Steroid hormones are active in the developing and adult brain

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One of the most important mechanisms giving rise to gender differences in brain function is the presence of molecules that bind to the steroid hormones in neuronal membranes.  Steroid hormones are the main sex hormones,  and I explain what they are in more detail in a further section.  These molecules are not evenly distributed in the brain.  They are mostly concentrated in a parts of the brain called the diencephalon and the limbic system.  The limbic system is a relatively primitive part of the brain, so called because it surrounds a core part of the brain called the diencephalon.  Limbic areas rich in estrogen-sensitive neurons include the septum and the amygdala,  two nuclei (neuron assemblies) heavily involved in emotional responses.  One part of the diencephalon,  the hypothalamus,  incidentally contains the most markedly sexually dimorphic brain nuclei.  A major difference between the limbic system and the hypothalamus is that the former regulates emotion whereas the latter is more involved in vegetative function (respiration, thermoregulation, reproductive cycles).  However,  molecules that bind to gender-specific hormones are not exclusively located in these primitive systems of the brain.  They are significantly present in the most advanced part of the brain which is termed neocortex.   The neocortex, or brain mantle,  is what is commonly referred to as the brain's gray matter.  And as the popular expression correctly denotes,  that is where intelligence lays.   Primitive animals such as reptiles have no neocortex,  because neocortex is a latecomer in evolution,  characterizing phylogenetically more recent species such as mammals,  and most particularly primates,  the last version of which is the human species (the smartest of all because the most neocorticalized).   It is now well established that steroid-binding molecules in neurons are distributed differently in the male and female mammalian brain,  rats in particular because this species has been most extensively studied.  Neurons containing estrogen receptors are more numerous in female guinea pig hypothalamus than in male guinea pig hypothalamus. However, it is now known that neurons containing progestin receptors are more numerous in the male mammalian brain !   This may appear surprising considering that progesterone and its derivatives is considered a "female" hormone.   A recent study conducted by researchers at the University of Massachusetts suggests that a major player in building the male brain may come from a surprising source - their mothers. The study, conducted by graduate student Princy Quadros and assistant psychology professor Christine Wagner, was presented recently at the meeting of the Society for Neuroscience in Miami, Fla. Scientists have known for nearly two decades that there are structural and neurobiological differences between the brains of males and females. The Umass study indicates that during pregnancy, the maternal hormone progesterone may play an important role in creating those differences. It was previously believed that fetal steroids were solely responsible for bringing about gender differences in the brain. Although the study was conducted on rats, researchers believe that the findings may be analogous for humans. "It's been known for many years that there are many gender differences in the human brain," said Wagner. "The sex differences in the brains of rats seem to parallel those found in humans. Therefore, this finding may offer us a window into the fetal development of human brains."  Progesterone is the most abundant hormone in the mother's body during pregnancy, Wagner said. It essentially maintains the pregnancy. "Our research demonstrated that progesterone from the mother's blood can enter the blood and brain of the fetus," said Wagner. Once it has entered the brain, the hormone fits into certain receptors, like two puzzle pieces that fit together. This linking together of progesterone and receptor actually modifies the function  of the brain cells, according to Wagner. Furthermore, fetal males appear to have a heightened sensitivity to this female hormone, because they have many more receptors that respond to progesterone than do female fetuses. The process is an intricate one: Testosterone, produced by testes in the fetal male, enters a specific part of the brain called the medial preoptic nucleus (MPN). There, the testosterone is converted to another hormone, estradiol. Estradiol, like a key opening a lock, activates the production of progesterone receptors during the brain's development by switching on a certain gene.

