pp 1-23 | Cite as

The Sexual Differentiation of the Human Brain: Role of Sex Hormones Versus Sex Chromosomes

  • Julie BakkerEmail author
Part of the Current Topics in Behavioral Neurosciences book series


Men and women differ, not only in their anatomy but also in their behavior. Research using animal models has convincingly shown that sex differences in the brain and behavior are induced by sex hormones during a specific, hormone-sensitive period during early development. Thus, male-typical psychosexual characteristics seem to develop under the influence of testosterone, mostly acting during early development. By contrast, female-typical psychosexual characteristics may actually be organized under the influence of estradiol during a specific prepubertal period. The sexual differentiation of the human brain also seems to proceed predominantly under the influence of sex hormones. Recent studies using magnetic resonance imaging have shown that several sexually differentiated aspects of brain structure and function are female-typical in women with complete androgen insensitivity syndrome (CAIS), who have a 46 XY karyotype but a female phenotype due to complete androgen resistance, suggesting that these sex differences most likely reflect androgen action, although feminizing effects of estrogens or female-typical socialization cannot be ruled out. By contrast, some male-typical neural characteristics were also observed in women with CAIS suggesting direct effects of sex chromosome genes in the sexual differentiation of the human brain. In conclusion, the sexual differentiation of the human brain is most likely a multifactorial process including both sex hormone and sex chromosome effects, acting in parallel or in combination.


Androgens Brain function Brain structure Complete androgen insensitivity syndrome Estrogens Magnetic resonance imaging Sex differences Sexual development 


  1. Allen LS, Hines M, Shryne JE, Gorski RA (1989) Two sexually dimorphic cell groups in the human brain. J Neurosci 9:497–506Google Scholar
  2. Arnold AP (2017) A general theory of sexual differentiation. J Neurosci Res 95:291–300Google Scholar
  3. Arnold AP, Chen X (2009) What does the “four core genotypes” mouse model tell us about sex differences in the brain and other tissues? Front Neuroendocrinol 30:1–9Google Scholar
  4. Arnold AP, Xu J, Grisham W, Chen X, Kim YH, Itoh Y (2004) Minireview: sex chromosomes and brain sexual differentiation. Endocrinology 145:1057–1062Google Scholar
  5. Babak T, DeVeale B, Tsang EK, Zhou Y, Li X, Smith KS, Kukurba KR, Zhang R, Li JB, van der Kooy D, Montgomery SB, Fraser HB (2015) Genetic conflict reflected in tissue-specific maps of genomic imprinting in human and mouse. Nat Genet 47:544–549Google Scholar
  6. Bakker J, Honda S, Harada N, Balthazart J (2002) The aromatase knockout mouse provides new evidence that estradiol is required during development for the expression of sociosexual behaviors in adulthood. J Neurosci 22:9104–9112Google Scholar
  7. Bakker J, De Mees C, Douhard Q, Balthazart J, Gabant P, Szpirer J, Szpirer C (2006) Alpha-fetoprotein protects the developing female mouse brain from masculinization and defeminization by estrogens. Nat Neurosci 9:220–226Google Scholar
  8. Balthazart J, Ball G (2012) Brain aromatase, estrogens, and behavior. Oxford University Press, OxfordGoogle Scholar
  9. Bao A-M, Swaab DF (2011) Sexual differentiation of the human brain: relation to gender identity, sexual orientation and neuropsychiatric disorders. Front Neuroendocrinol 32:214–226Google Scholar
