A sex difference in the hypothalamic uncinate nucleus: relationship to gender identity

Transsexuality is an individual's unshakable conviction of belonging to the opposite sex, resulting in a request for sex-reassignment surgery. We have shown previously that the bed nucleus of the stria terminalis (BSTc) is female in size and neuron number in male-to-female transsexual people. In the present study we investigated the hypothalamic uncinate nucleus, which is composed of two subnuclei, namely interstitial nucleus of the anterior hypothalamus (INAH) 3 and 4. Post-mortem brain material was used from 42 subjects: 14 control males, 11 control females, 11 male-to-female transsexual people, 1 female-to-male transsexual subject and 5 non-transsexual subjects who were castrated because of prostate cancer. To identify and delineate the nuclei and determine their volume and shape we used three different stainings throughout the nuclei in every 15th section, i.e. thionin, neuropeptide Y and synaptophysin, using an image analysis system. The most pronounced differences were found in the INAH3 subnucleus. Its volume in thionin sections was 1.9 times larger in control males than in females (P < 0.013) and contained 2.3 times as many cells (P < 0.002). We showed for the first time that INAH3 volume and number of neurons of male-to-female transsexual people is similar to that of control females. The female-to-male transsexual subject had an INAH3 volume and number of neurons within the male control range, even though the treatment with testosterone had been stopped three years before death. The castrated men had an INAH3 volume and neuron number that was intermediate between males (volume and number of neurons P > 0.117) and females (volume P > 0.245 and number of neurons P > 0.341). There was no difference in INAH3 between pre-and post-menopausal women, either in the volume (P > 0.84) or in the number of neurons (P < 0.439), indicating that the feminization of the INAH3 of male-to-female transsexuals was not due to estrogen treatment. We propose that the sex reversal of the INAH3 in transsexual people is at least partly a marker of an early atypical sexual differentiation of the brain and that the changes in INAH3 and the BSTc may belong to a complex network that may structurally and functionally be related to gender identity.