Steroid hormones are active in the developing and adult brain
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.
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