COMMENTARY

Sexual orientation and its basis in brain structure

and function
Dick F. Swaab*
Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Science, 1105 BA Amsterdam, The
Netherlands

C
urrent evidence indicates that tries in HoM and HoW as seen by Savic
sexual differentiation of the and Lindström (4). The first functional
human brain occurs during scanning paper by Kinnunen et al. (10),
fetal and neonatal development which described differences in the hypo-
and programs our gender identity— thalamus in relation to sexual orienta-
our feeling of being male or female and tion, received little scientific or public
our sexual orientation as hetero-, homo-, attention, although the results may have
or bisexual. This sexual differentiation had clinical relevance. The hypothala-
process is accompanied by many struc- mus of HoM, it turned out, was not as
tural and functional brain differences responsive to a classic antidepressant
among these groups (1). In previous (fluoxetine) as that of HeM, which
studies (2, 3), the Savic laboratory de- points to a difference in the activity of
tected a sex-differentiated activation of the serotonergic system. Subsequently,
the anterior hypothalamus in heterosex- Savic et al. (2) studied the effect of
ual men (HeM) and heterosexual scent—in particular, a pheromone de-
women (HeW) and a sex-atypical, al- rived from progesterone and excreted in
most reversed, pattern of activation in perspiration in concentrations 10 times
homosexual men (HoM) and homosex- higher in men than in women. Although
ual women (HoW). The hypothalamus pheromones influence sexual behavior
(Fig. 1) is a small brain area located and stimulate activation in the hypothal-
under the anterior commissure that is amus of HeW and HoM in the same
involved in many different functions, way, this pheromone did not elicit a re-
including reproduction. These observa- sponse in the hypothalamus of HeM.
tions raised several questions, one of Pheromones thus may play a part in our
which was whether the sexual dimor- behavior related to sexual orientation. A
phisms described could be sex-atypical follow-up study (3) showed that HoW
in homosexual subjects even with re- reacted in a sex-atypical, almost recipro-
spect to factors not directly associated cal, way to pheromones as compared
Fig. 1. The human hypothalamus is a small (4 cm3)
with reproduction. In a recent issue of brain structure between the anterior commissure with HeW, again indicating that some
PNAS, Savic and Lindström (4) re- (ac) and the optic chiasma (OC) and behind the hypothalamic circuits function in rela-
ported that hemispheric ratios, as well organum vasculosum of the lamina terminalis tion to sexual orientation. Kranz and
as patterns of amygdala connectivity, (OVLT). Under the corpus callosum (cc), the lateral Ishai (11) expanded this observation to
were sex-atypical in homosexual individ- ventricles are visible. cortical areas. Functional MRI was used
uals, with HoM exhibiting more female to measure activity changes in the brain
patterns than HeM and HoW showing when pictures of men and women were
more male-like features than HeW. matase inhibitor ATD in the neonatal shown to subjects. Viewing a female face
Whether the observed sex-atypical char- period (7). This experiment yielded bi- produced a strong reaction in the thala-
acteristics are the result of processes sexual adult rats that had a larger-than- mus and medial prefrontal cortex of HeM
that occur during the fetal or neonatal normal number of vasopressin neurons and HoW, whereas in HoM and HeW
periods, as is the case with gender iden- and total cells in their SCNs. The differ- these structures reacted more strongly to
tity and sexual orientation, is an open ence in the SCN of HoM was, therefore, the face of a man.
question. The excellent imaging research not caused by a difference in sexual be- Savic’s previous studies raised the
of Ivanka Savic’s group in past years has havior, as was suggested at the time, but question of whether certain sexually di-
provided strong evidence for structural by an atypical interaction between sex morphic features in the brain that are
and functional brain differences related hormones and the developing brain. In unlikely to be directly involved in repro-
to gender and sexual orientation. The 1991, LeVay (8) reported that HoM, duction may differ between homosexual
study of these differences has emerged like HeW, have a smaller area in the and heterosexual individuals. The article
from an era of prejudice and fear such frontal part of the hypothalamus (the by Savic and Lindström (4) provides the
as I experienced 20 years ago (5). INAH-3) than do HeM. In 1992, Allen answer. The authors measured hemi-
In 1990, we described the first brain and Gorski (9) found that the anterior spheric asymmetry with MRI volumetry
difference related to sexual orientation commissure (Fig. 1) of HoM is larger
in the suprachiasmatic nucleus (SCN)— than that of HeM. This structure, which
the brain’s ‘‘clock’’—which in HoM is is larger in women than in men, con- Author contributions: D.F.S. wrote the paper.
twice the size that it is in HeM (6). We nects the left and right temporal cor- The author declares no conflict of interest.
later induced a similar brain difference texes and is thus involved in sex differ- See companion article on page 9403 in issue 27 of volume
in rats by pharmacologically disturbing ences related to cognitive abilities and 105.
the interaction between testosterone and language. This difference may be related *E-mail: d.f.swaab@nin.knaw.nl
the developing brain, using the aro- to the sex-atypical hemispheric asymme- © 2008 by The National Academy of Sciences of the USA