  10. Baum MJ (1979) Differentiation of coital behavior in mammals: a comparative analysis. Neurosci Biobehav Rev 3:265–284Google Scholar
  11. Baum MJ (2006) Mammalian animal models of psychosexual differentiation: when is translation to the human situation possible? Horm Behav 50:579–588Google Scholar
  12. Berenbaum SA, Bryk KK, Nowak N, Quigley CA, Moffat S (2009) Fingers as a marker of prenatal androgen exposure. Endocrinology 150:5119–5124Google Scholar
  13. Berenbaum SA, Bryk KLK, Beltz AM (2012) Early androgen effects on spatial and mechanical abilities: evidence from congenital adrenal hyperplasia. Behav Neurosci 126:86–96Google Scholar
  14. Bertelloni S, Dati E, Baroncelli GI, Hiort O (2011) Hormonal management of complete androgen insensitivity syndrome from adolescence onward. Horm Res Paediatr 76:428–433Google Scholar
  15. Boehmer AL, Brüggenwirth H, van Assendelft C, Otten BJ, Verleun-Mooijman MC, Niermeijer MF, Brunner HG, Rouwé CW, Waelkens JJ, Oostdijk W, Kleijer WJ, van der Kwast TH, de Vroede MA, Drop SL (2001) Genotype versus phenotype in families with androgen insensitivity syndrome. J Clin Endocrinol Metab 86:4151–4160Google Scholar
  16. Breedlove SM (2017) Prenatal influences on human sexual orientation: expectations versus data. Arch Sex Behav 46:1583–1592Google Scholar
  17. Brock O, Douhard Q, Baum MJ, Bakker J (2010) Reduced prepubertal expression of progesterone receptor in the hypothalamus of female aromatase knockout mice. Endocrinology 151:1814–1821Google Scholar
  18. Brock O, Baum MJ, Bakker J (2011) The development of female sexual behavior requires prepubertal estradiol. J Neurosci 31:5574–5578Google Scholar
  19. Brunner F, Fliegner M, Krupp K, Rall K, Brucker S, Richter-Appelt H (2016) Gender role, gender identity and sexual orientation in CAIS (“XY-women”) compared with subfertile and infertile 46,XX women. J Sex Res 53:109–124Google Scholar
  20. Butler T, Imperato-McGinley J, Pan H, Voyer D, Cordero J, Zhu Y-S, Stern E, Silbersweig D (2006) Sex differences in mental rotation: top-down versus bottom-up processing. NeuroImage 32:445–456Google Scholar
  21. Byne W, Tobet S, Mattiace LA, Lasco MS, Kemether E, Edgar MA, Morgello S, Buchsbaum MS, Jones LB (2001) The interstitial nuclei of the human anterior hypothalamus: an investigation of variation with sex, sexual orientation, and HIV status. Horm Behav 40:86–92Google Scholar
  22. Carrel L, Willard HF (2005) X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434:400–404Google Scholar
  23. Carrel L, Cottle AA, Goglin KC, Willard HF (1999) A first-generation X-inactivation profile of the human X chromosome. Proc Natl Acad Sci U S A 96:14440–14444Google Scholar
  24. Chang SC, Tucker T, Thorogood NP, Brown CJ (2006) Mechanisms of X-chromosome inactivation. Front Biosci 11:852–866Google Scholar
  25. Chou K-H, Cheng Y, Chen I-Y, Lin C-P, Chu W-C (2011) Sex-linked white matter microstructure of the social and analytic brain. NeuroImage 54:725–733Google Scholar
  26. Collaer ML, Hines M (1995) Human behavioral sex differences: a role for gonadal hormones during early development? Psychol Bull 118:55–107Google Scholar
  27. Connor JM, Serbin LA (1977) Behaviorally based masculine- and feminine-activity-preference scales for preschoolers: correlates with other classroom behaviors and cognitive tests. Child Dev 48:1411–1416Google Scholar
  28. Cools M, Drop SLS, Wolffenbuttel KP, Oosterhuis JW, Looijenga LHJ (2006) Germ cell tumors in the intersex gonad: old paths, new directions, moving frontiers. Endocr Rev 27:468–484Google Scholar
