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

104 THE PREMENSTRUAL SYNDROMES
GABA constitute more than 90% of cortical neurons in
the adult mammalian brain 39 and are highly sensitive to
sex hormones and neurosteroids.
Before reviewing the literature demonstrating altered
GABAergic function in women with PMS/PMDD, it is
important to consider the synthetic relationship
between glutamate and GABA. In addition, glial cells,
which were once simply thought to support neuronal
function, are also sensitive to sex hormones and play a
critical role in glutamate and GABA uptake from the
synapse. Figure 11.1 depicts what is considered to be
the ‘tripartite synapse’, which is composed of a presynaptic
glutmatergic neuron, a postsynaptic neuron
(in this case a GABAergic neuron), with a glial cell in
close proximity to the synaptic cleft (reviewed by
Hyder et al 40 ). Glutamate is released from the presynaptic
neuron and taken into the GABAergic neuron; it
is transported and converted to GABA by glutamic acid
decarboxylase (GAD). The astrocyte rapidly removes
glutamate from the cleft via glutamate transporters,
converts glutamate, to glutamine, and then releases
glutamine, which can be recycled to supply glutamate
for further neuronal release.
Glutamatergic stimulation of brain glucose utilization
(reviewed by Sibson 41 ), and thus neuronal and glial
energetics, is yet another means by which sex hormones
may alter brain function and behavior at a fundamental
Glutamatergic
glut
neuron Glial cell
GABAergic
neuron
glut
glut
GAD
GABA
glut
gln
Figure 11.1 Normal glutamate–GABA–glutamine
cycling. Glutamate (glut) is released from
glutamatergic neurons. A portion of glut is taken up
by glial cells and converted to glutamine (gln), which
can then be released and taken up by glutamatergic
neurons and converted back to glut. Alternatively,
gln can be taken up by �-aminobutyric acid (GABA)
neurons, converted to glutamate and then to GABA
by glutamic acid decarboxylase (GAD).
level. One of the ways in which estrogen is thought to
mediate its neuroprotective effects is by enhancing astrocyte
uptake of glutamate from the synaptic cleft. 6,42
Glutamate uptake then triggers a cascade of intracellular
events, which leads to vasodilatation. 43 Through this
mechanism astrocytes provide the critical link between
neuronal activity, glucose utilization, and the functional
hyperemia underlying the BOLD effect measured in
fMRI studies (reviewed by Hyder et al 40 ). Furthermore,
postmenopausal women have relatively lower CBF
as measured using SPECT, than premenopausal
women. 44,45 Postmenopausal ET improves CBF in postmenopausal
women, even those with previous CBF
impairments due to cerebral vascular disease. 44 Whether
this effect of estrogen is solely mediated by estrogen’s
direct impact on vascular tone or whether estrogen
modulation of astrocytic glutamate uptake is a contributing
factor is not clear. However, a PET study suggests
that estrogen is responsible for the relatively higher
cerebral glucose utilization in women than in men. 46
Clinical evidence
The temporal association between the symptoms of
PMS/PMDD and postovulatory increases and decreases
in progesterone and its neurosteroid derivatives has
prompted much investigation. While findings from
studies focusing on peripheral measures of estradiol,
progesterone, ALLO, and PREG have been disappointingly
inconsistent, taken as a whole, they suggest that
peripheral abnormalities in steroid levels and/or ratios
are unlikely to be a major factor in the pathogenesis of
PMS/PMDD. Instead, it is generally held that negative
affective states occurring during the premenstruum,
pregnancy/postpartum, and perimenopause are due to
an anomalous interaction between steroids and their
CNS targets. Alternatively, altered brain production of
neurosteroids has not been ruled out.
In an effort to glean information regarding the role
of GABAergic function in PMS/PMDD, Backstrom,
Sundstrom, and colleagues from Sweden have conducted
a number of seminal studies in which women
with PMS/PMDD and healthy controls have been given
a series of GABA A receptor agonists during the follicular
and luteal phases of the menstrual cycle (described
in Chapter 13 and reviewed in detail by Sundstrom
Poromaa et al 47 ). Using saccadic eye velocity (SEV) as
an assay for GABA A receptor agonist activity, they
found that healthy women are more sensitive to these
agents during the mid-luteal phase when endogenous
progesterone, estrogen, and neurosteroid levels are
elevated than in the hypogonadal follicular phase.
However, women with PMS/PMDD did not show this
luteal phase sensitivity, a finding that is consistent with