8 Biology Of Sexual Identity

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Part 8 of "Science & Sexuality." Is sexual identity a biological reality? How does it develop? What determines a person's sexual identity?

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8 Biology Of Sexual Identity

  1. 1. Biology of Sexual Identity Harry Benjamin's Syndrome (HBS)   Estimated incidence of HBS is 1 in 100.000 live births
  2. 2. The Transsexual Brain <ul><li>Background: </li></ul><ul><li>Investigation of genetics, gonads, genitalia or hormone level of transsexuals does NOT explain their status </li></ul><ul><li>In experimental animals, the same gonadal hormones that prenatally determine the morphology of the genitalia also influence the morphology and function of the brain in a sexually dimorphic fashion </li></ul><ul><li>This led to the hypothesis that sexual differentiation of the brain in transsexuals might not have followed the line of sexual differentiation of the body as a whole </li></ul>
  3. 3. MtF Brains <ul><li>Six male-to-female transsexuals (T1-T6) </li></ul><ul><li>Searched for sexually dimorphic brain structure that was not influenced by sexual orientation (male-to-female transsexuals may be &quot;oriented&quot; to either sex with respect to sexual behavior) </li></ul><ul><li>Zhou, J.N. Hofman, M.A. Gooren, L.J. and Swaab, D.F.. A Sex Difference in the Human Brain and its Relation to Transsexuality. NATURE, 378: 68-70 (1995) </li></ul>
  4. 4. Bed Nucleus of the Stria Terminalis <ul><li>“ Although there is no accepted animal model for gender identity alterations, the bed nucleus of the stria terminalis (BST) turned out to be an appropriate candidate to study” because BST </li></ul><ul><ul><li>Plays an essential part in rodent sexual behavior </li></ul></ul><ul><ul><li>Has estrogen and androgen receptors </li></ul></ul><ul><ul><li>Is major aromatization center in developing rat brain </li></ul></ul><ul><ul><li>Receives projections mainly from the amygdala </li></ul></ul><ul><ul><li>Provides a strong input in the preoptic-hypothalamic region </li></ul></ul><ul><ul><li>Reciprocal connections well-documented between hypothalamus, BST and amygdala </li></ul></ul><ul><ul><li>Sex differences in the size and cell number of the BST have been described in rodents which are influenced by gonadal steroids in development </li></ul></ul><ul><ul><li>In humans a particular caudal part of the BST (BNST-dspm) has been reported to be 2.5 times larger in men than in women </li></ul></ul><ul><ul><li>The central part of the BST (BSTc) is characterized by its somatostatin cells and vasoactive intestinal polypeptide (VIP) innervation </li></ul></ul><ul><ul><li>Experimental endpoint: volume of the BSTc - based on its VIP innervation </li></ul></ul><ul><li>Zhou, J.N. Hofman, M.A. Gooren, L.J. and Swaab, D.F.. A Sex Difference in the Human Brain and its Relation to Transsexuality. NATURE, 378: 68-70 (1995) </li></ul>
  5. 5. Localization of the BST <ul><li>The central part of the BST (BSTc) is characterized by </li></ul><ul><ul><li>Somatostatin-producing cells </li></ul></ul><ul><ul><li>vasoactive intestinal polypeptide (VIP) innervation </li></ul></ul><ul><li>Investigators measured the volume of the BSTc on the basis of its VIP innervation </li></ul>Zhou, J.N. Hofman, M.A. Gooren, L.J. and Swaab, D.F.. A Sex Difference in the Human Brain and its Relation to Transsexuality. NATURE, 378: 68-70 (1995)
  6. 6. Bed Nucleus of the Stria Terminalis Figure 2 : Representative sections of the BSTc innervated by vasoactive intestinal polypeptide (VIP). A: heterosexual man; B: heterosexual woman; C: homosexual man; D: male-to-female transsexual. Bar=0.5 mm. LV: lateral ventricle. Note there are two parts of the BST in A and B: small sized medial subdivision (BSTm), and large oval-sized central subdivision (BSTc) Zhou, J.N. Hofman, M.A. Gooren, L.J. and Swaab, D.F.. A Sex Difference in the Human Brain and its Relation to Transsexuality. NATURE, 378: 68-70 (1995)
  7. 7. Bed Nucleus of the Stria Terminalis <ul><li>Figure 3 </li></ul><ul><ul><li>The six transsexuals are numbered T1-T6 </li></ul></ul><ul><ul><li>The patients with abnormal sex hormone levels are numbered S1-S4 </li></ul></ul><ul><ul><li>M1 and M2: postmenopausal women </li></ul></ul><ul><li>Zhou, J.N. Hofman, M.A. Gooren, L.J. and Swaab, D.F.. A Sex Difference in the Human Brain and its Relation to Transsexuality. NATURE, 378: 68-70 (1995) </li></ul>
