Sexual differentiation of the human brain in relation to gender identity and sexual orientation

doi:10.1016/B978-0-444-53630-3.00004-X

Progress in Brain Research

Volume 186, 2010, Pages 41-62

https://doi.org/10.1016/B978-0-444-53630-3.00004-X Get rights and content

Abstract

It is believed that during the intrauterine period the fetal brain develops in the male direction through a direct action of testosterone on the developing nerve cells, or in the female direction through the absence of this hormone surge. According to this concept, our gender identity (the conviction of belonging to the male or female gender) and sexual orientation should be programmed into our brain structures when we are still in the womb. However, since sexual differentiation of the genitals takes place in the first two months of pregnancy and sexual differentiation of the brain starts in the second half of pregnancy, these two processes can be influenced independently, which may result in transsexuality. This also means that in the event of ambiguous sex at birth, the degree of masculinization of the genitals may not reflect the degree of masculinization of the brain.

There is no proof that social environment after birth has an effect on gender identity or sexual orientation. Data on genetic and hormone independent influence on gender identity are presently divergent and do not provide convincing information about the underlying etiology. To what extent fetal programming may determine sexual orientation is also a matter of discussion. A number of studies show patterns of sex atypical cerebral dimorphism in homosexual subjects. Although the crucial question, namely how such complex functions as sexual orientation and identity are processed in the brain remains unanswered, emerging data point at a key role of specific neuronal circuits involving the hypothalamus.

Section snippets

General concepts

Gender identity and sexual orientation represent two fundamental functions in human neurobiology. These functions have hitherto mainly been discussed in relation to the specific signs of sexual dimorphism in the brain and the potential mechanisms thereof. By mapping differences between men and women in cerebral anatomy, function, and neurochemistry, neuroscientists are trying to identify sex typical and sex atypical actors in transsexual and homosexual individuals. This has been done in

Sexual organization and activation of the human brain

The process of sexual differentiation of the brain brings about permanent changes in brain structures and functions via interactions of the developing neurons with the environment, understood in its widest sense. The environment of a developing neuron is formed by the surrounding nerve cells and the child’s circulating hormones, as well as the hormones, nutrients, medication, and other chemical substances from the mother and the environment that enter the fetal circulation via the placenta.

Sex hormones and human brain development

During fetal development, the brain is influenced by sex hormones such as testosterone, estrogens, and progesterone (Swaab, 2004). From the earliest stages of fetal brain development, many neurons throughout the entire nervous system already have receptors for these hormones (Chung, 2003). The early development of boys shows two periods during which testosterone levels are known to be high. The first surge occurs during mid-pregnancy: testosterone levels peak in the fetal serum between weeks 12

Programmed gender identity is irreversible

The irreversibility of programmed gender identity is clearly illustrated by the sad story of the John–Joan–John case (i.e., the case of David Reimer). In the 1960s and 1970s, in the context of the concept of behaviorism, it was postulated that a child is born as a tabula rasa and is subsequently forced in the male or female direction by society’s conventions. Although it is true that, in humans, self-face recognition appears to emerge at around 18 months of age (Keenan et al., 2000) and that by

The mechanism of sexual differentiation of the brain: neurobiological factors

In male rats, testosterone is turned into estrogens by local aromatization in the brain, and these estrogens then masculinize certain brain areas. This finding agrees with the observation that, in partially androgen insensitive (testosterone feminized—Tfm) male rats, no reversion of the sex difference was present in the preoptic area (Gorski, 1984) and the bed nucleus of the stria terminalis (Garcia-Falgueras et al., 2005). These animals retained a male neuroanatomy. Other brain nuclei, such as

Sex differences in the human brain

A sex difference in brain weight is already present in children from the age of 2 years (Swaab and Hofman, 1984) and sex differences can thus be expected throughout the brain from early in development. In the adult human brain structural sex differences can be found from the macroscopic level (Goldstein et al., 2001) down to the ultramicroscopic level (Alonso-Nanclares et al., 2008). Functionally, too, a large number of sex differences in different brain regions have recently been described (

Sex hormone receptors and neurosteroids

Sex hormone receptors, too, are expressed in a sexually dimorphic way in the human hypothalamus and adjacent areas.

In most hypothalamic areas that show androgen receptor staining, nuclear staining, in particular, is less intense in women than in men. The strongest sex difference was found in the lateral and the medial mammillary nucleus (MMN; Fernandez-Guasti et al., 2000). The mammillary body complex is known to be involved in several aspects of sexual behavior, such as arousal of sexual

Transsexuality

There is a vast array of factors that may lead to gender problems (Table 1). Twin and family research has shown that genetic factors play a part (Coolidge et al., 2002, Gómez-Gil et al., 2010a, Hare et al., 2009, van Beijsterveldt et al., 2006). Rare chromosomal abnormalities may lead to transsexuality (Hengstschläger et al., 2003) and it was found that polymorphisms of the genes for ERα and ERβ, AR repeat length polymorphism and polymorphisms in the aromatase or CYP17 gene also produced an

Transsexuality and the brain

The theory on the origins of transsexuality is based on the fact that the differentiation of sexual organs takes place during the first couple of months of pregnancy, before the sexual differentiation of the brain. As these two processes have different timetables, it is possible, in principle, that they take different routes under the influence of different factors. If this is the case, one might expect to find, in transsexuals, female structures in a male brain and vice versa, and indeed, we

Sexual orientation: heterosexuality, homosexuality, and bisexuality

Sexual orientation in humans is also determined during early development, under the influence of our genetic background and factors that influence the interactions between the sex hormones and the developing brain (Table 2).

