Interestingly, in adult female canaries, testosterone treatment also resulted in singing behavior normally heard only from male canaries (23, 24). This implies that the sex hormone-induced plastic changes in brain anatomy may be functionally relevant. Indeed, in transsexuals, cross-sex hormone treatment induces changes in behavior and cognitive performance on tests that are known to manifest differences between males and females. In MFs, 3 months of estrogen addition and testosterone suppression resulted in a decline in anger and aggression proneness, sexual arousal, sexual desire, and spatial ability (usually males outperform females) and in an increase in verbal fluency (usually females outperform males) (24, 26, 27). In FMs, 3 months of testosterone treatment was associated with an increase in aggression proneness, sexual arousal, and spatial ability performance, whereas it had a deteriorating effect on verbal fluency tasks (25, 28). These behavioral and cognitive findings in transsexuals following cross-sex hormone treatment are in line with the studies reporting influences of endogenous and exogenous sex hormones on behavior and cognition, as well as on cortical brain activation, in non-transsexual adult humans (29, 30). Whether functional brain changes accompany the anatomical brain changes in transsexuals remains to be elucidated using functional brain imaging techniques.

Biological mechanisms underlying the gonadal hormone-related plasticity changes in young adult human brains are not known. However, we know that sex steroids have much in common with neurotropins. For instance, like neurotropins, they regulate cell death. Indeed, the most important mechanism by which steroid hormones alter neuron number in sexually dimorphic regions is by influencing cell death. In addition, they are involved in neuronal migration, neurogenesis, and neurotransmitter plasticity. More­over, these hormones direct formation of sex-specific neuronal networks by influencing axonal guidance and synaptogenesis (1, 31). Testosterone treatment in the adult female canary also induces newly activated and expanded vasculature in the vocal control nucleus, which substantially increases the production and

release of BDNF; BDNF is both spatially and temporally associated with the recruitment of new neurons (32). Functionally, sex hormones can alter neuronal excitability in a sex-specific way (33). The changes in excitability may be caused not only by altered electrical properties of the membrane, but may also be caused by alternations in neuronal morphology (34). Thus, our reported volume changes in the brains of transsexuals following cross-sex hormone treatment may represent alterations in neuronal cell numbers or the number of synapses. However, more work is needed to uncover particular cells and specific genes on which testosterone (and estrogen) act to regulate cell death in the central nervous system (35).

In conclusion, our data show that in young adult humans, androgen treatment increases the volume of the female brain towards male proportions and anti­androgenCestrogen treatment reduces the size of the male brain towards female proportions. The findings imply plasticity of adult human brain structure towards the opposite sex under the influence of cross-sex hormones.

Acknowledgements

The authors thank the coordinator of the gender team J Megens at the VU University Medical Center in Amsterdam for his support with patient recruitment and Dr E Fliers for comments on an earlier version of the manuscript.

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Received 30 April 2006 Accepted 7 July 2006