology, 171, 1–13.

    Article  PubMed  Google Scholar 

  • Lin, L. H., Baracat, M. C. P., Maciel, G. A. R., Soares, J. M. J., & Baracat, E. C. (2013). Androgen receptor gene polymorphism and polycystic ovary syndrome. International Journal of Gynaecology and Obstetrics, 120, 115–118.

    Article  PubMed  Google Scholar 

  • Lin, L., Ercan, O., Raza, J., Burren, C. P., Creighton, S. M., Auchus, R. J., et al. (2007). Variable phenotypes associated with aromatase (CYP19) insufficiency in humans. Journal of Clinical Endocrinology and Metabolism, 92, 982–990.

    Article  PubMed  Google Scholar 

  • Lippa, R., & Hershberger, S. (1999). Genetic and environmental influences on individual differences in masculinity, femininity, and gender diagnosticity: Analyzing data from a classic twin study. Journal of Personality, 67, 127–155.

    Article  PubMed  Google Scholar 

  • Loehlin, J. C., & Nichols, R. C. (1976). Heredity, environment, and personality: A study of 850 sets of twins. Austin: University of Texas Press.

    Article  PubMed  Google Scholar 

  • Loehlin, J. C., Jonsson, E. G., Gustavsson, J. P., Stallings, M. C., Gillespie, N. A., Wright, M. J., et al. (2005). Psychological masculinity-femininity via the gender diagnosticity approach: Heritability and consistency across ages and populations. Journal of Personality, 73, 1295–1319.

    Article  PubMed  Google Scholar 

  • Makridakis, N., Ross, R. K., Pike, M. C., Chang, L., Stanczyk, F. Z., Kolonel, L. N., et al. (1997). A prevalent missense substitution that modulates activity of prostatic steroid 5alpha-reductase. Cancer Research, 57, 1020–1022.

    PubMed  Google Scholar 

  • Masi, L., Becherini, L., Gennari, L., Amedei, A., Colli, E., Falchetti, A., et al. (2001). Polymorphism of the aromatase gene in postmenopausal Italian women: Distribution and correlation with bone mass and fracture risk. Journal of Clinical Endocrinology and Metabolism, 86, 2263–2269.

    Article  PubMed  Google Scholar 

  • Mayer, A., Mosler, G., Just, W., Pilgrim, C., & Reisert, I. (2000). Developmental profile of Sry transcripts in mouse brain. Neurogenetics, 3, 25–30.

    Article  PubMed  Google Scholar 

  • McCarthy, M. M., Arnold, A. P., Ball, G. F., Blaustein, J. D., & De Vries, G. J. (2012). Sex differences in the brain: The not so inconvenient truth. Journal of Neuroscience, 32, 2241–2247.

    Article  PubMed  Google Scholar 

  • McCauley, E., Feuillan, P., Kushner, H., & Ross, J. L. (2001). Psychosocial development in adolescents with Turner syndrome. Journal of Developmental and Behavioral Pediatrics, 22, 360–365.

    Article  PubMed  Google Scholar 

  • Means, G. D., Mahendroo, M. S., Corbin, C. J., Mathis, J. M., Powell, F. E., Mendelson, C. R., et al. (1989). Structural analysis of the gene encoding human aromatase cytochrome P-450, the enzyme responsible for estrogen biosynthesis. Journal of Biological Chemistry, 264, 19385–19391.

    PubMed  Google Scholar 

  • Menger, Y., Bettscheider, M., Murgatroyd, C., & Spengler, D. (2010). Sex differences in brain epigenetics. Epigenomics, 2, 807–821.

    Article  PubMed  Google Scholar 

  • Migeon, B. R. (2007). Why females are mosaics, X-chromosome inactivation, and sex differences in disease. Gender Medicine, 4, 97–105.

    Article  PubMed  Google Scholar 

  • Miller, W. L. (2005). Minireview: Regulation of steroidogenesis by electron transfer. Endocrinology, 146, 2544–2550.

