*So what causes schizophrenia?

     The most widely accepted hypothesis of the mechanism of schizophrenia is based on the action of dopamine, a major neurotransmitter in the brain. Early in schizophrenic research it was noticed that all the effective anti-psychotic drugs reduced dopamine activity.  Recent studies have shown that in schizophrenics, very high levels of dopamine are found in a part of the brain called the striatum, but strangely, the striatum has a normal amount of dopamine receptors.  However, the prefrontal cortex in brains of schizophrenics has an unusually low amount of receptors (7).  The idea that has become popular is that in a normal brain the activity of dopamine going on in the prefrontal cortex slows down the development of dopamine pathways in the striatum.  In a schizophrenic brain, however, for some reason there is little dopamine activity in the prefrontal cortex, so there is nothing to slow down the dopamine in the striatum and it grows disastrously. It is thought that the lack of dopamine activity in the prefrontal cortex could cause the negative symptoms seen in schizophrenics like lack of emotion and social interaction and the abundance in the striatum could cause the positive symptoms like delusions and incoherent thoughts (3).
 

*What exactly is estrogen and how does it work in the body?

    Estrogen is actually a generic term that encompasses several different types of similar female hormones.  The most potent form of estrogen is generally considered to be estradiol, which is the type used in many of the studies we describe.
    Estrogens achieve their effects in the body by changing the expression of certain genes in target cells.  Estradiol is soluble in cell membranes, so it can pass easily into the cell.  Once inside it binds with an estrogen receptor.  Estradiol will then fit into a specific site on the receptor specially coded for estrogen, so while it can probably enter many cell types, only the ones with estrogen receptors can respond to it (14).  For a long time it was unclear why estrogen seemed to cause effects in aspects of the body like the cardiovascular and skeletal systems, which had little to do with the sexual and hormonal effects estrogen was associated with.  Presumably the cells would have no need of receptors for estrogen to bind to and how estrogen affected these systems was a mystery.  Now scientists believe there are two types of estrogen receptors, ER-alpha and ER-beta.  ER-alpha receptors are associated with the traditional female sexual effects of estrogen and is found in the uterus, tests and adrenal gland.  While ER-beta is present here to a degree, it is found in more diverse parts of the body, including the brain.  ER-beta is localized in the learning and memory regions of the brain, implying that these receptors play a major part in estrogen's action in the schizophrenic brain (11).
    When two receptors are occupied by estrogen molecules, they come together to form a dimer.  The dimer then attaches to a regulating site on a gene called the estrogen response element, or ERE which is on the gene's promoter, or its on switch.  The dimerized molecules interact with proteins linked with transcription factors on the gene's promoter, and in this way regulate gene expression.  Through estrogen binding, gene expression can be turned on, modified, or suppressed completely (14).
    Some suggest that estrogen could also act on the brain by sharing pathways with neurotrophins, because their receptors are found in the same neurons.  Estrogen may be able to enter the cell and activate ERK’s that could relay neurotrophin signals to the nucleus, without the estrogen actually having to bind to the receptor (15).
 

*Why do scientists think estrogen is involved in schizophrenia?

    A puzzling trend has been evident to schizophrenia researchers for years: a discrepancy between the average age of diagnosis in men and women.  It has been shown in almost every demographic study that the peak age of schizophrenia diagnosis in men is about five years earlier than the peak in women.  Women's symptoms also tend to be less severe than men's.
    Another interesting trend is that, in addition to the first peak in diagnosis that women show several years later than men, women show another peak in diagnosis between the years of 45 and 49, which is completely unmatched in men (4).
Because this second peak corresponds to the age of menopause, these trends were the first suggestion that estrogen might have a delaying effect on schizophrenia.  It seems likely that the presence of estrogen prevents the development of schizophrenia in women at high risk for the disease, but when they lose their estrogen during menopause, the disease takes over.
    Since this first indication, many studies have shown a connection between estrogen and schizophrenia.  Research has shownsymptoms are often reduced when estrogen is high; fewer relapses tend to occur during pregnancy, a time of high estrogen levels.  On the other hand, symptoms tend to worsen around menstruation when estrogen levels are low (4).  Also, women are often more responsive to neuroleptic treatment than men.
    All of these trends seem to indicate that estrogen definitely has a delaying effect on schizophrenia, but the question still remains how it affects the course of the disease.  Here several possible mechanisms are suggested by which estrogen might delay schizophrenia, but it is still unknown which, if any of them, is correct; further research needs to be done.
 

Ways estrogen may affect schizophrenia:
 Mechanism #1
 Mechanism #2
 Mechanism #3
 Mechanism #4

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