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

a substance/enzyme is being measured. These studies
may enable investigators to determine both the metabolic
consequences of ovarian steroid exposure, as well
as the identity of candidate mediators of the differential
behavioral response (i.e. altered pattern of metabolites)
observed in women with PMDD.
A second possible site of differential steroid signal
modification is at the level of the steroid receptor.
Steroid receptor function is modified by an array of
tissue-specific factors including the relative concentration
of co-regulator proteins, the presence and activity
of receptors for other members of the steroid family or
receptor subtypes, and concurrent action of the steroid
at the cell membrane. In human disease one of the best
characterized sources of variation in steroid receptor
function is genomic. Polymorphisms in gonadal steroid
receptors have been shown to alter receptor transcriptional
efficacy (e.g. CAG repeat in exon 1 of the androgen
receptor; progins insertion in intron 7 of the progesterone
receptor; T1057G in exon 5 of �-estrogen receptor)
and to be associated with differential illness risk
(i.e. prostate cancer, breast cancer). 52–55 Additionally,
the susceptibility to the disruptive effects of estradiol
on reproductive development differs enormously (up to
100-fold) between mouse strains, with the genotype
contributing more to the variance than the dose of
estradiol employed. 56 Finally, a single nucleotide polymorphism
enables progesterone to activate a receptor,
the mineralocorticoid receptor, at which it normally
functions only as a competitive inhibitor, thus providing
a means by which normal steroid levels create a different
phenotype (hypertension). 57 There is precedent, then,
for expecting that polymorphisms in the gonadal steroid
signaling pathway or in gonadal steroid-regulated genes
could alter the nature or strength of the steroid signal
as well as phenotype. Alternatively, non-steroid-related
genes could be implicated in the vulnerability to develop
the differential behavioral response to ovarian steroids
in PMDD. For example, Caspi et al 58 demonstrated
that the risk of developing depression is predicted by
the experience of stressful life events in combination
with a specific genetic background but is not predicted
by either the genetic or environmental factors when
considered separately. Thus gene–environment interactions
represent a promising explanation for the differential
behavioral sensitivity to gonadal steroids seen in
women with PMDD. Analogous to the suggestion by
Caspi et al, PMDD symptoms could develop after a
hormonal stimulus (i.e. the environmental event)
against the background of a specific genetic context.
Whereas some earlier candidate gene studies did not
find significant associations with PMDD, 59 we have
recently identified a region of the ESR1 gene containing
multiple polymorphic alleles that associate with PMDD,
thus lending support to the idea that the effects of multiple
genes may interact in creating a dysphoric behavioral
response to normal gonadal steroid levels. 64
The contributions of genotypic variation to PMDD
phenotype could be modified by several other factors,
including both epigenetic processes as well as gene–
environment or gene–steroid interactions. For
example, Meaney et al 60,61 have demonstrated that the
behavioral phenotype can be determined by environment-induced
alterations in the expression of the
genome. Thus, early-life trauma or past episodes of
depression, both frequent accompaniments of
PMDD, 62 could potentially modify the substrate
response to the gonadal steroid trigger. As more is
learned about both the nature of gonadal steroid
signaling in the brain and the complexities of gonadal
steroid-regulated behaviors, the sources of the differential
response to gonadal steroids in PMDD will be
clarified. In summary, women with PMDD could have
excessive or deficient gonadal steroid signaling that
might alter the processing of stressors and lead to a
dysregulated affective response 63 or altered learning
that could favor the development of behavioral sensitization
or steroid-dependent interoceptive cueing of
behavioral states.
CONCLUSIONS
In PMDD there is a well-defined endocrine stimulus
that for many women with this condition is critical in
the precipitation of affective state disturbances. This
affords a unique opportunity to identify neural substrates
involved in the regulation of the affective state
that could be targeted in the development of novel
treatment strategies. Our pursuits of several testable
hypotheses in PMDD will advance our understanding
of this disorder, illuminate mechanisms by which reproductive
steroids may regulate the affective state, and
help identify the locus of the differential sensitivity that
permits reproductive steroids to destabilize mood in
some but not all women. A better understanding of the
pathophysiology of this complex disorder will permit the
development of theoretically driven treatment strategies
and, hopefully, predictors of therapeutic response
for the considerable number of women with PMDD
who are not responsive to either ovarian suppression
strategies or SSRIs.
ACKNOWLEDGMENT
FUTURE TREATMENTS 177
The research was supported by the Intramural Research
Programs of the NIMH.