Premenstrual Syndromes : PMS and PMDD - Rutuja :: The site ...

24 THE PREMENSTRUAL SYNDROMES
IS PMS DUE TO SEROTONERGIC
DYSFUNCTION?
Needless to say, the fact that enhancing or reducing serotonergic
activity may alleviate or aggravate PMS does not
necessarily mean that the symptoms are the result of
serotonergic dysfunction. As discussed below, many
studies however do lend support to the notion that
women with PMS/PMDD differ from controls with
respect to various indices of serotonergic activity, indicating
that serotonin in fact may play a significant part
in the pathophysiology of this condition.
One tentative way of assessing serotonergic activity in
living humans is to utilize the fact that certain serotoninrelated
proteins, including the serotonin transporter and
the serotonin-metabolizing enzyme monoamine oxidase
(MAO), are expressed not only by serotonergic neurons
in the brain but also by platelets. Several studies
comparing PMS subjects and controls with respect to
serotonin uptake into thrombocytes, platelet serotonin
transporter density, and platelet MAO activity, do suggest
a difference either throughout the menstrual cycle or at
a certain phase of the cycle. 43,44 Although it remains
unclear to what extent these peripheral markers reflect
brain serotonin activity, and how the observed differences
should be interpreted in terms of function, these
findings provide some evidence for the notion that PMS
may be associated with aberrations in serotonergic
activity.
Hypothalamic serotonergic neurons exert a stimulatory
influence on the release of prolactin from the pituitary.
One tentative way of addressing the function of
brain serotonergic neurons and/or the responsiveness of
central postsynaptic serotonin receptors is to assess the
prolactin response to indirect or direct serotonin receptor
agonists. Several studies indicate that women with PMS
differ from controls also with respect to this parameter.
45–47 However, how this measure corresponds to the
activity of those serotonergic neurons that are involved
in the regulation of mood and behavior remains to be
clarified.
Another crude way of assessing brain serotonergic
transmission is to measure levels of the serotonin
metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the
cerebrospinal fluid. One study has reported reduced
levels of the ratio between the dopamine metabolite
homovanillic acid and 5-HIAA in women with PMS. 48
This finding is of some interest since a similar aberration
has previously been reported in subjects with depression,
but it cannot be easily interpreted in terms of function.
A more sophisticated strategy to assess brain serotonergic
transmission in humans than those mentioned
above is the use of brain imaging techniques, such as
positron emission tomography. Although research on
PMS using this method are as yet sparse, there are two
recent pilot studies suggesting that symptomatic women
differ from non-symptomatic controls with respect to
uptake of a serotonin precursor and density of serotonergic
5HT1A receptors, respectively. 49,50 Both these
studies are small, and should be interpreted with caution
until replicated, but they do lend further support to the
notion that PMS may be associated with abnormal
serotonin activity.
It should be emphasized that all of the different techniques
mentioned above yield results that are difficult
to interpret, and that they provide, at best, an indirect
and/or very limited insight into the status of the different
serotonergic pathways in the brain. Moreover, most
of the studies that have been published in this field are
small, and should for this reason be regarded as preliminary
until replicated. Notwithstanding these caveats,
the fact that such a large number of studies indicate
that PMS women and controls differ significantly with
respect to various serotonin-related indices supports
the notion that PMS is indeed associated with serotonergic
dysfunction. In this context, the possible influence
of publication bias, i.e. the tendency for studies finding
a difference to get published more often than studies
not finding a difference, should however not be ignored.
If certain variants of serotonin-related genes were found
to increase the susceptibility to PMS, this would provide a
reasonable explanation both to the symptoms characterizing
this condition and to the many positive findings
regarding serotonin-related biological markers, including
peripheral indices of serotonergic function, that have been
published. However, association studies showing a relationship
between serotonin-related genes and PMS have
yet to be published. In one study, women with PMS were
found to display reduced platelet density of the serotonin
transporter, but this difference could not be linked to any
of the more well-known polymorphisms in the serotonin
transporter gene. 43
To conclude, the hypothesis that the enhanced responsiveness
to sex steroids in women with PMS is at least
partly due to a dysfunction in brain serotonergic neurons
is not far-fetched and gains some support from the
available literature, but remains to be confirmed. Brain
imaging studies and extensive studies of serotonin-related
genes in large and well-characterized cohorts should
shed further light on this issue.
THE POSSIBLE ROLE OF SEROTONIN IN
THE PATHOPHYSIOLOGY OF SOMATIC
SYMPTOMS
One issue that has for long been debated, but remains
unresolved, is if premenstrual somatic symptoms–such