Because females produce levels of testosterone that are insignificant, their brains produce far fewer progesterone receptors. In rats,  neurons containing testosterone receptors are virtually undetectable in the female hypothalamus,  whereas they are numerous in the male hypothalamus.  Such brain  receptors have been found,  by a team led by a researcher named Marian Diamond,  to be hemispherically asymmetric in both sexes of the rat species and these asymmetries differed as a function of the rat’s gender.   Androgen receptors of the brain have been mapped in non-human mammals,  even in monkeys.  One such monkey study found that androgen receptors in the brain are distributed asymmetrically in male brains,  but not in female brains. It has also been found that there are sex differences in the basic mapping and also in the developmental dynamics of progesterone-binding cells in the rat brain.  Fine-grained molecular details of the brain are usually discovered in animal brains in research laboratories long before they can be confirmed in the human species.   And this sex difference is a case in point.   A sex difference in the distribution of steroid receptors in the brain has not been refuted or demonstrated in humans as of yet.  It seems mind boggling to me that none of the numerous neuroendocrinologists regularly publishing work on brain sex differences have not seen fit,  after more than a dozen years since Diamond’s discovery,  to investigate asymmetry of estrogen receptors in men's and women's brains !  Assays of hormonal activity in human brain have,  to date,  unfortunately been rather general and unconcerned by specific findings reported in other mammals. In one investigation of human brains, the concentrations of progesterone, androstenedione, testosterone, 5 alpha-dihydrotestosterone and androsterone were determined in tissue samples from the human hypothalamus, anterior pituitary, pineal, amygdala and parietal cortex, taken at autopsy from male (n = 4) and female cadavers (n = 4) of various ages. The measurements were performed using radioimmunoassays for the individual steroids after the chromatographic purification of solvent extracts of tissue samples on Lipidex-5000TM. Preliminary qualitative analyses of the chromatographic profiles of various steroids by radioimmunoassay demonstrated the presence of these steroids in various regions of the brain, but an immunoreactive peak corresponding to 17-hydroxyprogesterone was not found. The concentrations of all steroids measured were either very low or below the limit of detection in brain tissues taken from male and female infants. In the adult brain, there was no difference in the distribution of steroids between the various regions studied. There was no sex difference in the brain tissue steroid concentrations, with the exception of testosterone which was clearly much higher in brain tissues from men as compared to women. Although testosterone was undetectable in most samples taken from adult women, 5 alpha-dihydrotestosterone could be measured in almost all samples, which suggests that this is the most important androgen in the human brain. When brain tissue steroid levels are compared with serum concentrations, it can be postulated that a state of equilibrium exists between the fraction of serum steroids which are not bound to high-affinity binding proteins and the amount of steroids in brain tissues.  In principle, steroid receptors in the brain might have little bearing on behavior, or on cognition.  After all,  classical teaching on the subject of steroid hormones establishes only reproductive and metabolic roles.  But then again,  they might.  There are several reasons to think that they probably do have some such bearing,  including in humans,  but these reasons will only become fully apparent from widely differing viewpoints treated in separate chapters of this book.

Steroid hormones are so called because they derive from sterol, and more specifically,  cholesterol.  They are produced by glands which are termed endocrine because their emanations are secreted into the blood stream.  All the steroid hormones, male (androgens) and female (estrogen, luteinizing, follicular, progesterone), have trophic (growth promoting, or anabolic) effects on brain development.  Testosterone, estrogen and progesterone have been investigated for their trophic effects in immature neurons in vitro.  All of these steroid hormones favor synaptogenesis (formation of synapses), axogenesis (elongation of axons), mitosis (neuronal proliferation), neuronal migration (displacement of infant neurons toward their developmental targets), and they all help prevent neuronal mortality (cell death) in most of the reports published.  In particular instances however,  they may have effects opposite to these.  It has been found that both parity itself (the number of children a women has given birth to) and the age of the mother have the effect of reducing the concentrations of all of the steroid hormones traveling through the umbilical cord to the embryo and fetus.   In short,  generally speaking,  the first born is the one who will have received the greatest doses of all the steroid hormones from his or her mother through the blood stream.   If these maternally provided steroid hormones have a generally favorable neurotrophic effect,  this ought to be reflected in intelligence,  measured by IQ tests,   as a function of birth rank.  This is exactly what has been observed.  IQ is highest in firstborns,  slightly lower in second-borns,  slightly lower still in third-borns,  and so on.  In one of the large-scale studies carried out by Camilla Benbow,  60% of her sample of geniuses consisted of first borns !  It has been argued that this effect is primarily caused by one of the steroid hormones,  testosterone.  Indeed, there is a higher incidence of geniuses within the male sex and it has been found that male fetuses receive more testosterone through the umbilical cord than female fetuses,  yet both sexes receive the same amounts of the other sex hormones (luteinizing, folliculostimulant, estrogen, progesterone).  Furthermore,  despite the fact that IQ tests (the Wechsler tests for example) were constructed in a manner attempting to equalize performances of the two sexes,   the male sex presently outperforms the female sex by one or two IQ points (which is really not much)  not only on measures of general (full scale) IQ,  but also on the so-called Verbal IQ scale as well as on the so-called Performance IQ sub scale.   Too much should not be made of these IQ differences:   it would be very easy to construct an IQ test favoring women.    Nevertheless,  a subtle effect of testosterone on brain development could be responsible for the observed sex difference,  but more research is required to be sure.   