  29. Corre C, Friedel M, Vousden DA, Metcalf A, Spring S, Qiu LR, Lerc JP, Palmert MR (2016) Separate effects of sex hormones and sex chromosomes on brain structure and function revealed by high-resolution magnetic resonance imaging and spatial navigation of the Four Core Genotype mouse model. Brain Struct Funct 221:997–1016Google Scholar
  30. Cosgrove KP, Mazure CM, Staley JK (2007) Evolving knowledge of sex differences in brain structure, function, and chemistry. Biol Psychiatry 62:847–855Google Scholar
  31. Davis H (1983) An active process in cochlear mechanics. Hear Res 9:79–90Google Scholar
  32. Davis SM, Rogol AD, Ross JL (2015) Testis development and fertility potential in boys with klinefelter syndrome. Endocrinol Metab Clin N Am 44:843–865Google Scholar
  33. de Vries GJ, Rissman EF, Simerly EB, Yang LY, Scordalakes EM, Auger CJ, Swain A, Lovell-Badge R, Burgoyne PS, Arnold AP (2002) A model system for sex chromosome effects on sexually dimorphic neural and behavioral traits. J Neurosci 22:9005–9014Google Scholar
  34. DeLisi LE, Maurizio AM, Svetina C, Ardekani B, Szulc K, Nierenberg J, Leonard J, Harvey PD (2005) Klinefelter’s syndrome (XXY) as a genetic model for psychotic disorders. Am J Med Genet B Neuropsychiatr Genet 135B:15–23Google Scholar
  35. Dewing P, Chiang CWK, Sinchak K, Sim H, Fernagut P-O, Kelly S, Chesselet M-F, Micevych PE, Albrecht KH, Harley VR, Vilain E (2006) Direct regulation of adult brain function by the male specific factor SRY. Curr Biol 16:415–420Google Scholar
  36. Disteche CM (2012) Dosage compensation of the sex chromosomes. Annu Rev Genet 46:537–560Google Scholar
  37. Doehnert U, Bertelloni S, Werner R, Dati E, Hiort O (2015) Characteristic features of reproductive hormone profiles in late adolescent and adult females with complete androgen insensitivity syndrome. Sex Dev 9:69–74Google Scholar
  38. Dörner G (1988) Neuroendocrine response to estrogen and brain differentiation in heterosexuals, homosexuals, and transsexuals. Arch Sex Behav 17:57–75Google Scholar
  39. Downey J, Ehrhardt AA, Gruen R, Bell JJ, Morishima A (1989) Psychopathology and social functioning in women with Turner syndrome. J Nerv Ment Dis 177:191–201Google Scholar
  40. Feder HH, Whalen RE (1964) Feminine behavior in neonatally castrated and estrogen-treated male rats. Science 147:306–307Google Scholar
  41. Feng J, Spence I, Pratt J (2007) Playing an action video game reduces gender differences in spatial cognition. Psychol Sci 18:850–855Google Scholar
  42. Finkelstein JS, Lee H, Burnett-Bowie SA, Pallais JC, Yu EW, Borges LF, Jones BF, Barry CV, Wulczyn KE, Thomas BJ, Leder BZ (2013) Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med 369:1011–1022Google Scholar
  43. Garcia-Falgueras A, Swaab DF (2008) A sex difference in the hypothalamic uncinate nucleus: relationship to gender identity. Brain 131:3132–3146Google Scholar
  44. Gizewski ER, Krause E, Wanke I, Forsting M, Senf W (2006) Gender-specific cerebral activation during cognitive tasks using functional MRI: comparison of women in mid-luteal phase and men. Neuroradiology 48:14–20Google Scholar
  45. Gizewski ER, Krause E, Schlamann M, Happich F, Ladd ME, Forsting M, Senf W (2009) Specific cerebral activation due to visual erotic stimuli in male-to-female transsexuals compared with male and female controls: an fMRI study. J Sex Med 6:440–448Google Scholar
  46. Gong G, He Y, Evans AC (2011) Brain connectivity: gender makes a difference. Neuroscientist 17:575–591Google Scholar
  47. Grady KL, Phoenix CH, Young WC (1965) Role of the developing rat testis in differentiation of the neural tissues mediating mating behavior. J Comp Physiol Psychol 59:176–182Google Scholar
