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Frank P. Pool, Michel A. Hofman, Louis J. Gooren, Dick F. Transsexuals experience themselves as being of the opposite sex, despite having the biological characteristics of one sex. A crucial question resulting from a brain study in male-to-female transsexuals was whether the reported difference according to gender identity in the central part of the bed nucleus of the stria terminalis BSTc was based on a neuronal difference in the BSTc itself or just a reflection of a difference in vasoactive intestinal polypeptide innervation from the amygdala, which was used as a marker.
Therefore, we determined in 42 subjects the of somatostatin-expressing neurons in the BSTc in relation to sex, sexual orientation, gender identity, and past or present hormonal status. In contrast, the neuron of a female-to-male transsexual was found to be in the male range. Hormone treatment or sex hormone level variations in adulthood did not seem to have influenced BSTc neuron s. The present findings of somatostatin neuronal sex differences in the BSTc and its sex reversal in the transsexual brain clearly support the paradigm that in transsexuals sexual differentiation of the brain and genitals may go into opposite directions and point to a neurobiological basis of gender identity disorder.
ANIMAL experiments and observations in human brains have convincingly shown that sexual differentiation not only concerns the genitalia but also the brain 1 , 2. The strongly connected and sexually differentiated hypothalamus, septum, bed nucleus of the stria terminalis BST , and amygdala are implicated in sexually dimorphic patterns of reproductive and nonreproductive behaviors 2 — Gender identity i. Transsexuals experience themselves as being of the opposite sex, despite having the biological characteristics of one sex 19 — In line with the hypothesis that in transsexuals sexual differentiation of the brain contrasts with that of the genetic and physical characteristics of sex, our group has recently found that the size of the central subdivision of the BST BSTc was within the female range in genetically male-to-female transsexuals In that study the, BSTc was defined on the basis of its vasoactive intestinal polypeptide innervation, which is probably mainly derived from the amygdala A crucial question resulting from that study was, therefore, whether the difference according to gender in the BSTc is based on a neuronal difference in the BSTc itself or rather a reflection of a difference in innervation from the amygdala.
To see whether the BSTc itself has a neuronal organization that is opposite to that of the genetic and genitalial characteristics of transsexuals, we determined the of somatostatin SOM -expressing neurons in the BSTc, which is the major neuronal population in this structure In the present study, 42 brains of patients were analyzed for an overview see Table 1.
The brains of 34 reference subjects 9 pd heterosexual males, 9 homosexual males, 10 pd heterosexual females, and 6 male-to-female transsexuals ranging from 20—53 yr of age, together with six brains three males and three females of patients with sex hormone disorders were obtained at autopsy, after the required permissions had been obtained. Twenty-six of the reference subjects were the same as used in the earlier study of Zhou et al. A nontreated individual with strong cross-gender identity feelings S7 , which were already present since his earliest childhood, was also analyzed.
In addition, we had the exceptional opportunity to be able to study the first collected brain ever of a female-to-male transsexual FMT. The brains were matched for age, postmortem time, and duration of formalin fixation. Neuropathology of all subjects was systematically performed by Dr. Subjects had no primary neurological or psychiatric diseases, unless stated otherwise. BSTc neuron s. Distribution of the BSTc neuron s among the different groups according to sex, sexual orientation, and gender identity. Note that the of neurons of the FMT is fully within the male range. The same holds true for heterosexual and homosexual men.
This shows that the BSTc of somatostatin neurons is not related to sexual orientation. A, AIDS patient. P, Postmenopausal woman. The hypothalamic area was subsequently dissected, dehydrated, and embedded in paraffin. To enhance antigen retrieval [for a review see Shi et al. S to prevent the antibody from diffusing. Both the scanning stage and the camera were mounted on a microscope Carl Zeiss equipped with planapo objectives. To provide optimal contrast and homogenous illumination of the section the voltage of the light source was set maximally.
The light was reduced by neutral gray filters 0. In this image the BSTc was outlined manually on the basis of the distribution of the SOM immunoreactivity in neurons and fibers see Fig. In each field, SOM-positive neurons containing a nucleolus were counted manually, taking into the exclusion lines according to Gundersen Neurons with double nucleoli were never seen. The spectrum of neuronal sizes was equally distributed among the different groups.
The image analysis procedure. Only somatostatin-positive neurons with a visible nucleolus were counted see Morphometry in Materials and Methods. The total volume of the BSTc was calculated by rostro-caudal integration of the outlined areas, taking into the distance between the measured sections. The neuronal density was calculated on the basis of the nucleolus counts in the sample volume.
An estimation of the total of SOM neurons was obtained by multiplying the total volume with the mean neuronal density. The finding that the mean BSTc volumes of the various groups are almost twice as large as those found in the study of Zhou et al. Differences among the groups were statistically evaluated by the nonparametric Kruskal-Wallis multiple comparison test.
To further test whether the differences in the BSTc between the groups were affected by possible confounding factors, such as paraffin-embedded storage time of sections, fixation time, postmortem time, or brain weight, an analysis of covariance was carried out.
The of neurons in the BSTc of male-to-female transsexuals was similar to that of females In addition, the neuron of the FMT was clearly in the male range see Fig. There seemed to be no clear difference in the BSTc of neurons between early onset T2, T5, T6 and late-onset transsexuals T1, T3 , indicating that their smaller of neurons is related to the gender identity per se rather than to the age at which it became apparent.
No indication was found for a relationship between cause of death and BSTc neuron s. Analysis of the BSTc volumes showed a similar pattern of differences among the groups with heterosexual men having a BSTc volume of 4. The BSTc volume of females 3. The volumes of all males, regardless of sexual orientation, vs. Representative immunocytochemical stainings of the somatostatin neurons and fibers in the BSTc of a reference man a , reference woman b , homosexual man c , and male-to-female transsexual d.