    Article  PubMed  Google Scholar 

  • Miller, W. L., & Auchus, R. J. (2011). The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocrine Reviews, 32, 81–151.

    Article  PubMed  Google Scholar 

  • Montelli, S., Peruffo, A., Zambenedetti, P., Rossipal, E., Giacomello, M., Zatta, P., et al. (2012). Expression of aromatase P450(AROM) in the human fetal and early postnatal cerebral cortex. Brain Research, 1475, 11–18.

    Article  PubMed  Google Scholar 

  • Ngun, T. C., Ghahramani, N., Sanchez, F. J., Bocklandt, S., & Vilain, E. (2011). The genetics of sex differences in brain and behavior. Frontiers in Neuroendocrinology, 32, 227–246.

    Article  PubMed  Google Scholar 

  • Ogawa, S., Hosoi, T., Shiraki, M., Orimo, H., Emi, M., Muramatsu, M., et al. (2000). Association of estrogen receptor beta gene polymorphism with bone mineral density. Biochemical and Biophysical Research Communications, 269, 537–541.

    Article  PubMed  Google Scholar 

  • Osterlund, M. K., Gustafsson, J. A., Keller, E., & Hurd, Y. L. (2000). Estrogen receptor beta (ERbeta) messenger ribonucleic acid (mRNA) expression within the human forebrain: Distinct distribution pattern to ERalpha mRNA. Journal of Clinical Endocrinology and Metabolism, 85, 3840–3846.

    Article  PubMed  Google Scholar 

  • Palazzolo, I., Gliozzi, A., Rusmini, P., Sau, D., Crippa, V., Simonini, F., et al. (2008). The role of the polyglutamine tract in androgen receptor. The Journal of Steroid Biochemistry and Molecular Biology, 108, 245–253.

    Article  PubMed  Google Scholar 

  • Pergament, E., Fiddler, M., Cho, N., Johnson, D., & Holmgren, W. J. (1994). Sexual differentiation and preimplantation cell growth. Human Reproduction, 9, 1730–1732.

    PubMed  Google Scholar 

  • Petry, C. J., Ong, K. K., Michelmore, K. F., Artigas, S., Wingate, D. L., Balen, A. H., et al. (2005). Association of aromatase (CYP 19) gene variation with features of hyperandrogenism in two populations of young women. Human Reproduction, 20, 1837–1843.

    Article  PubMed  Google Scholar 

  • Polymeropoulos, M. H., Xiao, H., Rath, D. S., & Merril, C. R. (1991). Tetranucleotide repeat polymorphism at the human aromatase cytochrome P-450 gene (CYP19). Nucleic Acids Research, 19, 195.

    Article  PubMed  Google Scholar 

  • Quadros, P. S., & Wagner, C. K. (2008). Regulation of progesterone receptor expression by estradiol is dependent on age, sex and region in the rat brain. Endocrinology, 149, 3054–3061.

    Article  PubMed  Google Scholar 

  • Reik, W. (2007). Stability and flexibility of epigenetic gene regulation in mammalian development. Nature, 447, 425–432.

    Article  PubMed  Google Scholar 

  • Reisert, I., & Pilgrim, C. (1991). Sexual differentiation of monoaminergic neurons—genetic or epigenetic? Trends in Neuroscience, 14, 468–473.

    Article  Google Scholar 

  • Roselli, C. E., Abdelgadir, S. E., & Resko, J. A. (1997). Regulation of aromatase gene expression in the adult rat brain. Brain Research Bulletin, 44, 351–357.

    Article  PubMed  Google Scholar 

  • Rubin, R. T., Sekula, L. K., O’Toole, S., Rhodes, M. E., & Czambel, R. K. (1999). Pituitary-adrenal cortical responses to low-dose physostigmine and arginine vasopressin administration in normal women and men. Neuropsychopharmacology, 20, 434–446.

    Article  PubMed  Google Scholar 

  • Schallert, T., Fleming, S. M., Leasure, J. L., Tillerson, J. L., & Bland, S. T. (2000). CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury. Neuropharmacology, 39, 777–787.

