Hi, Aisla,
I do not know how to attach a pdf, so I am pasting the whole thing below
Sexual differentiation in the human brain
D.F. Swaab1, A-M. Bao1, T. Ishunina1,2
1Netherlands Institute for Neuroscience, Amsterdam, The Netherlands, 2Department of Histology, Kursk State
Medical University, Kursk, Russia
Functional sex differences are expressed from early childhood onwards, e.g. in our playing
behaviour and drawings. Sex differences in cognition, reproduction, gender identity (the
feeling to be male or female) and sexual orientation, and in the incidence of neurological and
psychiatric disorders in adulthood are presumed to be based upon structural and functional
sex differences in the brain. Many of such sex differences have now been described in the
human brain. They arise during development by an interaction of sex hormones and the
developing neurons, although direct genetic effects are probably also involved [1]. Factors
influencing structural [2] and functional [1, 3] sex differences in the brain are genetic factors
like mutations or polymorphisms in the sex hormone receptors, abnormal prenatal hormone
levels and compounds such as anticonvulsants, Diethylstilbestrol (an estrogen-like
compound) and environmental endocrine disrupters. When given during pregnancy they
interact with the action of sex hormones on the fetal brain. An influence of postnatal social
factors on gender or sexual orientation has not been established. In rodents, masculinization
of the brain in development is due to estrogens that are formed by aromatization of
testosterone. In sexual differentiation of the human brain direct effects of testosterone seem
to be of primary importance based upon evidence shown e.g. from subjects with mutations in
the androgen receptor, estrogen receptor or in the aromatase gene [3].
In transsexuals we observed a reversal of the sex difference in the central nucleus of the bed
nucleus of the stria terminalis. The size, type of innervation and neuron number agreed with
their gender identity and not with their genetic sex [4,5]. Various structural and functional
brain differences related to sexual orientation have now also been reported [1,6,7].
There is a clear sex difference in psychiatric disorders such as depression: the prevalence,
incidence and morbidity risk is higher in females than in males, which may be due to both
organizing and activating effects of sex hormones on the hypothalamo-pituitary-adrenal-axis.
Fluctuations in sex hormone levels are considered to be involved in the susceptibility to
depression, seen e.g. in the premenstrual, ante- and postpartum period, during the transition
phase to the menopause and during oral contraceptives treatment. It was found that about
40% of the activated corticotropin releasing hormone (CRH) neurons in the hypothalamic
paraventricular nucleus in mood disorders expresses also the estrogen receptor (ER)- [8].
Estrogen-responsive elements are found in the CRH gene promoter region, while estrogens
stimulate CRH expression in animal studies. An androgen-responsive element in the CRH
gene promoter region has also been identified recently, which initiates a suppressing effect on
CRH expression [9].
In addition, there are sex differences present in the way the brain ages and in Alzheimer
neuropathology [3, 7]. The field is becoming extra complex by the presence of splice variants
(and isoforms) of ER- and the local production of steroid hormones in the brain. In the
human medial mamillary nucleus and hippocampus we detected, using RT-PCR, ER splice
forms skipping entire exons 7, 4 and 2 and we identified two novel variants: 1) MB1 that is
lacking 168 nucleotides in exon 1, and 2) TADDI, in which 31bp are missing in between exons
3 and 4, while 13bp are inserted from the middle of exon 2 [10,11]. In our recent work we
investigated whether canonical and alternatively spliced ER-mRNA and protein are affected
by age, menopause and Alzheimer disease (AD) in the hippocampus that is essential for
declarative memory. Experimental and clinical studies indeed suggested beneficial effects of
estrogens on hippocampus-dependent cognitive functions. Such positive effects have,
however, not been obtained in late AD stages. Interestingly, nuclear ER
immunocytochemical expression was prominently higher in young women (34-50 years of
age) than in young men (31-64 years of age), possibly due to higher plasma estrogen levels.
Moreover, nuclear ER, aromatase and the Golgi complex size which is indicative of neuronal
metabolic activity, enhanced during aging in women. Our data suggested that the elevated
expression of nuclear ER in postmenopausal women versus pre- and perimenopausal
women is due to a drop in circulating estrogen levels that seems to cause an increase in the
local estrogen production in the hippocampus, which may subsequently up-regulate ER.
Furthermore, locally synthesized estrogens may stimulate hippocampal neuronal metabolic
rate in postmenopausal women via rapid non-genomic mechanisms. In AD cases canonical
and alternatively spliced ER-mRNA, and aromatase gene transcripts were down-regulated,
suggesting reduced local estrogen levels and diminished signaling through ER. Whether this
finding may be related to a general genetic shut-down in the AD hippocampus remains to be
elucidated. Concluding, structural and functional sex differences in the brain are present in all
stages of life, and are involved in many functions in heath as well as in diseases.
References
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2 Swaab DF, Fliers E: A sexually dimorphic nucleus in the human brain. Science 1985; 228:1112-1115.
3 Swaab DF: Sexual differentiation of the human brain: Relevance for gender identity, transsexualism
and sexual orientation. Gynecol Endocrinol 2004;19: 301-312.
4 Zhou JN, Hofman MA, Gooren LJ, Swaab DF: A sex difference in the human brain and its relation to
transsexuality. Nature 1995; 378: 68-70.
5 Kruijver FP, Zhou JN, Pool CW, Hofman MA, Gooren LJ, Swaab DF: Male-to-female transsexuals
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7 Swaab DF: The Human Hypothalamus. Basic and Clinical Aspects. Part II: Neuropathology of the
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8 Bao AM, Hestiantoro A, Van Someren EJ, Swaab DF, Zhou JN: Colocalization of corticotropinreleasing
hormone and oestrogen receptor-alpha in the paraventricular nucleus of the hypothalamus in
mood disorders. Brain 2005; 128: 1301-1313.
9 Bao AM, Fischer DF, Wu YH, Hol EM, Balesar R, Unmehopa UA, Zhou JN, Swaab DF: A direct
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10 Ishunina TA, Swaab DF, Fischer DF: Estrogen receptor-alpha splice variants in the medial mamillary
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11 Ishunina TA, Fischer DF, Swaab DF: Estrogen receptor alpha and its splice variant
