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

during cognitive stimulation in the brain regions (i.e.
PFC) implicated in disorders of affect and cognition.
Secondly, Goldstein et al 31 observed an increase in
amygdala activity and arousal (as measured by fMRI
and skin conductance, respectively) during the late follicular
phase of the menstrual cycle (higher estradiol
levels) compared with the early follicular phase (characterized
by relatively low estradiol levels). Thirdly,
Protopopescu et al 32 employed an affective pictures
task in an fMRI study and observed increased OFC
activity (a region that in some studies exerts inhibitory
control over amygdala functioning) during the luteal
compared with the follicular phase. Moreover, preliminary
data from these same investigators in women with
PMDD (DC Silbersweig, pers comm) suggest a relative
loss of OFC activity (decreased inhibition) in women
with PMDD during the luteal phase. Notwithstanding
the caveat that decreased cortical ‘activity’ could also
reflect more efficient or optimal function, these data
suggest that a reduction in OFC inhibition of amygdala
function during the luteal phase is associated with
PMDD symptoms. Finally, Dreher et al 33 performed an
event-related fMRI study of reward processing across
the menstrual cycle in women with PMDD and controls.
The paradigm employed disentangles transient
reward error prediction (PFC) from sustained response
to reward uncertainty (ventral striatum). Preliminary
data in the controls demonstrate, for the first time in
humans, that ovarian steroids modulate reward system
function, with increased follicular phase activation of
the OFC and amygdala during reward anticipation and
of the midbrain, striatum, and left ventrolateral PFC
during reward delivery. New analytical approaches will
allow for testing the hypothesis that the hormonally
induced alteration in function includes changes in interregional
neural interactions. These findings then
suggest that cognitive and affective information
processes may serve as probes to identify candidate circuits
for the mediation of gonadal steroid-dependent
affective dysregulation. Additionally, neuroimaging
studies in women suggest that ovarian steroids can
influence many neural processes and systems relevant
to PMDD, including arousal, stress responsivity, and
reward processing.
The description of altered stress reactivity 34–36
during the luteal phase in women with PMDD suggest
that the HPA axis might also be an important target for
ovarian steroids in women with PMDD. Although
we 37,38 were unable to confirm reported (albeit inconsistent)
differences between patients and controls in
basal plasma �-endorphin, ACTH, or cortisol, we did
find significant differences in stimulated HPA axis
activity. 39,40 Consequently, we examined exercise stressstimulated
levels of arginine vasopressin (AVP), ACTH,
FUTURE TREATMENTS 175
and cortisol in PMDD patients and controls during
both the follicular and luteal phases of the menstrual
cycle. Women with PMDD failed to demonstrate the
luteal phase-enhanced HPA axis activation seen in the
controls. 41 These data are of interest for several
reasons. First, the luteal phase-related enhancement of
stimulated HPA axis activity seen in the controls complements
the observation that the HPA axis response is
significantly increased in the presence of progesterone
during GnRH agonist-induced ovarian suppression
(comparable to the luteal phase). 41 Thus, not only is it
progesterone rather than estradiol that has the greater
impact on HPA axis activation in humans (unlike in
rodents) but also the HPA axis response to progesterone
appears to differ in women with PMDD and controls.
Thus, several physiological substrates that control
both affective and stress adaptation are also regulated
by gonadal steroids and, therefore, could be sites of the
differential response to the hormone signal in PMDD.
Future studies employing probes of these systems combined
with multimodal brain imaging techniques will
better characterize and, possibly, confirm the relevance
of these substrates in PMDD.
GONADAL STEROID SIGNAL MODULATION:
ROLE OF CONTEXT
As more is learned about steroid–steroid receptor signaling,
the possible sources of altered steroid signaling
in PMDD grow exponentially. Several observations in
women with PMDD must be incorporated into the
search for the contextual variables that differentially
modulate steroid signaling in PMDD. First, the actions
of ovarian steroids at non-CNS sites appear to be
normal in women with PMDD and, therefore, the differential
steroid signal is substrate/tissue specific. Thus,
women with PMDD could have a differential metabolism
of steroids, resulting in locally (i.e. within specific
regions of the CNS) increased or decreased tissue levels
of steroids or their metabolites. Secondly, PMDD
demonstrates a high rate of heritability, suggesting genotypic
variation may contribute to altered (and tissuespecific)
steroid signaling. Finally, symptoms develop
over the course of reproductive life in those women
with PMDD, suggesting either behavioral sensitization
or possible epigenetic modification of steroid signaling
pathways, perhaps by interaction with other contextual
variables such as early-life trauma, reproductive aging, or
the occurrence of episodes of major/minor depressions
(both reproductive and non-reproductive-related).
Whereas mood disorders may be seen in association with
the pathological function of certain endocrine organs
(e.g. adrenal, thyroid), mood disturbances precipitated