    Article  PubMed  Google Scholar 

  • Schlinger, B. A., & Arnold, A. P. (1991). Androgen effects on the development of the zebra finch song system. Brain Research, 561, 99–105.

    Article  PubMed  Google Scholar 

  • Simanainen, U., Brogley, M., Gao, Y. R., Jimenez, M., Harwood, D. T., Handelsman, D. J., et al. (2011). Length of the human androgen receptor glutamine tract determines androgen sensitivity in vivo. Molecular Cell Endocrinology, 342, 81–86.

    Article  Google Scholar 

  • Skuse, D. H. (2000). Imprinting, the X-chromosome, and the male brain: Explaining sex differences in the liability to autism. Pediatric Research, 47, 9–16.

    Article  PubMed  Google Scholar 

  • Skuse, D. H., James, R. S., Bishop, D. V., Coppin, B., Dalton, P., Damodt-Leeper, G., et al. (1997). Evidence from Turner’s syndrome of an imprinted X-linked locus affecting cognitive function. Nature, 387, 705–708.

    Article  PubMed  Google Scholar 

  • Sleddens, H. F., Oostra, B. A., Brinkmann, A. O., & Trapman, J. (1992). Trinucleotide repeat polymorphism in the androgen receptor gene (AR). Nucleic Acids Research, 20, 1427.

    Article  PubMed  Google Scholar 

  • Sundermann, E. E., Maki, P. M., & Bishop, J. R. (2010). A review of estrogen receptor alpha gene (ESR1) polymorphisms, mood, and cognition. Menopause, 17, 874–886.

    Article  PubMed  Google Scholar 

  • Ter Horst, G. J. (2010). Estrogen in the limbic system. Vitamins and Hormones, 82, 319–338.

    Article  PubMed  Google Scholar 

  • Thai, H. T. T., Kalbasi, M., Lagerstedt, K., Frisen, L., Kockum, I., & Nordenskjold, A. (2005). The valine allele of the V89L polymorphism in the 5-alpha-reductase gene confers a reduced risk for hypospadias. Journal of Clinical Endocrinology and Metabolism, 90, 6695–6698.

    Article  PubMed  Google Scholar 

  • Trapman, J., Klaassen, P., Kuiper, G. G., van der Korput, J. A., Faber, P. W., van Rooij, H. C., et al. (1988). Cloning, structure and expression of a cDNA encoding the human androgen receptor. Biochemical and Biophysical Research Communications, 153, 241–248.

    Article  PubMed  Google Scholar 

  • 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. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 33, 1241–1244.

    Article  PubMed  Google Scholar 

  • Van Beijsterveldt, C. E. M., Hudziak, J. J., & Boomsma, D. I. (2006). Genetic and environmental influences on cross-gender behavior and relation to behavior problems: A study of Dutch twins at ages 7 and 10 years. Archives of Sexual Behavior, 35, 647–658.

    Article  PubMed  Google Scholar 

  • Van Den Akker, E. L. T., Koper, J. W., Boehmer, A. L. M., Themmen, A. P. N., Verhoef-Post, M., Timmerman, M. A., et al. (2002). Differential inhibition of 17alpha-hydroxylase and 17,20-lyase activities by three novel missense CYP17 mutations identified in patients with P450c17 deficiency. Journal of Clinical Endocrinology and Metabolism, 87, 5714–5721.

    Article  Google Scholar 

  • Van Pottelbergh, I., Goemaere, S., & Kaufman, J. M. (2003). Bioavailable estradiol and an aromatase gene polymorphism are determinants of bone mineral density changes in men over 70 years of age. Journal of Clinical Endocrinology and Metabolism, 88, 3075–3081.

    Article  PubMed  Google Scholar 

  • Voorhoeve, P. G., van Mechelen, W., Uitterlinden, A. G., Delemarre-van de Waal, H., & Lamberts, S. W. J. (2011). Androgen receptor gene CAG repeat polymorphism in longitudinal height and body composition in children and adolescents. Clinical Endocrinology (Oxf), 74, 732–735.