Several theorists have proposed that the sex steroid testosterone acts on the fetal brain during a critical period of development to influence cerebral lateralization (Geschwind, Galaburda, Hines, Shipley  and Witelson).   In one recent study relations were examined between prenatal testosterone levels in 2nd trimester amniotic fluid and lateralization of speech, affect, and handedness at age 10.   Girls with higher prenatal testosterone levels were more strongly right-handed and had stronger left-hemisphere speech representation. Boys with higher prenatal testosterone levels had stronger right-hemisphere specialization for the recognition of emotion.  Synthetic estrogens absorbed during pregnancy are known to partially feminize and demasculinize male animals and humans and to masculinize female animals and humans.  Reinisch recently reported results of a study of boys whose mother received synthetic estrogen (diethylstilbestrol) during pregnancy.  She found that these boys were less lateralized than sibling same-sex controls on neuropsychological tests and had reduced visuospatial abilities.  This pattern of results is most consistent with Witelson's (1991) claim that prenatal testosterone leads to greater lateralization of function. Indeed, we will see in chapter 3 that boys are more lateralized on most behavioral and cognitive functions.

My own (partial and limited) reading of the complex and voluminous literature on hormonal modulations of mental life, cognitive abilities and behavior leads me to recommend great interpretive prudence. I recommend this attitude not because I think hormones have no influence,   but because I believe their influence is very subtle and rather complex.  There are many sex-specific hormones whose functions change in development,  which cycle more or less,  and which interact in mysterious ways.    Psychological traits have rarely been associated significantly in any simple way with variations of hormone status in humans. Some authors have dared to try to formulate general models of these complex interactions.   The more general models must perforce adhere,  to explain such frequently negative results, to some sort of notion of multivariate dynamic equilibrium.  Nyborg, for example, has proposed that human behavior is conditioned by balances of various sex-specific hormones rather than by absolute concentration of any single one.   Evidence in support of a general model such as Nyborg’s includes the following.    The vast majority of tests of hypotheses of a linear relation between any one hormone level measurement and any psychological trait have failed to reach significance.   This is true of research investigating individual differences in normals,  or hormonal variations within individuals.   In some of his own research,  and in his reading of research carried out by others,  Nyborg observed that men with high estradiol concentrations and women with low estradiol concentrations score better on tests of visuospatial perception.  Estradiol is a precursor of both androgens and of estrogen.   His basic idea is that there are optimal levels of the various hormones which favor both the development and the actual expression of a given cognitive skill,  and these optimal levels are not necessarily at the highest concentrations of these hormones.    One example of an empirical finding which fits this model has been reported very recently by Doreen Kimura:   men perform best on spatial tasks in spring, when testosterone  levels are low, and worst in fall, when testosterone is high. She proposes a non-linear relationship between testosterone and spatial skills: according to her interpretation most men have more testosterone than is good for them (spatially)...     despîte the fact that the male gender has a basic visuospatial superiority over the female gender.