  48. Halari R, Hines M, Kumari V, Mehrotra R, Wheeler M, Ng V, Sharma T (2005) Sex differences and individual differences in cognitive performance and their relationship to endogenous gonadal hormones and gonadotropins. Behav Neurosci 119:104–117Google Scholar
  49. Hamann S, Herman RA, Nolan CL, Wallen K (2004) Men and women differ in amygdala response to visual sexual stimuli. Nat Neurosci 7:411–416Google Scholar
  50. Hamann S, Stevens J, Vick JH, Bryk K, Quigley CA, Berenbaum SA, Wallen K (2014) Brain responses to sexual images in 46XY, women with complete androgen insensitivity syndrome are female-typical. Horm Behav 66:724–730Google Scholar
  51. Hare L, Bernard P, Sanchez FJ, Baird PN, Vilain E, Kennedy T, Harley VR (2009) Androgen receptor repeat length polymorphism associated with male-to-female transsexualism. Biol Psychiatry 65:93–96Google Scholar
  52. Hausmann M, Schoofs D, Rosenthal HES, Jordan K (2009) Interactive effects of sex hormones and gender stereotypes on cognitive sex differences – a psychobiosocial approach. Psychoneuroendocrinology 34:389–401Google Scholar
  53. Hier DB, Crowley WF (1982) Spatial ability in androgen-deficient men. N Engl J Med 306:1202–1205Google Scholar
  54. Hines M, Ahmed SF, Hughes IA (2003) Psychological outcomes and gender-related development in complete androgen insensitivity syndrome. Arch Sex Behav 32:93–101Google Scholar
  55. Hines M, Pasterski V, Spencer D, Neufeld S, Patalay P, Hindmarsh PC, Hughes IA, Acerini CL (2016) Prenatal androgen exposure alters girls’ responses to information regarding gender-appropriate behaviour. Philos Trans R Soc B Biol Sci 371:20150125Google Scholar
  56. Holzapfel M, Barnea-Goraly N, Eckert MA, Kesler SR, Reiss AL (2006) Selective alterations of white matter associated with visuospatial and sensorimotor dysfunction in Turner syndrome. J Neurosci 26:7007–7013Google Scholar
  57. Hönekopp J, Watson S (2010) Meta-analysis of digit ratio 2D:4D shows greater sex difference in the right hand. Am J Hum Biol 22:619–630Google Scholar
  58. Hoppe C, Fliessbach K, Stausberg S, Stojanovic J, Trautner P, Elger CE, Weber B (2012) A key role for experimental task performance: effects of math talent, gender and performance on the neural correlates of mental rotation. Brain Cogn 78:14–27Google Scholar
  59. Hsiao PW, Lin DL, Nakao R, Chang C (1999) The linkage of Kennedy’s neuron disease to ARA24, the first identified androgen receptor polyglutamine region-associated coactivator. J Biol Chem 274:20229–20234Google Scholar
  60. Hughes IA, Deeb A (2006) Androgen resistance. Best Pract Res Clin Endocrinol Metab 20:577–598Google Scholar
  61. Hughes IA, Houk C, Ahmed SF, Lee PA (2006) Consensus statement on management of intersex disorders. J Pediatr Urol 2:148–162Google Scholar
  62. Hughes IA, Davies JD, Bunch TI, Pasterski V, Mastroyannopoulou K, MacDougall J (2012) Androgen insensitivity syndrome. Lancet 380:1419–1428Google Scholar
  63. Imperato-McGinley J, Pichardo M, Gautier T, Voyer D, Bryden MP (1991) Cognitive abilities in androgen-insensitive subjects: comparison with control males and females from the same kindred. Clin Endocrinol 34:341–347Google Scholar
  64. Inano S, Takao H, Hayashi N, Abe O, Ohtomo K (2011) Effects of age and gender on white matter integrity. AJNR Am J Neuroradiol 32:2103–2109Google Scholar
  65. Irvine RA, Ma H, Yu MC, Ross RK, Stallcup MR, Coetzee GA (2000) Inhibition of p160-mediated coactivation with increasing androgen receptor polyglutamine length. Hum Mol Genet 9:267–274Google Scholar
