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As this aspect of sexual differentiation is androgen-dependent, it has been possible to experiment with it in lower mammals. It does seem that a male copulatory pattern can be induced in a rat with a female gonadal/genital differentiation. Similarly, a female copulatory pattern can be induced in a male rat by depriving it of androgenic stimulus at the time of the brain’s sexual differentiation. 16

In clinical studies of transsexuals, it has not been possible to demonstrate any hormonal disruptions at any point that display patterns typical of the opposite sex. 3 However, inter-sexed subjects exposed to an atypical hor-monal environment at the supposed time of brain sexual differentiation do show that pre-natal androgen exposure affects their future gender role and may induce a degree of mas-culinity. 3 In lower mammals, it is now well established that exposure of the brain to androgens during the critical period of sexual differentiation induces male brain develop-ment, while lack of exposure to androgens results in a female brain; also, that male and female rat brains differ in their neuroanato-mical structures.

Naturally, there has been an effort to deter-mine whether these neuroanatomical differ-ences can also be found in humans. Several researchers have anticipated such differences because of the close parallels between lower mammals and humans in the process of sex-ual differentiation of the gonads and gen-italia. And indeed sex differences in the size and shape of certain nuclei in the hypothal-amus have been described in the human, though replication studies are still needed to corroborate the findings (for review, see Refs. 16 and 17).

In the past decade, post-mortem research on the brains of transsexuals at the Dutch Brain Research Institute has been able to demonstrate that one of the brain nuclei that is sex-dimorphic in the human, the bed nuc-leus of the stria terminalis, shows all the char-acteristics of female differentiation in a sample of male-to-female transsexuals. 18–20

This observation was refined, and it could further be shown that the one brain of a female-to-male transsexual available for post-mortem examination showed a male differentiation of the bed nucleus of the stria terminalis. 20

This finding of a biological index of female brain differentiation in male-to-female trans-sexuals could mark a conceptual turning point in the approach to transsexualism. For the medical profession, transsexuals could be ‘reha-bilitated’ from mentally disturbed to sufferers of a sexual differentiation disorder, namely, of the brain. Also, medical insurance policies could be (legally) obliged to pay for the costs of sex reassignment similar to other forms of intersexed states and the legal system could be held to treating transsexuals analogously to other intersexed individuals. The public might also begin to change its attitude towards this startling phenomenon. The establishment of a biological basis to transsexualismmay well have consequences that will reverberate throughout society. At this time, however, brain imaging techniques are not sufficiently refined to detect in living subjects what the post-mortem research has indicated. For this reason, these neuroanatomical differences in transsexuals are not yet part of the diagnostic process.

SUMMARY

Manhood and womanhood, and all shades in between, are part of medicine. While solutions are mostly technical and based on insights into biomedical science, issues in medical care arise that cannot currently be satisfactorily solved on the basis of biomedical science alone. Disorders of sexual differentiation and the phenomenon of transsexualism require a dif-ferent approach. The self-experience of be-longing to one sex or the other weighs on the medical decisions to be made for the well-being of subjects in these situations. This marks the point where medicine becomes an art as well as a science. Some may conceive statements of this nature as woolly. It goes without saying that no treatment procedure is beyond verification by biostatistical meth-ods. Increasingly, studies prove that the above approach helps people to live fuller lives. 7,21–24

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4 Meyer-Bahlburg HF. Gender assignment and reas-signment in intersexuality: controversies, data, and guidelines for research. Adv Exp Med Biol 2002; 511: 199–223.

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9 van Kesteren PJ, Gooren LJ, Megens JA. An epidemiological and demographic study of trans-sexuals in The Netherlands. Arch Sex Behav 1996; 25: 589–600.

10 Baba T, Endo T, Ikeda K, Shimizu A, Honnma H et al. Distinctive features of female-to-male transsexualism and prevalence of gender identity disorder in Japan. J Sex Med 2011; 8: 1686–1693.

11 Vujovic S, Popovic S, Sbutega-Milosevic G, Djordjevic M, Gooren L. Transsexualism in Serbia: a twenty-year follow-up study. J Sex Med 2009; 6: 1018–23. 12 Tsoi WF. Male and female transsexuals: a comparison. Singapore Med J 1992; 33: 182–5.

13 Coleman E, Colgan P, Gooren L. Male cross-gender behavior in Myanmar (Burma): a description of the acault. Arch Sex Behav 1992; 21: 313–21. 14 Gupta R, Murarka A. Treating transsexuals in India: history, prerequisites for surgery and legal issues. Indian J Plast Surg 2009; 42: 226–33. 15 Money J. Transexualism and the philosophy of healing. J Am Soc Psychosom Dent Med 1971; 18: 25–6.

16 Arnold AP. The organizational-activational hypothesis as the foundation for a unified theory of sexual differentiation of all mammalian tissues. Horm Behav 2009; 55: 570–8.

17 Swaab DF, Garcia-Falgueras A. Sexual differentiation of the human brain in relation to gender identity and sexual orientation. Funct Neurol 2009; 24: 17–28. 18 Zhou JN, Hofman MA, Gooren LJ, Swaab DF. A sex difference in the human brain and its relation to transsexuality. Nature 1995; 378: 68–70. 19 Kruijver FP, Zhou JN, Pool CW, Hofman MA, Gooren LJ et al. Male-to-female transsexuals have female neuron numbers in a limbic nucleus. J Clin Endocrinol Metab 2000; 85: 2034–41. 20 Garcia-Falgueras A, Swaab DF. A sex difference in the hypothalamic uncinate nucleus: relationship to gender identity. Brain 2008; 131: 3132–46. 21 GillamLH, Hewitt JK, Warne GL. Ethical principles for the management of infants with disorders of sex development. Horm Res Paediatr 2011; 74: 412–8. 22 Cohen-Kettenis PT, Gooren LJ. Transsexualism: a review of etiology, diagnosis and treatment. J Psy-chosom Res 1999; 46: 315–33.

23 Murad MH, Elamin MB, Garcia MZ, Mullan RJ, Murad A et al. Hormonal therapy and sex reassignment: a systematic review and meta-analysis of quality of life and psychosocial outcomes. Clin Endocrinol (Oxf) 2010; 72: 214–31.

24 Weyers S, Elaut E, de Sutter P, Gerris J, T’Sjoen G et al. Long-term assessment of the physical, mental, and sexual health among transsexual women. J Sex Med 2009; 6: 752–60.

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