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Introduction

            Schizophrenia is a
severe psychiatric disorder classified within the broader category of
psychosis. Hanlon et al. (2017) cites that approximately 2% of the population
is affected by psychosis and nearly 1% of that is affected specifically by
schizophrenia (Wu, Hill, Gogos, & Buuse, 2013). Schizophrenia is a complex
disorder with patients suffering from symptoms that occur as a syndrome (Wu et
al., 2013). These symptoms are classified as positive or negative, as well as
cognitive deficits. It has been shown that schizophrenia is a combination of
both genetic and environmental factors (Wu et al., 2013). Both genders are
greatly affected by schizophrenia, however, gender differences have been
documented in every aspect of the disease.

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            These gender
differences have been studied extensively in recent years, and though some
definite findings have been established, much is still up for debate. After
providing an overview of schizophrenia’s most understood gender differences,
this paper will summarize some relevant research done on the role of
physiological factors in schizophrenia. Specifically, these factors include
dopaminergic effects dysfunction, neuro-steroids, estrogen and brain-derived
neurotrophic factor (BDNF).

An Overview of Schizophrenia

            Though dependent
on age group, the genetic susceptibilities would explain why schizophrenia has
a higher incidence in men, compared to women (Hill, 2015). Men experience a
peak age of onset that is younger than women, occurring between the ages of 15
to 24 years. Whereas, women experience a peak age of onset between 20 to 29
years, and then again after the age of 45 (Hill, 2015, p. 42).

            In general, men
suffering from schizophrenia experience more cognitive dysfunction and negative
symptoms, which include apathy, social withdrawal, alogia, and lack of
motivation (Huang et al., 2017). Specifically, men have been found to perform
more poorly on attention, language, and executive functioning tasks (Hill,
2015). In contrast, women tend to suffer more from positive symptoms, including
hallucinations and persecutory delusions. As well, they have been shown to
suffer more from affective disorders, like depression (Hill, 2015).

            Overall, the
prognosis of schizophrenia is worse for men than women. Women were found to
have better remission, less relapses, and were more likely to benefit from
better marital and housing situations. Which, is believed to help alleviate
some symptoms of schizophrenia (Hanlong et al., 2017).

Dopaminergic Dysfunction

As will be seen, dopamine is a major contributing factor to the
development of schizophrenia. Therefore, it is beneficial to highlight specific
gender differences in relation to dopaminergic systems, as these systems are
also affected by the remainder of the physiological factors.

One sex-specific characteristic that was found, was the role of catechol-O-methyl-transferase
(COMT), which metabolizes dopamine (Hill, 2015). Simply, a polymorphism in a
single nucleotide in the human COMT gene at codon 158 of Valine to Methionine
has been linked to reduced COMT enzymatic activity, and thus, schizophrenia (Witte
& Flöel, 2012; Hill, 2015). Interestingly, Risbrough, Ji, Hauger, &
Zhou (2014) developed the first “‘humanized'” COMT mouse model by inserting
COMT 158Met alleles into the mouse genome. Risbrough et al. (2014) tested the mice
who were Val/Val versus Met/Met, and found that male Val/Val mice were more
deficient in pre-pulse inhibition (PPI) and the opposite was true in female
mice. However, Met/Met female mice were more likely to experience fear
potentiated memory difficulties (Risbrough et al., 2014).

In Hill’s (2015) studies with mice it was found that males expressed 17%
more COMT activity in the prefrontal cortex, but also showed higher levels of
COMT dysfunction in the frontal cortex. Likewise, Gogos et al., (1998) found a
similar increase in dopamine levels of male frontal cortexes. Male mice showed
increased levels of aggression, and their performance on medial prefrontal
cortex (MPFC)-dependent visuospatial learning tasks were deficient (Papaleo et
al., 2008; Gogos et al., 1998). It has also been established that cognitive
function was more impaired in male COMT knockout mice compared to females, with
stress playing a factor as a sex x genotype x environment interaction (Papaleo
et al., 2012). Whereas, female mice deficient in COMT were only shown to
express impaired emotional reactivity (Gogos et al., 1998).

Overall, mice lacking the dopamine transporter showed increased levels of
dopamine, impaired PPI, and hyperactivity (Hill, 2015). However, studies on the
role of elevated dopamine levels show that males are more vulnerable to changes
in dopaminergic signaling. Specifically, males showed a greater deficit in PPI,
and this may be because female models have been shown to have more efficient
recovery and packaging of extracellular dopamine. Though dependent on specific
types of mutation and cognitive tasks, males also tended to show a greater
detriment in cognitive phenotype (Hill, 2015).