  66. Jordan K, Wüstenberg T, Heinze HJ, Peters M, Jäncke L (2002) Women and men exhibit different cortical activation patterns during mental rotation tasks. Neuropsychologia 40:2397–2408Google Scholar
  67. Kemp DT (1978) Stimulated acoustic emissions from within the human auditory system. J Acoust Soc Am 64:1386–1391Google Scholar
  68. Kemp DT (2008) Otoacoustic emissions: concepts and origins. In: Manley GA, Fay RR, Popper AN (eds) Active processes and otoacoustic emissions in hearing. Springer handbook of auditory research. Springer, New York, pp 1–38Google Scholar
  69. Koopman P, Munsterberg A, Capel B, Vivian N, Lovell-Badge R (1990) Expression of a candidate sex-determining gene during mouse testis differentiation. Nature 348:450–452Google Scholar
  70. Kruijver FP, Zhou JN, Pool CW, Hofman MA, Gooren LJ, Swaab DF (2000) Male-to-female transsexuals have female neuron numbers in a limbic nucleus. J Clin Endocrinol Metab 85:2034–2041Google Scholar
  71. Kucian K, Loenneker T, Dietrich T, Martin E, von Aster M (2005) Gender differences in brain activation patterns during mental rotation and number related cognitive tasks. Psychol Sci 47:112–131Google Scholar
  72. Kuiri-Hänninen T, Sankilampi U, Dunkel L (2014) Activation of the hypothalamic-pituitary-gonadal axis in infancy: minipuberty. Horm Res Paediatr 82:73–80Google Scholar
  73. Lamprecht SA, Kohen F, Ausher J, Zor U, Lindner HR (1976) Hormonal stimulation of oestradiol-17 beta release from the rat ovary during early postnatal development. J Endocrinol 68:343–344Google Scholar
  74. Lee PA, Nordenström A, Houk CP, Ahmed SF, Auchus R, Baratz A, Baratz Dalke K, Liao L-M, Lin-Su K, Looijenga LHJ, Mazur T, Meyer-Bahlburg HFL, Mouriquand P, Quigley CA, Sandberg DE, Vilain E, Witchel S (2016) Global disorders of sex development update since 2006: perceptions, approach and care. Horm Res Paediatr 85:158–180Google Scholar
  75. Lentini E, Kasahara M, Arver S, Savic I (2012) Sex differences in the human brain and the impact of sex chromosomes and sex hormones. Cereb Cortex 23:2322–2336Google Scholar
  76. Lessov-Schlaggar CN, Reed T, Swan GE, Krasnow RE, DeCarli C, Marcus R, Holloway L, Wolf PA, Carmelli D (2005) Association of sex steroid hormones with brain morphology and cognition in healthy elderly men. Neurology 65:1591–1596Google Scholar
  77. LeVay S (1991) A difference in hypothalamic structure between heterosexual and homosexual men. Science 253:1034–1037Google Scholar
  78. Linn MC, Petersen AC (1985) Emergence and characterization of sex differences in spatial ability: a meta-analysis. Child Dev 56:1479–1498Google Scholar
  79. Lombardo MV, Ashwin E, Auyeung B, Chakrabarti B, Taylor K, Hackett G, Bullmore ET, Baron-Cohen S (2012) Fetal testosterone influences sexually dimorphic gray matter in the human brain. J Neurosci 32:674–680Google Scholar
  80. Lutchmaya S, Baron-Cohen S, Raggatt P, Knickmeyer R, Manning JT (2004) 2nd to 4th digit ratios, fetal testosterone and estradiol. Early Hum Dev 77:23–28Google Scholar
  81. Maccoby EE, Jacklin CN (1974) The psychology of sex differences. Stanford University Press, Palo AltoGoogle Scholar
  82. Maguire EA, Woollett K, Spiers HJ (2006) London taxi drivers and bus drivers: a structural MRI and neuropsychological analysis. Hippocampus 16:1091–1101Google Scholar
  83. Maki PM, Rich JB, Shayna Rosenbaum R (2002) Implicit memory varies across the menstrual cycle: estrogen effects in young women. Neuropsychologia 40:518–529Google Scholar
  84. Masica DN, Money J, Ehrhardt AA, Lewis VG (1969) IQ, fetal sex hormones and cognitive patterns: studies in the testicular feminizing syndrome of androgen insensitivity. Johns Hopkins Med J 124:34–43Google Scholar