    Article  Google Scholar 

  • Voyer, D., Voyer, S., & Bryden, M. P. (1995). Magnitude of sex differences in spatial abilities: A meta-analysis and consideration of critical variables. Psychological Bulletin, 117, 250–270.

    Article  PubMed  Google Scholar 

  • Weisz, J., & Ward, I. L. (1980). Plasma testosterone and progesterone titers of pregnant rats, their male and female fetuses, and neonatal offspring. Endocrinology, 106, 306–316.

    Article  PubMed  Google Scholar 

  • Werner, R., Holterhus, P. M., Binder, G., Schwarz, H. P., Morlot, M., Struve, D., et al. (2006). The A645D mutation in the hinge region of the human androgen receptor (AR) gene modulates AR activity, depending on the context of the polymorphic glutamine and glycine repeats. Journal of Clinical Endocrinology and Metabolism, 91, 3515–3520.

    Article  PubMed  Google Scholar 

  • 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. Journal of Clinical Endocrinology and Metabolism, 86, 2562–2568.

    Article  PubMed  Google Scholar 

  • Westberg, L., & Eriksson, E. (2008). Sex steroid-related candidate genes in psychiatric disorders. Journal of Psychiatry and Neuroscience, 33, 319–330.

    PubMed  Google Scholar 

  • Wilson, J. D., Griffin, J. E., & Russell, D. W. (1993). Steroid 5 alpha-reductase 2 deficiency. Endocrine Reviews, 14, 577–593.

    PubMed  Google Scholar 

  • Zhang, W., & Yu, Y. Y. (2007). Polymorphisms of short tandem repeat of genes and breast cancer susceptibility. European Journal of Surgical Oncology, 33, 529–534.

    Article  PubMed  Google Scholar 

  • Zhou, J. N., Hofman, M. A., Gooren, L. J., & Swaab, D. F. (1995). A sex difference in the human brain and its relation to transsexuality. Nature, 378, 68–70.

    Article  PubMed  Google Scholar 

  • Zwingman, T., Erickson, R. P., Boyer, T., & Ao, A. (1993). Transcription of the sex-determining region genes Sry and Zfy in the mouse preimplantation embryo. Proceedings of the National Academy of Sciences of the United States of America, 90, 814–817.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatric Endocrinology, Center of Expertise on Gender Dysphoria, VU University Medical Center, 7057, 1007 MB, Amsterdam, The Netherlands

    Daniel Klink M.D., Ph.D.

  2. Department of Endocrinology, Center of Expertise on Gender Dysphoria, VU University Medical Center, 7057, 1007 MB, Amsterdam, The Netherlands

    Martin Den Heijer M.D., Ph.D.

  3. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands

    Martin Den Heijer M.D., Ph.D.

Authors
  1. Martin Den Heijer M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniel Klink M.D., Ph.D. .

Editor information

Editors and Affiliations

  1. Center of Expertise on Gender Dysphoria, Department of Medical Psychology, VU University Medical Center, ...., Amsterdam, 1007 MB, Netherlands

    Baudewijntje P.C. Kreukels

  2. Center of Expertise on Gender Dysphoria, Department of Medical Psychology, VU University Medical Center, Amsterdam, 1007 MB, Netherlands

    Thomas D. Steensma

  3. Center of Expertise on Gender Dysphoria, Department of Child and Adolescent Psych, VU University Medical Center, P.O. Box 7057, Amsterdam, 1007 MB, Netherlands

    Annelou L.C. de Vries

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Klink, D., Den Heijer, M. (2014). Genetic Aspects of Gender Identity Development and Gender Dysphoria. In: Kreukels, B., Steensma, T., de Vries, A. (eds) Gender Dysphoria and Disorders of Sex Development. Focus on Sexuality Research. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-7441-8_2

Download citation

Publish with us

Policies and ethics

Search

Navigation