The apparent impossibility of getting someone to change their sexual orientation is a major argument against the importance of the social environment in the emergence of homosexuality, as well as against the idea that homosexuality is a lifestyle choice. The mind boggles at

Sexual orientation and the brain

Clinical observations have shown the involvement of a number of brain structures in sexual orientation. It has been reported that in some patients with Klüver-Bucy syndrome, which involves lesions of the temporal lobe, orientation changed from heterosexual to homosexual. Shifts in sexual orientation (to homosexual and pedophile) have also been reported in connection with tumors in the temporal lobe and hypothalamus. Lesions in the preoptic area of the hypothalamus in male rodents, such as

Conclusions

The human fetal brain becomes sex differentiated through direct hormone-independent effects of X and Y chromosome genes or through different levels of gonadal hormones during both prenatal and postnatal periods. The latter pathway is more powerful. By a direct action of testosterone the fetal brain develops into the male direction, and in absence of this hormone into the female direction. During the intrauterine period, gender identity (the conviction of belonging to the male or female gender),

Acknowledgments

We thank Bart Fisser, Unga Unmehopa, Rawien Balesar, Arja A. Sluiter, Joop Van Heerikhuize, and Ton Puts for their technical help, Wilma Verweij for her secretarial help, Jenneke Kruisbrink for her literature resource help, and Mrs. Terry Reed, Dr. Michel Hofman, and Dr. Ronald W.H. Verwer for their critical comments. Brain material was provided by the Netherlands Brain Bank (coordinator Dr. Inge Huitinga). We are very grateful to all the anonymous brain donors.

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Chapter 4 - Sexual differentiation of the human brain in relation to gender identity and sexual orientation

Abstract

Section snippets

General concepts

Sexual organization and activation of the human brain

Sex hormones and human brain development

Programmed gender identity is irreversible

The mechanism of sexual differentiation of the brain: neurobiological factors

Sex differences in the human brain

Sex hormone receptors and neurosteroids

Transsexuality

Transsexuality and the brain

Sexual orientation: heterosexuality, homosexuality, and bisexuality

Sexual orientation and the brain

Conclusions

Acknowledgments

Psychoneuroendocrinology

NeuroImage

NeuroImage

Frontiers in Neuroendocrinology

Fertility and Sterility

Hormones and Behavior

Advances in Genetics

Brain Research

Hormones and Behavior

Psychoneuroendocrinology

Journal of Psychosomatic Research

Physiology & Behavior

Personality and Individual Differences

Brain Research

Journal of Sexual Medicine

Progress in Brain Research

Biological Psychiatry

Fertility and Sterility

Psychoneuroendocrinology

Journal of Steroid Biochemistry

Neurobiology of Aging

Hormones and Behavior

Trends in Cognitive Sciences

Hormones and Behavior

Brain Research

Current Biology

Psychoneuroendocrinology

NeuroImage

Hormones and Behavior

NeuroImage

Psychiatric comorbidity of gender identity disorders: a survey among dutch psychiatrists

The American Journal of Psychiatry

Intersex and gender assignment; the third way?

Archives of Disease in Childhood

Sexual dimorphism of the anterior commissure and massa intermedia of the human brain

Journal of Comparative Neurology

Sexual orientation and the size of the anterior commissure in the human brain

Proceedings of the National Academy of Sciences of the United States of America

Two sexually dimorphic cell groups in the human brain

Journal of Neuroscience

Gender differences in human cortical synaptic density

Proceedings of the National Academy of Sciences of the United States of America

Broca’s region revisited: Cytoarchitecture and intersubject variability

Journal of Comparative Neurology

Familiality of female and male homosexuality

Behavior Genetics

A test of the maternal stress theory of human male homosexuality

Archives of Sexual Behavior

Alpha-fetoprotein protects the developing female mouse brain from masculinization and defeminization by estrogens

Nature Neuroscience

Gender difference in age-related number of corticotropin-releasing hormone-expressing neurons in the human hypothalamic paraventricular nucleus and the role of sex hormones

Neuroendocrinology

Male-to-female transsexuals show sex-atypical hypothalamus activation when smelling odorous steroids

Cerebral Cortex

Brain response to putative pheromones in lesbian women

Proceedings of the National Academy of Sciences of the United States of America

Extreme skewing of X chromosome inactivation in mothers of homosexual men

Human Genetics

The interaction of fraternal birth order and body size in male sexual orientation

Behavioral Neuroscience

The hypothalamus of the human adult: Chiasmatic region

Anatomy and Embryology

Experiment of nurture: Ablatio penis at 2 months, sex reassignment at 7 months, and a psychosexual follow-up in young adulthood

Pediatrics