  85. Masica DN, Money J, Ehrhardt AA (1971) Fetal feminization and female gender identity in the testicular feminizing syndrome of androgen insensitivity. Arch Sex Behav 1:131–142Google Scholar
  86. McFadden D, Pasanen EG (1998) Comparison of the auditory systems of heterosexuals and homosexuals: click-evoked otoacoustic emissions. Proc Natl Acad Sci U S A 95:2709–2713Google Scholar
  87. Melo KFS, Mendonca BB, Billerbeck AEC, Costa EMF, Inacio M, Sliva FAQ, Leal AMO, Latronico AC, Arnhold IJP (2003) Clinical, hormonal, behavioral, and genetic characteristics of androgen insensitivity syndrome in a Brazilian cohort: five novel mutations in the androgen receptor gene. J Clin Endocrinol Metab 88:3241–3250Google Scholar
  88. Merke DP, Fields JD, Keil MF, Vaituzis AC, Chrousos GP, Giedd JN (2003) Children with classic congenital adrenal hyperplasia have decreased amygdala volume: potential prenatal and postnatal hormonal effects. J Clin Endocrinol Metab 88:1760–1765Google Scholar
  89. Meyer-Bahlburg HFL, Dolezal C, Baker SW, New MI (2008) Sexual orientation in women with classical or non-classical congenital adrenal hyperplasia as a function of degree of prenatal androgen excess. Arch Sex Behav 37:85–99Google Scholar
  90. Modi DN, Sane S, Bhartiya D (2003) Accelerated germ cell apoptosis in sex chromosome aneuploid fetal human gonads. Mol Hum Reprod 9:219–225Google Scholar
  91. Morris JA, Jordan CL, Breedlove SM (2004) Sexual differentiation of the vertebrate nervous system. Nat Neurosci 7:1034–1039Google Scholar
  92. Nagamani M, McDonough PG, Ellegood JO, Mahesh VB (1979) Maternal and amniotic fluid steroids throughout human pregnancy. Am J Obstet Gynecol 134:674–680Google Scholar
  93. Pasterski VL, Geffner ME, Brain C, Hindmarsh P, Brook C, Hines M (2005) Prenatal hormones and postnatal socialization by parents as determinants of male-typical toy play in girls with congenital adrenal hyperplasia. Child Dev 76:264–278Google Scholar
  94. Paus T, Nawaz-Khan I, Leonard G, Perron M, Pike GB, Pitiot A, Richer L, Susman E, Weillette S, Pausova Z (2010) Sexual dimorphism in the adolescent brain: role of testosterone and androgen receptor in global and local volumes of grey and white matter. Horm Behav 57:63–75Google Scholar
  95. Perrin JS, Hervé P-Y, Leonard G, Perron M, Pike GB, Pitiot A, Richer L, Veillette S, Pausova Z, Paus T (2008) Growth of white matter in the adolescent brain: role of testosterone and androgen receptor. J Neuro-Oncol 28:9519–9524Google Scholar
  96. Peters M, Laeng B, Latham K, Jackson M, Zaiyouna R, Richardson C (1995) A redrawn Vandenberg and Kuse mental rotation test: different versions and factors that affect performance. Brain Cogn 28:39–58Google Scholar
  97. Pierpaoli C, Basser PJ (1996) Toward a quantitative assessment of diffusion anisotropy. Magn Reson Med 36:893–906Google Scholar
  98. Printzlau F, Wolstencroft J, Skuse DH (2017) Cognitive, behavioral and neural consequences of sex chromosome aneuploidy. J Neurosci Res 95:311–319Google Scholar
  99. Puts DA, McDaniel MA, Jordan CL, Breedlove SM (2008) Spatial ability and prenatal androgens: meta-analyses of congenital adrenal hyperplasia and digit ratio (2D:4D) studies. Arch Sex Behav 37:100–111Google Scholar
  100. Raznahan A, Lee Y, Stidd R, Long R, Greenstein D, Clasen L, Addington A, Gogtay N, Rapoport JL, Giedd JN (2010) Longitudinally mapping the influence of sex and androgen signaling on the dynamics of human cortical maturation in adolescence. Proc Natl Acad Sci U S A 107:16988–16993Google Scholar