www.pnas.org兾cgi兾doi兾10.1073兾pnas.0805542105 PNAS 兩 July 29, 2008 兩 vol. 105 兩 no. 30 兩 10273–10274

and functional connectivity of the amyg- were more widespread from the right tween sexual orientation and neurobio-
dala with PET scans of cerebral blood amygdala. Furthermore, in HoM and logical entities. Further research is
flow. In HeM and HoW, volumetric HeW the connections were primarily needed on the putative influence of tes-
measurements showed a rightward cere- displayed with the contralateral amyg- tosterone on the same parameters (e.g.,
bral asymmetry, whereas the volumes of dala and the anterior cingulate; in HeM in individuals with complete androgen-
the cerebral hemispheres were symmet- and HoW, they were displayed with insensitivity syndrome). Neurobiological
rical in HoM and HeW. Moreover, the caudate, putamen, and prefrontal research related to sexual orientation in
homosexual subjects also showed sex- cortex. Savic and Lindström describe humans is only just gathering momentum,
atypical amygdala connections. In HoM, sex-atypical cerebral asymmetry and but the evidence already shows that hu-
as in HeW, the connections were more functional connections in homosexual mans have a vast array of brain differ-
widespread from the left amygdala. In subjects that cannot be primarily linked ences, not only in relation to gender, but
HoW and HeM, on the other hand, they to reproduction and suggest a link be- also in relation to sexual orientation.

1. Swaab DF (2007) Sexual differentiation of the brain 5. Swaab DF (2007) Seksuele differentiatie van het 8. LeVay S (1991) A difference in hypothalamic structure
and behavior. Best Pract Res Clin Endocrinol Metab brein: Bepalen je hersenen of je hetero of homo between heterosexual and homosexual men. Science
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2. Savic I, Berglund H, Lindström P (2005) Brain response brein, ed Geurts JJG (Scriptum Psychologie, Schie- 9. Allen LS, Gorski RA (1992) Sexual orientation and the
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Acad Sci USA 103:8269 – 8274. 7. Swaab DF, Slob AK, Houtsmuller EJ, Brand T, Zhou J-N heterosexual men produced by the selective serotonin
4. Savic I, Lindström P (2008) PET and MRI show differ- (1995) Increased number of vasopressin neurons in the reuptake inhibitor, fluoxetine. Brain Res 1024:251–
ences in cerebral asymmetry and functional connectiv- suprachiasmatic nucleus (SCN) of ‘‘bisexual’’ adult male 254.
ity between homo- and heterosexual subjects. Proc rats following perinatal treatment with the aromatase 11. Kranz F, Ishai A (2006) Face perception is modulated by
Natl Acad Sci USA 105:9403–9408. blocker ATD. Dev Brain Res 85:273–279. sexual preference. Curr Biol 16:63– 68.

10274 兩 www.pnas.org兾cgi兾doi兾10.1073兾pnas.0805542105 Swaab