  8. 8. BSTc Volume Is Not Affected by Varying Sex Hormone Levels in Adulthood <ul><li>S1: BSTc volume of a 46-year-old woman who had suffered for at least 1 year from a tumor of the adrenal cortex that produced very high blood levels of androstenedione and testosterone, was within the range of that of other women </li></ul><ul><li>M1, M2: Two postmenopausal women (aged over 70 years) showed a completely normal female-sized BSTc </li></ul><ul><li>Zhou, J.N. Hofman, M.A. Gooren, L.J. and Swaab, D.F.. A Sex Difference in the Human Brain and its Relation to Transsexuality. NATURE, 378: 68-70 (1995) </li></ul>
  9. 9. Small-Sized BSTc in MtF Not Due to Estrogen Treatment <ul><li>All the transsexuals had been treated with estrogens, so could the reduced size of the BSTc be due to high estrogen levels? </li></ul><ul><ul><li>T2 and T3: both showed a small, female-like BSTc </li></ul></ul><ul><ul><ul><li>T2 stopped taking estrogen about 15 months before death (since her prolactin levels were too high) </li></ul></ul></ul><ul><ul><ul><li>T3 stopped hormone treatment since a sarcoma was found about three months before death </li></ul></ul></ul><ul><ul><li>S2: 31-year-old man who suffered from a feminizing adrenal tumor which induced high blood levels of estrogen, nevertheless had a very large BSTc </li></ul></ul><ul><li>Zhou, J.N. Hofman, M.A. Gooren, L.J. and Swaab, D.F.. A Sex Difference in the Human Brain and its Relation to Transsexuality. NATURE, 378: 68-70 (1995) </li></ul>
  10. 10. Large-sized BSTc in MtF Not Due to Lack of Androgens <ul><li>All had been orchidectomized except for T4 </li></ul><ul><li>S4 and S3: orchidectomized because of prostate cancer (one and three months before death respectively) - found that their BSTc sizes were at the high end of the normal male range </li></ul><ul><li>T4: single transsexual who had not been orchidectomized - ranged in the middle of the transsexual scores (Fig. 3) </li></ul><ul><li>Not only were five of the transsexuals orchidectomized, they all used the antiandrogen cyproterone acetate (CPA) </li></ul><ul><li>T3 & T6: A CPA effect on the BSTc does not seem likely, because T6 had not taken CPA for the past 10 years, and T3 took no CPA during the two years before death and still had a female-sized BSTc </li></ul><ul><li>Zhou, J.N. Hofman, M.A. Gooren, L.J. and Swaab, D.F.. A Sex Difference in the Human Brain and its Relation to Transsexuality. NATURE, 378: 68-70 (1995) </li></ul>
  11. 11. Results & Conclusions <ul><li>Verified that the volume of the central subdivision of the bed nucleus of the stria terminalis (BSTc) is larger in typical men than in typical women </li></ul><ul><li>A female-sized BSTc was found in male-to-female transsexuals </li></ul><ul><li>The size of the BSTc was not influenced by sex hormones in adulthood and was independent of sexual orientation </li></ul><ul><li>This is the first study to show a female brain structure in genetically male transsexuals and supports the hypothesis that gender identity develops as a result of an interaction between the developing brain and sex hormones </li></ul><ul><li>Zhou, J.N. Hofman, M.A. Gooren, L.J. and Swaab, D.F.. A Sex Difference in the Human Brain and its Relation to Transsexuality. NATURE, 378: 68-70 (1995) </li></ul>
  12. 12. 2 nd Study: Methodology to Study BSTc <ul><li>Figure 3. The image analysis procedure. a, Illustration of a somatostatin immunoreactive BSTc. b, The BSTc is outlined manually. c, Outlined BSTc is divided automatically into rectangular fields. d, Fifty percent of the fields is selected by a random systematic sampling procedure. e, Higher magnification of somatostatin neurons in a field displayed by the camera when the x 40 objective is installed. Only somatostatin-positive neurons with a visible nucleolus were counted (see Morphometry in Materials and Methods ). Bar represents 40 µm. f, Example of a clearly visible nucleolus in a somatostatin immunoreactive neuron </li></ul><ul><li>Kruijver, Frank P. M., Zhou, Jiang-Ning, Pool, Chris W. Hofman, Michel A.,. Gooren, Louis J. G And Swaab, Dick F. Male-To-Female Transsexuals Have Female Neuron Numbers In A Limbic Nucleus. J CLIN ENDOCRINOL METAB, 85: 2034-2041 (2000) </li></ul>