Note the sex difference regardless of sexual orientation. The male-to-female transsexual has a BSTc in the female range. Bar represents 0. In the present study, we show regardless of sexual orientation: 1 a sex difference in SOM neuron s in the human BSTc, with males having almost twice as many SOM neurons as females; 2 a of SOM neurons in the BSTc of male-to-female transsexuals in the female range; and 3 an opposite pattern in the BSTc of a female-to-male transsexual with a SOM neuron in the male range. Analysis of the total of SOM neurons of the human BSTc in individual patients with highly different hormone levels does not give any indication that changes in sex hormone levels in adulthood change the neuron s.
Because the transsexuals had all been treated with estrogens, at least for some time see Table 2 , the reduced neuron s of the BSTc could theoretically be due to the presence of high levels of circulating estrogens. Our might theoretically also be explained by a lack of androgens in the transsexual group because all subjects, except for T4, had been orchiectomized. We, therefore, studied two nontranssexual men S3 and S5 who had been orchiectomized because of prostate cancer 3 months and 2 yr before death, respectively, and found that the BSTc neuron of S3 was close to the mean of the male group and that the BSTc of neurons of S5 was even the highest observed Fig.
Not only were five of the transsexuals orchiectomized, they all used the antiandrogen cyproterone acetate CPA. The BSTc SOM neuron s of two postmenopausal women [ M2 and yr-old P ] and of a yr-old woman with Turner syndrome S6: complete 45,X0, with ovarian hypoplasia were completely within the normal female range Fig. If high estrogen levels would have a reducing effect on BSTc neuron s, the opposite effect high neuron s would be expected in the postmenopausal women and the Turner syndrome patient due to their low endogenous sex hormone level status. However, this was not the case. Noteworthy is that according to the available clinical data the two postmenopausal women did not receive any estrogen replacement therapy either.
Although the Turner syndrome patient had been receiving hormone replacement therapy since she was 16 yr of age, her neuron s were even higher than P, whereas she had almost the same BSTc neuron as M2 who did not receive such a therapy. Again, this argues against the probability of an estrogen-induced reduction effect on the of SOM neurons. Finally, the BSTc neuron of a yr-old woman who had suffered for at least 1 yr from a virilizing tumor of the adrenal cortex that produced very high blood levels of androstendione and testosterone was also clearly within the lower spectrum of that of other women Fig.
Thus, an increasing effect of testosterone on the BSTc neurons does not seem likely to be the case either. Furthermore, it should be noted that the FMT stopped taking testosterone 3 yr before death while having a BSTc neuron clearly within the male range. In addition, we had the unique opportunity to study the brain of an yr-old man S7 who also had very strong cross-gender identity feelings but was never orchiectomized, sex re-ased, or treated with CPA or estrogens. This case provides an additional argument against the view that orchiectomy, CPA, or adult estrogen treatment of the transsexuals would be responsible for the reduced somatostatinergic neuron s.
Moreover, studies that investigated the effects of estrogen treatment on hypothalamic SOM neurons in castrated rats are also not in support of such an effect. Moreover, another animal study indicates that, although changes occur in the hypothalamic neuronal expression of SOM mRNA due to castration or testosterone treatment of male rats, no differences in hypothalamic SOM neuron s are induced at all by either of such treatments This observation is also in agreement with the control SOM neuron s of the castrated male patients S3, S5 and testosterone-exposed S1 female patient.
Together, all these data clearly indicate that sex hormone-mediated reduction or enhancement effects on transsexual BSTc neurons in adulthood are extremely unlikely to be the underlying mechanism of the observed somatostatinergic BSTc differences. In short, our findings seem to support the hypothesis that the somatostatinergic sex differences, the female of SOM neurons in the BSTc of the male-to-female transsexual brain and the male of SOM neurons in the BSTc of the FMT are not the result of changes of sex hormone levels in adulthood.
Instead, the neuronal differences are likely to have been established earlier during development [see also Zhou et al. In line with this reasoning are the developmental data on the rat BST showing that adult volumes and neuron s of BST subdivisions are orchestrated by androgen exposure during early brain development 31 , Such a mechanism is also in agreement with data of Breedlove 33 , 34 showing that perinatal androgens but not adult variations in androgen exposure induce differences in the total neuron of the rat spinal nucleus bulbocavernosus.
However, despite that we were still able to find striking sexual dimorphic differences that become even more ificant if patients S1, S2, S3, S5, S6, S7, and M2 are included in their respective gender groups; see statistics and the legend to Fig.
Although our collection of male-to-female transsexual brains is small, it offers new opportunities to explore neurobiological correlates of transsexualism, as has ly been done in relation to sexual orientation 4 — 6. The development of high resolution imaging techniques may allow in vivo volume measurements of particular brain areas in much larger groups of transsexuals, which could extend our findings in the distant future.
Although brain imaging proved to be useful in visualizing [ e. It is conceivable that this dichotomy is just the tip of the iceberg and holds also true for many other sexually dimorphic brain areas. Because the sexually differentiated brain in general 41 may be the basis of sex differences in the prevalence of many neurobiological diseases and disorders 7 , more studies are needed to further unravel the potential determinants of the sexual dimorphic brain and its related clinical disorders.
Mariann Fodor is thanked for critically reading the manuscript. Brain material was provided by the Netherlands Brain Bank coordinator Dr. Rivka Ravid. Google Scholar. Kawata M. Neurosci Res. J Comp Neurol.Shemales doing males
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