  101. Reyes FI, Boroditsky RS, Winter JS, Faiman C (1974) Studies on human sexual development. II. Fetal and maternal serum gonadotropin and sex steroid concentrations. J Clin Endocrinol Metab 38:612–617Google Scholar
  102. Rolstad SG, Moller A, Bryman I, Boman UW (2007) Sexual functioning and partner relationships in women with Turner syndrome: some empirical data and theoretical considerations regarding sexual desire. J Sex Marital Ther 33:231–247Google Scholar
  103. Ross JL, Roeltgen D, Feuillan P, Kushner H, Cutler GB (1998) Effects of estrogen on nonverbal processing speed and motor function in girls with Turner’s Syndrome. J Clin Endocrinol Metab 83:3198–3204Google Scholar
  104. Ruigrok ANV, Salimi-Khorshidi G, Lai M-C, Baron-Cohen S, Lombardo MV, Tait RJ, Suckling J (2014) A meta-analysis of sex differences in human brain structure. Neurosci Biobehav Rev 39:34–50Google Scholar
  105. Sacher J, Neumann J, Okon-Singer H, Gotowiec S, Villringer A (2013) Sexual dimorphism in the human brain: evidence from neuroimaging. Magn Reson Imaging 31:366–375Google Scholar
  106. Savic I, Frisen L, Manzouri A, Nordenstrom A, Lindén Hirschberg A (2017) Role of testosterone and Y chromosome genes for the masculinization of the human brain. Hum Brain Mapp 38:1801–1814Google Scholar
  107. Schirmer A, Zysset S, Kotz SA, Yves von Cramon D (2004) Gender differences in the activation of inferior frontal cortex during emotional speech perception. NeuroImage 21:1114–1123Google Scholar
  108. Schöning S, Engelien A, Kugel H, Schäfer S, Schiffbauer H, Zwitserlood P, Pletziger E, Beizai P, Kersting A, Ohrann P (2007) Functional anatomy of visuo-spatial working memory during mental rotation is influenced by sex, menstrual cycle, and sex steroid hormones. Neuropsychologia 45:3203–3214Google Scholar
  109. Schoonheim MM, Rueda Lopes FC, Pouwels PJW, Polman CH, Barkhof F, Geurts JJG (2014) Sex-specific extent and severity of white matter damage in multiple sclerosis: implications for cognitive decline. Hum Brain Mapp 35:2348–2358Google Scholar
  110. Seurinck R, Vingerhoets G, de Lange FP, Achten E (2004) Does egocentric mental rotation elicit sex differences? NeuroImage 23:1440–1449Google Scholar
  111. Shaeffer AT, Lange E, Bondy CA (2008) Sexual function in women with Turner syndrome. J Womens Health 17:27–33Google Scholar
  112. Shephard RN, Metzler J (1971) Mental rotation of three-dimensional objects. Science 171:701–703Google Scholar
  113. Shinur AWK, Hampson E (2011) Sex and ear differences in spontaneous and click-evoked otoacoustic emissions in young adults. Brain Cogn 77:40–47Google Scholar
  114. Swaab DF (2007) Sexual differentiation of the brain and behavior. Best Pract Res Clin Endocrinol Metab 21:431–444Google Scholar
  115. Swaab DF, Hofman MA (1990) An enlarged suprachiasmatic nucleus in homosexual men. Brain Res 537:141–148Google Scholar
  116. T’Sjoen G, de Cuypere G, Monstrey S, Hoebeke P, Freedman FK, Appari M, Holterhus P-M, van Borsel J, Cools M (2011) Male gender identity in complete androgen insensitivity syndrome. Arch Sex Behav 40:635–638Google Scholar
  117. Tadokoro-Cuccaro R, Hughes IA (2014) Androgen insensitivity syndrome. Curr Opin Endocrinol Diabetes Obes 21:499–503Google Scholar
  118. Takao H, Hayashi N, Ohtomo K (2014) Sex dimorphism in the white matter: fractional anisotropy and brain size. J Magn Reson Imaging 39:917–923Google Scholar
  119. Taziaux M, Swaab DF, Bakker J (2012) Sex differences in the neurokinin B system in the human infundibular nucleus. J Clin Endocrinol Metab 97:E2210–E2220Google Scholar
