imbalance by corticosteroid treatment, affected females often present with various degrees of boy-typical behavior including toy preference. Later in life, women with CAH tend to be more often homosexual or bisexual than unaffected sisters or controls [6] and they may later in life show lower verbal capabilities, enhanced spatial abilities, and increased aggression during adolescence - all features which are usually associated with ‘maleness’. An opposite experiment of nature is the X-linked ‘androgen insensitivity syndrome (AIS)’ in genetic males, which is characterized by adequate intrauterine testosterone secretion but lack of functional receptors. Affected individuals are very rarely diagnosed postnatally as they are born as phenotypical females and also develop later in life as females, including behavior patterns, core gender identity, and sexual preference. Since affected individuals lack a uterus and ovaries, they usually present with primary amenorrhea which is not responsive to sex steroid treatment. Both CAH and AIS clearly demonstrate the crucial role played by intrauterine androgen levels and its functional receptors on subsequent physical, behavioral, and cognitive development. Excessive prenatal exposure to testosterone has been implicated in the development of dyslexia and autism [7]. On the other hand, reduced levels of fetal testosterone can be found in situations where the pregnant women is under acute and chronic stress, such as in times of war or when exposed to natural or personal disasters. Prenatal maternal stress and anxiety have been shown to be associated with impaired neurodevelopmental outcomes, including attention deficit and hyperactivity in boys [8].
The Sexual Dimorphous Brain – Organizational and Activational Effects of Sex Hormones
Hormones seem to exert a bitemporal effect on the brain. The organizational effect induces specific cell processes, occurs during intrauterine life, and permanently determines the development and function of sex organs, the brain, and other bodily systems. The activational effects may be transient or permanent, may occur throughout life, or may not occur at all. While this two-process theory has been challenged as being overall simplicist, it is helpful for the purpose of understanding the way sex hormones affect our brain. Juvenile play behavior has been used traditionally as an indicator of the degree of masculinization or feminization of offspring. Organizational and activational effects of testosterone also seem to be involved in inflammatory pain and response to morphine analgesia. This may explain the reported higher pain thresholds in men compared to women.
The sexual dimorphous development of the brain has fascinated researchers for over a century [9] and it is now generally accepted that fetal testosterone secretion plays a crucial role in the differentiation process. This has been demonstrated in animal studies as well as in humans [9]. Sex dimorphism of the human brain is evident at the cellular level, in the synaptic and dendritic organization, and also in the volume of specific cell groups and nuclei [7]. In the rat brain, the sexually dimorphic nucleus of the preoptic area (which also has a human equivalent) is such an example. In the human brain, dimorphic changes have been reported in the hypothalamus, cortex, and amygdale. Of great importance in this context is the hypothalamus which governs central functions like reproduction, eating, and sleeping. Gender differences in these major functions are partly a result of brain dimorphism. These differences are governed to a great extent by intrauterine levels of sex hormones, which exert organizational and activational effects. With the advent of functional MRI the brain, as the most complex organ in the human body, has become more accessible to functional neuroresearch. Moreover, while until rather recently it has been assumed that the brain, once established, is no longer capable of neurogenesis, there is now evidence that in primates new neurons are being created throughout life in various parts of the neocortex. This phenomenon of brain plasticity which includes anatomical and functional changes of the brain in response to environmental stimuli is of paramount importance and reflects the sensitivity of the brain to input. Again [3], an eminent genetician has stated that: ‘from the perspective of brain neuroscience, the environmental world of the developing embryo and fetus is as important as any information by the genes’. If both sides of the brain were to be constructed as mirror images, like mirrored hard disks, the resulting redundancy would provide a readily available repair resource to correct focal insults. Nature has implemented such a strategy for chromosome pairs but not for the brain. Here nature has opted mainly for maximal usage of available ‘real estate’ resources at the expense of redundancy. Therefore many (but not all) activity centers in the brain are unilateral. This modification of lateralization is neither predetermined solely by genetics nor absolute. Sex differences in lateralization have been the object of great scientific interest and the functional organization of laterality of language function has been of particular interest. Several language-related tasks are more left lateralized in males and more bilateralized in females. The corpus callosum is the main conduit of information between the two hemispheres of the brain and any asymmetric development may affect intrabrain connectivity between homologous and heterologous brain foci. Not only the corpus callosum but also the hemispheres show sexual differences which are related to fetal testosterone levels. Increased fetal testosterone levels in the male lead to a smaller corpus callosum and hence decreased connectivity between the left and the right brain. This may be the cause for greater lateralization of various cognitive functions and may explain why females use both sides of their brains more easily [7]. Using high resolution MRI in a cohort of 28 boys whose mothers had undergone second trimester amniocentesis, Chura et al. [9] studied the correlation of fetal testosterone levels with the size and the symmetry of the corpus callosum. The authors observed a positive correlation between fetal testosterone levels and increasing rightward asymmetry of a posterior subsection of the corpus callosum leading to an increased size of the right part of this particular segment.
Intrauterine Exposure to Sex Steroids and Physical, Cognitive, and Behavioral Outcomes
Baron-Cohen et al. [7] discussed a number of amniocentesis-based correlational studies, which indicate a positive correlation between the mental rotation rate and fetal testosterone and an inverse relation between fetal testosterone levels and language comprehension. The authors used stored samples of amniotic fluid and performed longitudinal studies in these ‘amniocentized children’ over 48 months after delivery. At 12 months of life they correlated fetal testosterone (fT) and the ability to make eye contact as a marker for social development in 71 children. Girls made significantly more eye contact than did boys. Eye contact decreased with increasing levels of fT. The authors further examined language development between 18 and 24 months of age in 87 toddlers and found that girls had a significantly higher vocabulary size than did boys and that there was a significantly inverse relationship between fT and vocabulary size for the children as a group but not within either sex group.
Maternal and Fetal Nutrition and Programming of Adult Disease
The concept of a relationship between fetal undernutrition and subsequent development of adult disease was introduced two decades ago by Barker et al. [10]. The ‘Barker theory’ or the ‘fetal origin hypothesis’ states that low birth weight reflects intrauterine malnutrition which programs the fetus for later cardiovascular disease, diabetes, and hypertension. Today it is generally accepted that the maternal diet affects fetal health and that maternal nutrition and specifically undernutrition with a low protein diet may be associated with subsequent development of obesity, cardiovascular disease, and hypertension. Leeson et al. [11]