Estrogen and
Brain-Derived Neurotrophic Factor

            As
will be illustrated, the role of estrogen, brain-derived neurotrophic factor
(BDNF), and their interaction pose another deficit to men in the onset and
progression of schizophrenia. Estrogen itself is a naturally occurring, sex
steroid found predominantly in females. Interestingly, estrogen modulates many
neurotransmitter systems. For example, they can exhibit post-synaptic
anti-dopaminergic effects (Wu et al., 2013; Sanchez, Bourque, Morissette, &
Di Paolo, 2010). Moreover, Wu et al. (2013), state that many studies have
established neuroprotective effects exerted by estrogens, and these same
authors postulate that estrogen contributes to sex differences in psychiatric
disorders, such as schizophrenia.

            This
fact is illustrated by the varying ages of schizophrenia onset between men and
women. Men have a younger age of peak onset, potentially because they lack
estrogen to act as a mediator for the illness (Wu et al., 2013). As well,
levels of estrogen decline with age in women, which may explain later age of
onset. Characterized especially, by those over the age of 45, when it is
typical to begin experiencing menopause, as estrogen levels rapidly decline
(Hill, 2015; Wu et al., 2013).

            Likewise,
brain-derived neurotrophic factor (BDNF) is involved with proper neurological
function. Specifically, BDNF regulates synaptic plasticity and long-term
potentiation – both of which are considered to affect learning and memory (Wu
et al., 2013). Alterations in neurotrophins, such as BDNF, are believed to
contribute to the development of schizophrenia. Specifically, a polymorphism in
the BDNF gene at codon 66 from Valine to Methionine has shown that altered
levels of BDNF are released (Chen et al., 2004). Many studies have found a link
between this polymorphism and schizophrenia. For instance, the authors state
that variants in BDNF genes have been shown to affect verbal tasks, brain blood
flow, and brain volume.

            However
interesting as individual parts, the interactions between estrogen and BDNF factors
greatly into schizophrenia. One function of estrogen is to act through various
estrogen receptors (ERs). Action can only take place once estrogen binds and
causes a conformational change in the ERs. This allows it to bind to an
estrogen response element (ERE) – thus, causing a response (Wu et al.,
2013). Interestingly, the authors cite that BDNF contain ERE-like sequences,
suggesting that estrogen can modulate their expression. If an individual is
lacking estrogen, they may also be lacking the ability to fully express BDNF
because of its ER regulated properties.

Neurosteroids

            Neurosteroids
naturally occur due to steroid-producing glands or they can be built in the
central nervous system from precursors of sterols (Baulieu & Robel, 1998).
Dehydroepiandrosterone (DHEA) and its sulfate ester, DHEA-S, are among the most
common forms of neurosteroids available in the body (Huang et al., 2017).
Baulieu and Robel (1998) have indicated that DHEA and DHEA-S regulate the
receptors of neurotransmitters, including those of the dopamine system.
Therefore, with less DHEA and DHEA-S present, individuals are susceptible to
dysfunctions in dopaminergic signaling – a previously established schizophrenia
factor. Researchers have also established that neurosteroids play a role in
stress, mood stability, and aggression (Compagnone & Mellon, 1998). With
decreased levels of these neurosteroids, an individual may have reduced
neuroprotection, especially when exposed to other stressors. Thus, disturbance
in DHEA and DHEA-S levels play a role in various psychiatric illnesses, like
schizophrenia.

Though DHEA and its sulfate ester function differently, Huang et al.
(2017) established that neurosteroids, in general, exert sex-specific effects.
In their discussion, the authors state that an early onset of schizophrenia is
associated with lower levels of DHEA and DHEA-S, but only in males.
Specifically, lower levels of DHEA may make men more susceptible because they
may require more DHEA just to maintain brain development and stability, when
compared to women (Huang et al., 2017). It can be assumed that these
neurosteroids could be understood as a potential influencer of schizophrenia,
but only in men, as these same effects were not observed in females.  

Conclusion

            Strong
bodies of evidence from both clinical studies and animal models have
established a clear deficit to men in the development and progression of
schizophrenia. In discussion of dopaminergic effects, men show a clear
vulnerability, especially regarding expression of the COMT gene. Likewise, men were
found to be deficient in estrogen, as a natural biological factor, which also
affects expression of BDNF and its subsequent neuroprotective effects. A final
physiological factor playing a role in gender specific schizophrenia expression
are neurosteroids, DHEA and DHEA-S. It has been shown that lower levels of
these neurosteroids affects only men.

            Overall,
men are seen to be implicated in all aspects of schizophrenia on a greater
level, compared to women. As an important note, it may be effective to continue
research in the avenue of using treatment to impact these specific
physiological effects.   

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