From the British Medical Journal Brain (9/2008)
A sex difference in the hypothalamic uncinate
nucleus: relationship to gender identity
Alicia Garcia-Falgueras1,2 and Dick F. Swaab1
1Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences,
The Netherlands and 2Departamento de Psicobiologi¤a de la Universidad Nacional de Educacio¤n a Distancia, Madrid, Spain
Correspondence to: Dick F. Swaab, MD, PhD, Professor of Neurobiology, Netherlands Institute for Neuroscience,
Meibergdreef 47, 1105 BA Amsterdam, The Netherlands
E-mail:
[email protected]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-mortembrainmaterial was used from 42 subjects: 14 controlmales, 11 control
females, 11male-to-female transsexual people, 1 female-to-male transsexual subject and 5 non-transsexual
subjects whowere 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.
Conclusion: Our data reveal a sex-atypical INAH3 volume and neuron
number in transsexual male-to-female people to be in the
female range, while the values of a female-to-male subject
were in the male range. Differences in adult testosterone
levels can only partly explain the observed differences in the
INAH3 subdivision of transsexual people while estrogen
levels do not seem to have an influence. In male-to-female
subjects the number of neurons in the INAH3 does not
seem to be related to sexual orientation, nor to the onset
time of transsexuality, but rather to atypical early femalebiased
gender. The differences observed between the INAH3
structure, its innervation in relation to sexual orientation
and gender identity and its putative connection to the BSTc
suggest that these two nuclei, together with the SDN-POA
(= intermediate nucleus, = INAH1 and 2) and the SCN
(Swaab et al., 1985) are part of a complex network involved
in various aspects of sexual behaviour. For the INAH4
subdivision of the uncinate nucleus, the only difference
found among the groups was in relation to its shape, which
was similar in all genetically male groups studied
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