  13. 13. <ul><li>Figure 2. Representative immunocytochemical stainings of the somatostatin neurons and fibers in the BSTc </li></ul><ul><ul><li>(a) a reference man </li></ul></ul><ul><ul><li>(b) reference woman </li></ul></ul><ul><ul><li>(c) homosexual man </li></ul></ul><ul><ul><li>(d) male-to-female transsexual </li></ul></ul><ul><li>Note the sex difference regardless of sexual orientation </li></ul><ul><li>The male-to-female transsexual has a BSTc in the female range </li></ul><ul><li>Kruijver, Frank P. M., Zhou, Jiang-Ning, Pool, Chris W. Hofman, Michel A.,. Gooren, Louis J. G And Swaab, Dick F. Male-To-Female Transsexuals Have Female Neuron Numbers In A Limbic Nucleus. J CLIN ENDOCRINOL METAB, 85: 2034-2041 (2000) </li></ul>Somatostatin Results Parallel VIP Results
  14. 14. What’s Missing in the Sexual Identity Picture? <ul><li>FtM </li></ul><ul><ul><li>Has male sexual identity </li></ul></ul><ul><ul><li>Work so far predicts that BSTc of FtM should be same size as typical male’s </li></ul></ul>
  15. 15. FtM Has Same Neuron Number in BSTc as Typical Male <ul><li>Figure 1. </li></ul><ul><li>BSTc neuron numbers. Distribution of the BSTc neuron numbers among the different groups according to sex, sexual orientation, and gender identity. M, Heterosexual male reference group; HM, homosexual male group; F, female group; TM, male-to-female transsexuals </li></ul><ul><li>The sex hormone disorder patients S1, S2, S3, S5, S6, and M2 indicate that changes in sex hormone levels in adulthood do not change the neuron numbers of the BSTc </li></ul><ul><li>Note that the number of neurons of the FMT is fully within the male range </li></ul><ul><li>Kruijver, Frank P. M., Zhou, Jiang-Ning, Pool, Chris W. Hofman, Michel A.,. Gooren, Louis J. G And Swaab, Dick F. Male-To-Female Transsexuals Have Female Neuron Numbers In A Limbic Nucleus. J CLIN ENDOCRINOL METAB, 85: 2034-2041 (2000) </li></ul>
  16. 16. BSTc Neuron Number Is Not Related to Sexual Orientation <ul><li>Whether the transsexuals were male oriented (T1, T6), female oriented (T2, T3, T5), or both (T4) did not have any relationship with the neuron number of the BSTc </li></ul><ul><li>The same holds true for heterosexual and homosexual men </li></ul><ul><li>This shows that the BSTc number of somatostatin neurons is not related to sexual orientation </li></ul>Kruijver, Frank P. M., Zhou, Jiang-Ning, Pool, Chris W. Hofman, Michel A.,. Gooren, Louis J. G And Swaab, Dick F. Male-To-Female Transsexuals Have Female Neuron Numbers In A Limbic Nucleus. J CLIN ENDOCRINOL METAB, 85: 2034-2041 (2000)
  17. 17. Genetics of MtF Transsexuality <ul><li>Looked for potential differences in three genes known to be involved in sex development </li></ul><ul><ul><li>Gene for the androgen receptor </li></ul></ul><ul><ul><li>Gene for estrogen receptor </li></ul></ul><ul><ul><li>Aromatase enzyme which converts testosterone to estrogen </li></ul></ul><ul><li>Comparison of the DNA from the MtF transsexual participants with controls showed a significant link with a long version of the androgen receptor gene and transsexualism </li></ul><ul><ul><li>Hare, Lauren and Harley, Vincent. BBC News–10/26/2008 </li></ul></ul>
  18. 18. Genetics of FtM Transsexuality <ul><li>Gene variant for 17  -Hydroxylase* </li></ul><ul><ul><li>Leads to higher than average tissue concentrations of androgens and estrogen hormones </li></ul></ul><ul><ul><li>These hormones may in turn influence early brain development </li></ul></ul><ul><li>44% of FtM transsexuals carried it, compared with 31% of non-transsexual women </li></ul><ul><ul><li>Proportion of MtF transsexuals with variant was similar to that in non-transsexual men </li></ul></ul><ul><li>*Also called cytochrome P17 </li></ul><ul><li>Tempfer, Clemens et al. 2008 </li></ul>
  19. 20. Different Routes to Sexual Identity <ul><li>In some trans people, there may be a genetic trigger to the development of an atypical gender identity </li></ul><ul><li>It may be just one of several routes </li></ul><ul><li>Unlikely that developmental pathways are the same in all individuals </li></ul>

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