  120. Taziaux M, Staphorsius AS, Ghatei MA, Bloom SR, Swaab DF, Bakker J (2016) Kisspeptin expression in the human infundibular nucleus in relation to sex, gender identity, and sexual orientation. J Clin Endocrinol Metab 101:2380–2389Google Scholar
  121. Thomsen T, Hugdahl K, Ersland L, Barndon R, Lundervold A, Smievoll AI, Roscher BE, Sundberg H (2000) Functional magnetic resonance imaging (fMRI) study of sex differences in a mental rotation task. Med Sci Monit 6:1186–1196Google Scholar
  122. van Hemmen J, Veltman DJ, Hoekzema E, Cohen-Kettenis PT, Dessens AB (2016) Neural activation during mental rotation in complete androgen insensitivity syndrome: the influence of sex hormones and sex chromosomes. Cereb Cortex 26:1036–1045Google Scholar
  123. van Hemmen J, Cohen-Kettenis PT, Steensma TD, Veltman DJ, Bakker J (2017a) Do sex differences in CEOAEs and 2D:4D ratios reflect androgen exposure? A study in women with complete androgen insensitivity syndrome. Biol Sex Differ 8:11Google Scholar
  124. van Hemmen J, Saris IMJ, Cohen-Kettenis PT, Veltman DJ, Pouwels PJW, Bakker J (2017b) Sex differences in white matter microstructure in the human brain predominantly reflect differences in sex hormone exposure. Cereb Cortex 27:2994–3001Google Scholar
  125. Ventura T, Gomes MC, Pita A, Neto MT, Taylor A (2013) Digit ratio (2D,4D) in newborns: influences of prenatal testosterone and maternal environment. Early Hum Dev 89:107–112Google Scholar
  126. Wallen K (2005) Hormonal influences on sexually differentiated behavior in nonhuman primates. Front Neuroendocrinol 26:7–26Google Scholar
  127. Weiss E, Siedentopf CM, Hofer A, Deisenhammer EA, Hoptman MJ, Kremser C, Golaszewski S, Felber S, Fleischhacker WW, Delazer M (2003) Sex differences in brain activation pattern during a visuospatial cognitive task: a functional magnetic resonance imaging study in healthy volunteers. Neurosci Lett 344:169–172Google Scholar
  128. Winter JS, Hughes IA, Reyes FI, Faiman C (1976) Pituitary-gonadal relations in infancy: 2. Patterns of serum gonadal steroid concentrations in man from birth to two years of age. J Clin Endocrinol Metab 42:679–686Google Scholar
  129. Wisniewski AB, Migeon CJ, Meyer-Bahlburg HF, Gearhart JP, Berkovitz GD, Brown TR, Money J (2000) Complete androgen insensitivity syndrome: long-term medical, surgical, and psychosexual outcome. J Clin Endocrinol Metab 85:2664–2669Google Scholar
  130. Witte AV, Savli M, Holik A, Kasper S, Lanzenberger R (2010) Regional sex differences in grey matter volume are associated with sex hormones in the young adult human brain. NeuroImage 49:1205–1212Google Scholar
  131. Zachmann M, Prader A, Sobel EH, Crigler JF Jr, Ritzen EM, Atares M, Ferrandez A (1986) Pubertal growth in patients with androgen insensitivity: indirect evidence for the importance of estrogens in pubertal growth of girls. J Pediatr 108:694–697Google Scholar
  132. Zachs JM (2008) Neuroimaging studies of mental rotation: a meta-analysis and review. J Cogn Neurosci 20:1–19Google Scholar
  133. Zhou JN, Hofman MA, Gooren LJ, Swaab DF (1995) A sex difference in the human brain and its relation to transsexuality. Nature 378:68–70Google Scholar
  134. Zitzmann M, Weckesser M, Schober O, Nieschlag E (2001) Changes in cerebral glucose metabolism and visuospatial capability in hypogonadal males under testosterone substitution. Exp Clin Endocrinol Diabetes 109:302–304Google Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Laboratory of Neuroendocrinology, GIGA NeurosciencesLiège UniversityLiègeBelgium

Personalised recommendations